Laboratory 1 .il
General and Systemic Pathology
Laboratory Manual
Prof. A. Abramovici
Dr. D.Y. Cohen
Laboratory 1
309
309. Anthracosis and chronic emphysema of the lungs
A 68-year-old man was found dead on the right side of the road. The medico-legal expertise revealed multiple skull factures, subdural hematoma and laceration of brain. Incidental autopsy findings revealed inflated lungs with black, pigmented linear streaks especially near the hilar region which also showed blackened lymph nodes.
Note the markedly enlarged, almost cystic formation of the alveoli. This is the basic feature of emphysema and is due to rupture of the interalveolar septae. There is peribronchial fibrosis that extends from the bronchial areas into the alveolar septae. Black, carbon pigment is abundant in the lymphatic tissue in the specimen, as well as in type-1 pneumocytes.
Formalin pigment in contrast - representing overfixation artifact presents as fine black granules not as phagocytised material in cells.
401
401 Cardiac hypertrophy
Note : The same slide shows representative sections of infant myocardium; normal myocardium and hypertrophied myocardium.
A post-mortem specimen from a 62 year-old man showed he had died of an intracranial hemorrhage of the right temporo-occipital lobe. He had been known to have a blood pressure of 210-110 mm Hg for the past 5 years but had refused treatment. At autopsy the heart weight was 450gr. and showed marked hypertrophy of the left ventricle, it’s lateral wall measuring 24 mm thickness (normal 13-15 mm). A moderate aortic stenosis was also found.
Microscopy : The hypertrophied myocardium is cut in different planes and shows myocardial fibres of variable thickness, mostly being thicker than normal (cf. normal and infant’s myocardium). The striations are also thickened and increased in number. The chromatin rich nuclei are enlarged and irregular in size and shape. Some are bizarre in shape and may resemble “stag horns”. The total number of nuclei per microscopic field is, due to the increase in size thereof, reduced. Surrounding and adjacent to these enlarged nuclei, in some of the hypertrophied fibres, a granular golden-yellow pigment (lipofuscin) can be found. This is the so-called “wear and tear” pigment (that can be found in normal myocardium too). Scattered areas of fibrosis, in between the hypertrophied muscle fibres can be seen - repreenting areas of hypoxia with resultant fibrosis.
Compare the findings of the hypertrophied muscle with the normal muscle represented.
650
650 Fatty change, liver
(Steatosis; Fatty metamorphosis)
Macroscopically the liver may appear enlarged and flabby, yellowish in color and have a greasy cut surface.
Microscopic examination shows liver tissue in which the lobular pattern is preserved. The prominent pathologic change is the swollen appearance of hepatocytes. These distended cells contain many fat vacuoles in their cytoplasm, compressing the nucleus to the periphery of the cell. In some cells, the nucleus may not be visible at all. Kuppfer cells are not affected.
Questions.
1. What is the pathogenesis of fatty change?
3. What are the causes of fatty change in the liver?
4. In which other organs does fatty change occur and what are the causes?
5. What is meant by the term fatty infiltration?
660
660/A Hemachromatosis, liver (& Prussian blue stain).
A 58 year-old man who suffered for years from diabetes, bronze pigmentation of skin and hepatomegaly (“bronze diabetes”), developed ascites and died of cardiac failure.
Full blown hemochromatosis is characterized by a triad of pigment cirrhosis, diabetes and skin pigmentation (hence the old term “bronze diabetes).
Morphologically hemachromatosis shows pigment cirrhosis (hemosiderin) of the liver and systemic hemosiderin, involving pancreas, endocrine glands, myocardium, skin and any other parenchymal organ.
In the liver, the involvement varies from delicate fibrous scarring around portal tracts to the full blown picture of thick bands of fibrous tissue resulting in cirrhosis.
The cirrhotic liver, macroscopically, shows a nodularity with nodules that vary in diameter from several millimetres to 1cm and are of similar size to those encountered in alcoholic cirrhosis.
Microscopic features show liver architecture distorted and obliterated by broad bands of fibrous tissue that bridge portal tract to portal tract. As a result, regenerative pseudolobules of liver tissue appear, circumscribed by the dense fibrous tissue. These pseudolobules are devoid of central veins. Within the fibrous connective tissue, numerous hemosiderin-laden macrophages (siderophages) are noted. The iron deposits are also noted within hepatocytes as well as within Kuppfer cells.
Note : Compare these features of pigment cirrhosis with the slides 659 and 664 where cirrhosis is also present.
Laboratory 2
101
101 Subcutaneous abscess
This specimen is intended to show suppuration (acute inflammatory cell infiltration with necrosis), as an example of acute inflammation. It shows the skin of a rat, that can be recognized as not being of human origin, as:
1. The epithelium is of the thin keratinizing squamous epithelium
type.
2. Numerous dermal adnexal structures are present, (hair follicles, sebaceous glands and sweat glands).
The acute inflammation was elicited by the injection of turpentine into sub-cutaneous tissue that resulted in the acute inflammatory process shown.
Identify the epithelium first.
Identify the deep margin of the specimen that shows skeletal muscle (the Platysma muscle).
The pathologic lesion is seen in the superficial and mid dermis, as an elliptical area of hypercellularity. There is central karyorrhexis and karyolysis where nuclear and cell debris fills the center of the cavity – (central suppuration). This central zone is surrounded by a poorly circumscribed area of granulation tissue (congested capillary vessels, fibroblastic cells, inflammatory cells and extracellular proteinaceous material).
Note: From this line you should also :
1. Find normal layers of the epithelium.
2. Name and identify inflammatory cells under the titles – (“Acute” and “Chronic”).
327
327 Inflammatory polyp of nose
Polypoid tissue fragments lined on the surface by pseudostratified cilliated columnar epithelium of the respiratory tract. Areas of metaplastic change (usually squamous) may be noted. Mucous secreting glands may also be noted near the surface. The stroma of the polyps is edematous and includes congested small arterioles. A diffuse scattering of inflammatory cells is present within the stromal tissue. The infiltrate includes numerous eosinophils and plasma cells. Smaller numbers of lymphocytes and neutrophils are also noted. (acute cells = Neutrophils and ? eosinophils; Chronic cells = lymphocytes, plasma cells, histiocytes and ? eosinophils).
756
756 Chronic salpingitis
The naked eye appearance of the slide shows a tubular structure with a thick muscular wall and a central folded lumen.
Microscopic examination shows areas of normal mucosal folds of the Fallopian tube lined by ciliated columnar epithelium. Some of the cells appear more flattened and are devoid of cilia. In some areas, the mucosal folds appear fused together forming pseudoglandular formations. In the submucosa, there is an infiltrate of lymphocytes as well as neutrophils. This inflammatory infiltrate is noted to extend into the muscular coat and even onto the serosal aspect. In some areas, the aggregates of lymphocytes forming lymphoid follicles may be seen. Serosal blood vessels are congested.
Questions:
1. What do you understand by the clinical term - pelvic inflammatory disease?
2. What is salpingitis istimica nodosa?
3. What do the terms pyosalpinx, hematosalpinx and hydrosalpinx mean?
625
625 Acute appendicitis
An 8 year-old boy presented a 24 hour history of right sided fosse pain and vomiting. Upon hospitalization tenderness of the abdominal wall with mild fever and leukocyte (17,500 cells/µm3) were noted. Appendectomy wasfperformed.
On macroscopical examination the serosal surface showed acute congestion and yellowish fibrinose exudate.
Macro : Cross section of a tubular structure - can be confused with the ileum of a neonate.
Micro : The mucosa of the bowel is ulcerated. Within the lumen there are fecal remnants present, sometimes occluding the entire lumen. Admixed therein are necrotic epithelial cells and neutrophils. These neutrophils are noted for infiltrating the entire wall of the appendix. Small abscesses are noted within the submucosa and muscularis mucosa (Phlegmonous inflammation). The serosal layer shows fibrinous threads with neutrophils admixed - (peritonitis).
Questions.
1. The histologic diagnosis of acute appendicitis is dependent on what microscopic finding?
2. What is a fecolith?
3. What other causes, particularly in children, are there for acute appendicitis?
603
603 Acute pancreatitis with fat necrosis
Whatever the etiology of the pancreatitis, essentially four histologic changes occur:
0. enzymatic destruction of pancreatic tissue - (? autodigestion).
1. hemorrhage
2. fat necrosis due to lipolytic enzymes
3. severe inflammatory reaction
In the example examined one can clearly differentiate areas of normal pancreatic tissue - both endocrine as well as exocrine areas. Interspersed between the intact elements are variable areas of necrosis with a heavy acute (neutrophilic) inflammatory cell infiltrate. Hemorrhage is also present. In some areas, basophilic material is present (calcifications.
Questions.
1. What enzymes are the principle culprits in the production of the tissue necrosis?
Laboratory 3
706
706 Recent infarct, kidney
Examination of the slide using the naked eye shows two distinct areas :
1. the central area, being wedge shaped - the area of infarction
2. the areas around it representing intact renal parenchyma
Microscopic examination shows a central area of infarction bordered clearly by normal renal tissue. The infarcted area shows shadows of glomeruli that are still clearly identifiable. The tubular epithelium is eosinophilic and nuclei are barely recognized. At the border between the normal and infarcted areas, neutrophilic infiltration is present.
310
310 Edema of lungs (pulmonary edema)
Histologic examination of the lungs shows alveolar capillaries that are engorged with blood. The intra-alveolar space is partially to totally filled with a granular pink precipitate. Alveolar microhemorrhages and hemosiderin laden macrophages (“heart failure cells”), are noted. Such changes as these not only impair normal respiratory function but also predispose to final onslaught to the patient - hypostatic pneumonia. Within the lung tissue anthracosis, emphysema and atelectasis may also be present.
Questions:
1. What are the mechanisms of edema?
2. What do the terms anasarca and ascites mean?
3. What is the difference between an exudate and a transudate?
324
324 Chronic passive congestion, lung
Macro The affected lung is heavy, dark red and firm; abundant frothy red fluid can be squeezed from it.
Micro The lung parenchyma shows large inflated alveoli - emphysema - alternating with collapsed ones - atelectasis. The large blood vessels as well as the capillaries in the interalveolar septae look distended and engorged with erythrocytes - congestion. The interalveolar septae look fibrotic at various extends.
The alveolar spaces contain many large round to ovoid cells with small nuclei - histiocytes. In most of these cells dark brown granules are seen - “heart failure cells” or siderophages. In some cases the alveolar lumen is filled with an eosinophobic proteinous material - edema (see specimen 310) and inflammatory exudate of WBC as well as small hemorrhagic foci.
331
331 Pulmonary emboli
The lung parenchymal histology is normal. The lumina of small arteries are occluded by thrombus - representing the emboli. The emboli lie freely within the lumina, not attached to the vessel wall, indicating origin from a far removed site and not originating within the vessel. The emboli consists of the constituents of a thrombus - fibrin, erythrocytes and debris.
Note: Septic emboli contain basophilic bacterial clusters. Within the sections, adjacent lung tissue may show emphysema, atelectasis and anthracosis.
Questions :
1. What is the most probable origin of the emboli?
2. What is Virchow’s triad?
3. What do you understand by the term “paradoxical emboli”?
4. What are the clinical symptoms and signs of pulmonary emboli?
404
404 Recent myocardial infarction
Examine the section to identify normal myocardial fibres with well preserved striations and nuclei. Scan the slide until an area is encountered where there is marked eosinophilia and necrosis of the myocardial fibres. Here striations and cytological detail is lost. The nuclei are pyknotic or even absent. Within this area of infarction, a marked P.M.N. infiltrate is present. The infarcted area of myocardium is surrounded by a hemorrhagic zone or rim. Using the lecture notes on this process (or other references) attempt to date this region of infarction.
Questions :
1. What do the terms transmural and sub-endocardial infarction mean?
2. What are the complications of these lesions ?
405
405 Organizing myocardial infarction
On microscopic examination, large areas of myocardial fibres are absent and replaced by granulation tissue. This tissue (as described in slide 102) is composed of an admixture of capillaries and inflammatory cells. Histiocytes with large round nuclei are also evident, some with hemosiderin in the cytoplasm (siderophages), representing old areas of hemorrhage. Other areas of more recent hemorrhage are also noted.
As in the case of slide 404, attempt to date this infarction using lecture notes (or other references)
406
406 Scar of old Myocardial Infarction
(5-8 wks)
The myocardium shows large regions of replacement by hypocellular fibrous scar tissue. Within the scar tissue as well as around the periphery, hypertrophied cardiac muscle fibres can be seen. A chronic inflammatory cell may also be noted in these areas. In some of the slides recurrent infarcts can be seen as fresh areas of necrosis and inflammation.
Laboratory 4
703
703 Amyloidosis kidney
(Review slide 510)
A 73 year-old man suffered from heavy proteinuria, hypoalbuminemia and edema (chronic renal failure) and died of myocardial infarct. At autopsy the kidney was slightly enlarged but firm with a pale, waxy appearance. On section a blurring of thecortico-medullary junction typical of amyloidosis was seen
Macroscopically the kidneys are usually pale and enlarged.
Microscopic examination shows involvement of the glomeruli that first appears in the mesangium. The deposits of amyloid are nodular and expansive, ultimately compressing and collapsing the capillaries.
Examine the glomeruli : Amyloid is unevenly distributed and in some, almost the entire glomerulus is replaced by amyloid.
Examine blood vessels : Amyloid is deposited along capillary walls as well as in afferent arterioles and media of arcuate arteries.
510
510 Amyloidosis of the spleen
Amyloidosis in its systemic form involves the spleen more frequently than any other organ. The splenic involvement may cause splenomegaly and it may involve the spleen in either a nodular or in a diffuse pattern. The macroscopic examination of such a spleen is described in the nodular form as “sago spleen” and in the diffuse form as “lardaceous spleen”. Macroscopically, the spleen on its cut surface has a characteristic “waxy” nature. The Malpighian bodies appear exaggerated and translucent rather than gray-white. In the diffuse type, amyloid is deposited within the red pulp.
Microscopic examination shows pale pink (Salmon pink) amyloid deposits that have replaced the Malipighian corpuscles. Smaller areas of amyloid are seen in connective tissue trabeculi as well as in the splenic capsule. Note the deposits of amyloid in the arterial vessels.
Questions:
1. What is amyloid?
2. What is the classification of amyloid?
3. What is the most common cause of amyloidosis in Israel?
4. What specific stains are used to identify amyloid?
5. What other organs are affected by amyloidosis?
314
314 Miliary tuberculosis of lung
Case History
A female foreign worker in Israel, aged 24 years, for 4 months before being hospitalized, had complained of dyspnea, intermittent fever and constipation with abdominal pains. The family physician had treated her with antipyretics for a common cold.
At admission she showed vomiting and mental confusion . Because of a suspicion of meningitis, a lumbar puncture was performed. The laboratory tests showed CSF that was opalescent and contained a mixture of neutrophils and lymphocytes. The protein value was 1.75gr / lt. (normal range 0.15 – 0.40 gr. / lt. No glucose was found. Antibiotic treatment was started but 24 hours later, the woman died.
The post-mortem examination revealed the following main lesions :
1. Congestion of lungs and presence of small nodules (1-2 mm in diameter), pale but firm, randomly distributed under the pleural surface and deep into the parenchyma.
2. The small intestine presented irregular ulcers with undermined edges of the mucosa. The ulcers were situated in the transverse axis of the bowel and contained friable white caseous material. The mesenteric lymph nodes were enlarged and on cut surface they showed a diffuse, soft, cheesy-white material.
3. The meninges at the basal cisternae region contained a gelatinous grey, viscous exudate which penetrated into the regional sulci. Near the blood vessels a few grey tubercles were also found.
Questions :
1. What is the cause of death?
2. Which organ shows the primary lesion?
3. Describe the etiology and pathogenesis of the event.
In the histologic sections two types of granuloma ** are represented:-
Soft tubercle: The hallmark of tuberculosis - caseous necrosis is noted at the centre of the tubercle and appears as eosinophilic areas lacking cellular detail and appearing granular. These areas are surrounded peripherally by the epithelioid histiocytes and giant cells described above typical of a granuloma.
Hard tubercle: The same cellular constituents are present as in the soft tubercle but there is no central caseation.
Questions:
1. What other causes are there for granulomata?
2. What does the term “naked granuloma” denote?
3. How would you confirm your presumptive diagnosis of Tuberculosis?
* The term miliary refers to spread of tuberculosis organisms gaining access to blood and lymphatic vessels with subsequent seeding to distant organs. The term miliary is descriptive of the character of the minute lesions which are small, yellow-white and resemble canary bird seed or millet [milium (Latin)] seeds.
**A granuloma is a collection of inflammatory cells, principally modified macrophages, usually surrounded by a rim of inflammatory cells (lymphocytes). Giant cells that are coalescent and fused macrophages are often part of granulomata, (in tuberculosis these giant cells are called Langhans cells). When used in the context of tuberculosis, the tuberculous granulomata are referred to as Tubercles.
732
732 Rejected kidney, (acute phase)
The renal capsule is thickened and edematous with foci of hemorrhage. There is almost universal affectation of nephrons with cystic dilatation of the space of Bowman. The glomerular tufts are atrophic as too are the tubuli. The tubular epithelial cells show hydropic changes and pyknotic nuclei. The tubular lumina contain hyaline casts and desquamated epithelial cells. There is edema and hemorrhage in the interstitium with an inflammatory cell infiltrate of many neutrophils, as well as lymphocytes, plasma cells and macrophages. Surrounding medullary blood vessels, a neutrophilic infiltrate is also seen. These vessels may be occluded by thrombus. The muscular media of some arterioles may show fibrinoid necrosis.
Some glomeruli show crescent formation, indicating proliferative glomerulonephritis - unrelated to the rejection process, but related to the original underlying disorder that caused the original renal failure in this patient.
803
803 Hashimoto’s thyroiditis (diffuse lymphocytic thyroiditis)
This entity is characterized by thyroid enlargement, lymphocytic infiltration of the gland and occurrence of thyroid autoantibodies. The disease is common in women, especially around menopause. It is an autoimmune disease that is immunologically closely related to Grave’s disease - HLA-DR5 related.
Macroscopically the thyroid is enlarged (40-50gr) and is firm and rubbery.
Microscopic examination has the most prominent feature of a very marked lymphocytic infiltrate in the thyroid gland with the formation of lymphoid follicles with germinal centres. The thyroid gland may be so heavily infiltrated as to almost efface all recognizable normal thyroid follicles. The follicles that can be discerned are generally small and are often devoid of colloid. The epithelial cells have an abundant oxyphilic and faintly granular cytoplasm (Ashkenazy cells, oxyphilic cells or Hurthle cells). In most cases there is fibrosis of the septae and evidence of recent and old hemorrhage (hemosiderin laden macrophages). Foci of squamous metaplasia may also be found.
Questions :
1. What serious complications are there of this entity?
306
306 Asthma - lung
There is marked hypertrophy of the muscular coat of the bronchi and bronchioli with a thickened eosinophilic basal membrane. The bronchial epithelium is tall and contains basally situated nuclei. There is apical mucous vacuoles in the cytoplasm. Metaplastic cells (squamous) may also be present. Some areas may show sloughing of the mucosal cells. The bronchial lumen is filled with basophilic, inspissated mucous forming a plug. This mucous may contain neutrophils and desquamated mucosal cells. The bronchial wall has lymphocytes and plasma cells representing a chronic bronchitis. Eosinophils and mast cells, representing the basic hypersensitive process are also noted. The inflammatory infiltrate may extend into the adjacent lung parenchyma. An incidental finding of emphysema, atelectasis and anthracosis may be present.
Laboratory 5
113
111. Squamous carcinoma of the skin.
All squamous carcinomas, from the epidermis as well as those from internal organs show similar histological features whereas they have markedly different etiologies and prognoses.
Whatever the site of the tumor, the squamoid nature of the cell of origin should be identifiable:-
- Bulky eosinophilic cytoplasm.
- Intercellular bridges (desmosomes) - best seen on high power as cellular junctions.
- The presence of keratin pearls - a variable feature as not all squamous carcinomata produce keratin.
The tumor on the skin has an association with long term solar damage (as for B.C.C) and occurs both on hair and non-hair bearing skin. It is a tumor often occurring in an older people and particularly is associated with pre-existing - premalignant skin conditions such as solar keratoses (so-called "liver spots").
The development of squamous carcinoma in the skin involves a pre-existing in-situ state before the tumor becomes frankly invasive.
The in-situ condition is reflected by malignant squamous cells that fill the entire thickness of the epithelium but that are still confined to the epithelium by an intact basement membrane. This is referred to as Bowen's disease of the skin.
When the tumor cells break through the basement membrane of the epithelium, they infiltrate into the dermal tissue beneath the epidermis. In the dermis, the tumor consists of irregularly shaped clusters and aggregates of malignant squamous cells that have no connection to the epidermis.
Questions:
1. What other organs may show squamous carcinoma as a primary tumor?
2. What are the following: Bowenoid papulosis and Erythroplasia of Queyrat.
3. If you had to choose between having either a basal cell carcinoma or a squamous cell carcinoma of the skin, which would you choose and why?
4. What is a keratoacanthoma?
115
115. Fibroma
A fibroma is a benign tumor composed of an admixture of fibrocytes and fibroblasts. These cells are spindle shaped when cut longitudinally. The nuclei of the fibroblast - on longitudinal section is fusiform. On cross section, the nucleus appears vesicular and round. The tumor is surrounded by a thin compact fibrous capsule. The tumor shows a criss-cross pattern of fibroblastic cells depending on the plane of sectioning. In-between the fibroblasts, there is a collagenous matrix.
Diff. Diagnosis : Keloid
Radiation dermatitis
Questions :
1. What are the pathologic features of a benign neoplasm?
766
766 Squamous cell carcinoma of the cervix
Review slide 751 - Carcinoma in situ of the cervix and revise the histologic features of the cervix.
Identify the ectocervical, endocervical and transitional zone on the slide. In some of the slides, residual carcinoma in situ may be found in the ectocervical epithelium that lines the specimen. Note how in this slide (cf. 751) nests of malignant squamous cells are noted to have infiltrated and penetrated throughout the basement membrane into the cervical fibromuscular stromal tissue. The tumor is composed of irregular nests of squamous cells showing evidence of central keratohyalin production (pearls). The squamous nature of the cells can further be identified by the presence of desmosomes. Note the marked pleomorphism and mitotic activity of the tumor cells.
Questions:
1. What other tumors are found in the cervix?
2. How is cervical carcinoma staged?
328
328 Metastasis of Adenocarcinoma in lungs
Variably sized tumor nodules are randomly dispersed within :
(a) alveolar walls and interlobar septae
(b) undefined positions when the tumor nodules are large.
The interface between the tumor and the healthy lung parenchyma is not well defined. The tumor is composed of columnar secretory cells showing small nuclei. The primary tumor is most probably of gastrointestinal or endometrial origin.
Incidental findings of emphysema, edema, chronic passive congestion and macrophages with hemosiderin.
Questions :
1 Where could the possible primary tumor have arisen?
624
624 Adenocarcinoma of the colon
* Prior to viewing this slide revise the histologic layers of the colon.
Follow the edges of the section and identify normal colonic mucosa. The colonic mucosa undergoes abrupt ulceration where the ulcerated area may be lined by fibrinopurrulent debris and sloughed off tumor cells and glands. The tumor is formed by malignant cells that form irregular glandular and tubular structures. Individual tumor cells are columnar to cuboidal in shape and show all the cytologic features of malignancy.
In some areas tumor cells form isolated “signet ring” forms and in other areas lakes of mucous may be seen (not in all sections). Note the infiltration of the tumor into the colonic wall.
Questions.
1. What is Duke’s staging of carcinoma of the colon?
2. What are the clinical symptoms and signs of colonic carcinoma?
SLIDE DESCRIPTIONS
101 Subcutaneous abscess
This specimen is intended to show suppuration (acute inflammatory cell infiltration with necrosis), as an example of acute inflammation. It shows the skin of a rat, that can be recognized as not being of human origin, as:
3. The epithelium is of the thin keratinizing squamous epithelium
type.
4. Numerous dermal adnexal structures are present, (hair follicles, sebaceous glands and sweat glands).
The acute inflammation was elicited by the injection of turpentine into sub-cutaneous tissue that resulted in the acute inflammatory process shown.
Identify the epithelium first.
Identify the deep margin of the specimen that shows skeletal muscle (the Platysma muscle).
The pathologic lesion is seen in the superficial and mid dermis, as an elliptical area of hypercellularity. There is central karyorrhexis and karyolysis where nuclear and cell debris fills the center of the cavity – (central suppuration). This central zone is surrounded by a poorly circumscribed area of granulation tissue (congested capillary vessels, fibroblastic cells, inflammatory cells and extracellular proteinaceous material).
Note: From this line you should also :
3. Find normal layers of the epithelium.
4. Name and identify inflammatory cells under the titles – (“Acute” and “Chronic”).
102 Granulation tissue
Granulation tissue is the earliest cellular infiltrate that is seen as wound healing begins. It is derived from the granular appearance of the soft friable tissue on the surface of wounds, early on in the healing process. Granulation tissue consists of :
1 Capillary vessels, often congested with erythrocytes (neoascularization and angiogenesis)
1 Fibroblastic cell infiltration – identified as pyramidal to elongated, spindle shaped cells with rounded central nuclei.
1 Edematous stroma with fine collagen fibril deposition.
1 Variable degree of inflammatory cell infiltration.
Although granulation tissue may be seen in all areas of repair and wound healing, there are differences between wound healing by “first intention” and those by “second intention”.
Questions :
1 How would granulation tissue in repair by “second intention” differ from granulation tissue as a result of repair by “first intention”?
1 What do you understand by the term “proud flesh”?
103 Wound healing
The sequences of healing of a wound of a rodent’s skin are shown following vertical incision with a surgical blade – (a “laceration” wound).
24 hours post injury :
Follow the epithelial surface from one edge of the section until, near the center, the epidermis shows a defect being the site of the laceration. This defect is filled with a “crust” or a “scab” which is deeply eosinophilic and is composed of degenerate polymorphs and admixed fibrin. This scab fills the “gap” between the edges of the incision, so that the skin edges are reasonably well apposed and aligned.
Beneath the epithelium the defect of the incision is filled with extravasated erythrocytes and inflammatory cells. The inflammatory cells will include polymorphs, macrophages (histiocytes) and even occasional lymphocytes. This predominantly acute inflammatory infiltrate (in some of the sections0 is seen between the fascicles of the skeletal muscle (Platysma) that was also incised.
5-7 days post injury :
Once again follow the skin surface from the lateral margins to identify the central incision site, that in some slides may still show a surface crust whereas in other sections, may show a thin re-epithelialized layer. The epithelial cells bordering the central incision will show regenerative features and mitotic figures may be seen in these epithelial cells as the regenerate so as to re-epithelialize the defect.
Beneath the epithelium, the incision will show granulation tissue (see slide 102)
Questions :
1. What are the systemic and what are the local host factors that influence the adequacy of healing?
2. A pathologic or “aberrant” form of healing is referred to as a …?
3. What are the morphological features – clinical, macroscopic and microscopic, of this aberrant form of wound healing?
104. Epidermal cyst
This benign cystic lesion is a very common benign cyst that forms a nodular lesion below the skin, very slowly enlarges and is generally not painful unless it is traumatically ruptured when a severe inflammatory reaction may be elicited.
For some unexplained reason, clinicians erroneously term these cysts as “sebaceous cysts” or even as “atheroma of the skin”.
Histologically, the cyst is in the dermis with no connection to the overlying epidermis. The cyst is formed by a benign, stratified, keratinizing epithelial lining with a clear granular layer and with the formation of surface keratin that fills the cyst lumen.
If the cyst has been traumatically ruptured the keratinaceous debris will be expelled into the surrounding connective tissue and will elicit a very heavy mixed acute and chronic inflammatory cell infiltration. This will include foamy macrophages, “cholesterol clefts” and histiocytic foreign body type giant cells - as reactions to the keratin.
Questions :
1 When would the diagnosis of a “sebaceous cyst” be appropriate?
1 When would the diagnosis of a “dermoid cyst” in the skin be appropriate?
1 What is the difference between an epidermal cyst and a pilar cyst both histologically and clinically?
1 If surgical intervention does not take place in a ruptured epidermal cyst what would be the final outcome of the inflammatory process and the keratinaceous debris?
108 Verruca vulgaris of skin. (“Papillomatous”)
This specimen shows the histology of the common viral wart, caused by Human Papilloma virus. The student is referred to the lecture notes for the clinical and macroscopic features.
Briefly, the lesion is a common benign skin tumor due to a viral infection in the epidermis. A whole range of serological sub-types is known with the common viral wart being caused by subtype 4.
The lesion forms an exophytic keratotic papule on the skin surface that is generally non-tender and that if left alone is generally self-limited and involutes spontaneously. The reason for medical consultation is generally for diagnosis and due to cosmetic considerations.
Microscopically the specimen shows a central keratotic lesion that is bordered by margins on either side, of normal keratinzing epithelium. The central keratotic lesion is exophytic – (i.e. it grows outwards) and has the following histologic features :
1. Acanthosis : Increased thickening of the prickle layer of the epidermis with some areas showing increased keratohyaline granules (referred to as hypergranulosis).
2. Hyperkeratosis : Excess keratin formation on the skin surface.
3. Parakeratosis: Excessive keratin on the surface with pyknotic nuclei in the keratinous layer.
4. Papillomatosis : “finger-like” elongation of the rete ridges.
5. Koilocytosis : These epithelial cells (=koilocytes) are the squamous cells that are infected by the virus with the viral particles being represented as intra-nuclear, large basophilic granules. These cells generally have a vacuolated appearance of both the nucleus and cytoplasm.
6. Dyskeratocytosis : Epithelial cells (dyskeratocytes) that show keratin formation in layers beneath the corneal layer where keratin production is normally seen. The eosinophilic keratohyaline is seen in the cytoplasm of these cells, within the prickle layer (spinous layer) of the epithelium.
Other features that may be present in the specimen include a mononuclear (chronic) inflammatory cell infiltrate in the dermis, and spongiosis – a term used to denote intra-epithelial edema.
Questions :
1. What other viral infections are commonly seen as tumor-like papules on the skin?
2. Human papilloma virus infection in other organs may be associated with
malignancy:
3. Which organs are involved in this progression?
4. What serological sub-types are involved in this progression?
5. What does the term condyloma mean?
6. What is a giant condyloma and where does it occur?
109. Melanocytic nevus
The student is referred to the lecture notes for further detail on this specimen.
Melanocytic nevi are benign proliferations of melanocytic cells that have a range of both morphological and clinical presentations. Melanocytes take origin from the neural crest and migrate to their final location in the skin, (explaining the similar staining properties of neural elements and melanocytic cells with the immunohistochemical marker S-100).
Melanocytic cell lesions that are benign, are termed nevi, (the common “birth mark” or “beauty spot”). Benign melanocytic nevi macroscopically may be flat (a pigmented macule), may be raised and nodular, polypoid and even papillomatous. Pigmentation may vary, form being flesh coloured, deep black or even blue (so-called blue nevus). Some may even have hairs on the surface.
Benign nevi are generally static in growth, well circumscribed, uniform in colour, do not spontaneously bleed, and are non-pruritic.
The most common nevi can be divided into three main types:
1. Intradermal nevus – melanocytes present in the superficial and mid dermis.
2. Junctional nevus – melanocyes occuring at the epidermo-dermal junction.
3. Compound nevus – Combination of 1&2.
Melanocytic cells (nevus cells) in these three main types show nests and clusters of uniform melanocytes in the areas described above. Melanocytes appear as round aggregates, often in nests where individual cells have clear cytoplasm with round nuclei. Nucleoli are not prominent (compare with melanoma cells) Mitotic activity in benign melanocytes are generally absent. Melanin content varies from nevus to nevus – some being deeply pigmented and others having scant to absent melanin content. Often, the nevus cell may show a “pseudo-inclusion” in the nucleus, that represents invagination of the nuclear membrane into the nucleus forming a vacuole (seen under high power). A common feature too, is the presence of pigment containing melanophores – inbetween the melanocytic cells, that are not to be mistaken for melanocytes.
Questions:
1. What are the following:- Spitz nevus, blue nevus, balloon cell nevus,
Becker’s nevus?
2. What are Ephelides?
3. What is the B-K mole syndrome?
112. Hemangioma of skin.
This specimen is an example of a benign tumor of blood vessels.
Hemangiomas are composed of vascular channels, most commonly of capillary size, where the capillary vessels are lined by a benign layer of single endothelial cells. The vascular spaces often still are congested with erythrocytes. Hemangiomata are commonly seen on the skin, often in infancy and childhood, but hemangiomata occur in many other organs too. In the skin, the tumor occurs in the superficial and mid dermis and the surface is usually lined by an intact, benign, but occasionally flattened epidermis.
If the vascular channels present in the lesion are small, and capillary in size, then the lesion is termed a capillary hemangioma. If on the other hand, the tumor is composed of large vessels, often with thick walls, then the lesion is termed a cavernous hemangioma.
Further studies:
A whole range of hemangiomata have associations with other conditions, look up the following entities and get their associations.
- Strawberry nevus.
1. Nevus araneus (Spider nevus)
2. von-Hippel Lindua disease.
3. Sterge Weber syndrome.
4. Peliosis hepatis.
5. List the satient features an angiosarcoma (malignant tumor of blood vessels), including the important associations of carcinogenesis.
Questions:
1. What is a pyogenic granuloma?
2. What is Kaposi's sarcoma? In what clinical settings does this lesion occur?
3. What is a glomus tumor?
4. What is Osler-Rendu-Weber disease (Hereditory hemorrhagic telangiectasia)?.
5. What immunohistochemical stain can be used to stain endothelial cells?
113. Basal cell carcinoma (Rodent ulcer)
This common, locally invasive skin tumor occurs mostly in skin that has had long term exposure to sun with ultraviolet ray damage to the epithelium. Basal cell carcinomata (BCC) occurs only on hair bairing skin and therefore does not occur on the lip, but may encroach onto the lip from the vermilion border where it arises.
The tumor occurs most commonly in older patients, who are also fair skinned and who have had long term solar damage. The tumor is locally invasive and destroys adjacent structures by invading them but only in exceptional instances, does the tumor metastasize.
The tumor often appears macroscopically as a small non-healing ulcer on the skin, that slowly enlarges and is generally painless.
Microscopically, the characteristic feature is the presence of nests of peripherally palisading small, basophilic cells that closely resemble the basal cells in normal epithelium. Often, the tumor only focally shows the palisaded, nested pattern and a more infiltrating pattern is seen (morphea variant).
Although the tumor cells are basaloid in appearance, it is not uncommon for basal cell carcinoma to show melanin pigmentation inbetween the cell nests (pigmented basal cell carcinoma), that must not be confused with a malignant melanoma. Similarly, basal cell carcinomata may often show squamous cell differentiation even with the formation of keratin pearls. These are then termed keratotic basal cell carcinomata.
Questions.
1. What is the Gorlin's syndrome, (basal cell nevus syndrome)?
2. What is Xeroderma pigmentosum?
3. What does is the entity - "superficial basal cell carcinoma"?
4. What surgical technique is used, (mostly by plastic surgeons) to ensure the adequate removal of basal cell carcinomata?
114. Squamous carcinoma of the skin.
All squamous carcinomas, from the epidermis as well as those from internal organs show similar histological features whereas they have markedly different etiologies and prognoses.
Whatever the site of the tumor, the squamoid nature of the cell of origin should be identifiable:-
- Bulky eosinophilic cytoplasm.
- Intercellular bridges (desmosomes) - best seen on high power as cellular junctions.
- The presence of keratin pearls - a variable feature as not all squamous carcinomata produce keratin.
The tumor on the skin has an association with long term solar damage (as for B.C.C) and occurs both on hair and non-hair bearing skin. It is a tumor often occurring in an older people and particularly is associated with pre-existing - premalignant skin conditions such as solar keratoses (so-called "liver spots").
The development of squamous carcinoma in the skin involves a pre-existing in-situ state before the tumor becomes frankly invasive.
The in-situ condition is reflected by malignant squamous cells that fill the entire thickness of the epithelium but that are still confined to the epithelium by an intact basement membrane. This is referred to as Bowen's disease of the skin.
When the tumor cells break through the basement membrane of the epithelium, they infiltrate into the dermal tissue beneath the epidermis. In the dermis, the tumor consists of irregularly shaped clusters and aggregates of malignant squamous cells that have no connection to the epidermis.
Questions:
5. What other organs may show squamous carcinoma as a primary tumor?
6. What are the following: Bowenoid papulosis and Erythroplasia of Queyrat.
7. If you had to choose between having either a basal cell carcinoma or a squamous cell carcinoma of the skin, which would you choose and why?
8. What is a keratoacanthoma?
115. Malignant melanoma of the skin.
Malignant melanoma is a malignant proliferation of melanocytic cells (see slide 109).
This is one of the tumors that as yet, depending on depth of invasion in particular, is still associated with a very poor prognosis.
Pigmented lesions of the skin are of concern if:-
1. There is irregular pigmentation of the lesion.
2. The borders of the lesion are not uniform and "satellite" nodules are present.
3. The lesion bleeds spontaneously.
4. The lesion becomes pruritic
5. There is a change in the size and shape of the lesion.
Malignant melanoma, developing in the skin, has two distinct growth phases;
1. Upward and horizontal growth phase: - Melanoma cells grow upwards within the epidermis, reaching the corneal layer and growing laterally beyond the main melanocytic lesion, ("buckshot scatter").
2. Vertical growth phase: Melanoma cells invade the underlying dermis.
Malignant melanoma cells have typical histologic features too. They are generally markedly pleomorphic, have abundant, bulky, often vacuolated cytoplasm with variable amounts of melanin pigment. They have large vesicular nuclei and typically very large, pleomorphic nucleoli.
Malignant melanomas have been grouped in the following typical types : (space has been left for student to fill in the typical clinical, histologic and prognostic characteristics of each of these tuomor types).
1. Nodular melanoma.
2. Acral lentiginous malignant melanoma.
3. Superficial spreading malignant melanoma.
4. Hutchinson’s melanotic freckle.
Questions:
1. What immunohistochemical markers are there that stain malignant melanoma cells?
2. What grading systmes for melanoma are there?
3. How do these grading systems correlate with prognosis?
115. Fibroma
A fibroma is a benign tumor composed of an admixture of fibrocytes and fibroblasts. These cells are spindle shaped when cut longitudinally. The nuclei of the fibroblast - on longitudinal section is fusiform. On cross section, the nucleus appears vesicular and round. The tumor is surrounded by a thin compact fibrous capsule. The tumor shows a criss-cross pattern of fibroblastic cells depending on the plane of sectioning. In-between the fibroblasts, there is a collagenous matrix.
Diff. Diagnosis : Keloid
Radiation dermatitis
Questions :
2. What are the pathologic features of a benign neoplasm?
116 Liposarcoma.
Liposarcoma, though a rare tumor, represents ~ 25% of all soft tissue sarcomas. It is however ~ 100 times less common than benign lipomata.
In general, tumors of adipocytes may be divided into 3 main groups:
1. Benign ( lipoma
2. Atypical lipoma.
3. Liposarcoma – of which several variants are identified.
Liposarcoma is a disease of adults with most patients being in their fifth to sixth decade. Unlike lipomas, liposarcomas only very rarely occur as sub-cutaneous masses. With only few exceptions, liposarcomas develop de-novo and not from pre-existing lipomata.
Liposarcomas usually are situated between major muscular groups – e.g. in the popliteal fossa, retroperitoneally around the kidneys, in the buttocks, inguinal or paratesticular areas.
Grossly, liposarcomas appear as nodular masses usually greater than 5cm in diameter. The retro-peritoneal tumors may reach enormous sizes prior to diagnosis thereby making resection a very difficult, if not impossible procedure. The tumors are generally soft, gelatinous and resemble brain tissue, and have areas of necrosis and hemorrhage.
The diagnosis of a liposarcoma rests on the identification of lipoblasts. Lipoblasts may vary greatly among the different sub-types of liposarcoma and in some may be rare whereas in others may be ubiquitous.
Lipoblasts may be univacuolated or multivacuolated and show these vacuoles that occupy the cytoplasm of the cells with lateral compression of the nucleus due to the cytoplasmic fat, (these cells bear a strong resemblance to signet ring cells as seen in adenocarcinomata – see gastric and ovarian pathology lectures).
Mitotic figures in general, in lipoblasts are a rare finding. A typical feature of liposarcomas is the presence of a vascularized matrix between the tumor cells with branching, thin walled vascular channels.
The prognosis of liposarcomas depends on a range of factors, with histological type & location of tumor being of paramount importance.
Questions:
1. What are the histological sub-types of liposarcoma?
2. List these sub-types in order of prognosis from best to worst.
3. What do you understand by the term “brown fat”?
4. What is a tumor of brown fat and what is the most common anatomical site?
5. In what conditions can lipoblasts occur that are not related to liposarcomas?
119. Fibrosarcoma
This is a malignant tumor of fibroblasts. The tumor comprises spindle-shaped fibroblasts having an overall fascicular pattern. In areas, the pattern, when viewed under low power, resembles that of a “herring bone”. Scattered collagenous tissue is present between the tumor cells. Note the cellular features of a malignant neoplasm - pleomorphism of cells, hyperchromatic nuclei and mitotic activity. Search to find atypical mitotic figures - e.g. tripolar forms. Some giant cells may also be present.
Questions :
1. What is a sarcoma vs. a carcinoma?
2. What are the malignant tumors of : nerve tissue, muscle -both striated and smooth, cartilage, bone, adipose tissue?
3. How do sarcomas spread?
204. Giant cell tumor of bone (Osteoclastoma).
An uncommon, benign bone tumor mostly located around the knee but with the possibility of involvement of any bone. Generally in patients over 20 years of age and more common in women.
Radiographically, the tumor is a lytic lesion that expands the epiphysis.
Microscopically the tumor has two main components :
1. Giant cells : Osteoclast like multinucleated giant cells that are regularly distributed in a background of smaller neoplastic stromal cells.
2. Stromal cells : Mononuclear stromal cells whose nuclei resemble those seen in the giant cells. Mitotic figures may be frequent but atypical mitoses should not be seen in classic giant cell tumors.
Additional components may include clusters of histiocytic foam cells as well as hemosiderin laden macrophages that indicate old hemorrhage.
Questions :
1. Name four differential diagnoses of this lesion based only on the histologic appearance.
2. What are the complications of giant cell tumors of bone?
207. Paget’s disease of bone (Osteitis deformans)
Macro : Distorted trabeculae are noted varying in shape and thickness
Micro : Both osteoclasts and osteoblasts line the bony trabeculae (active stage of the disease). Basophilic calcification lines - “cement lines” are present - running in different directions within the trabeculae. Trabeculae form pathognomonic mosaic pattern (tile-like pattern). The bone marrow is fibrotic and highly vascularised.
Clinical findings : Blood - high ALP corresponds to osteoblastic activity
Urine - Hydroxyproline corresponds to collagen destruction
Questions :
1. What is the current thinking regarding the etiology of this condition?
2. What are the complications of this condition?
212. Chondrosarcoma
Malignant tumor of cartilage occurring in older patients except for the mesenchymal variant. Tend to occur in central positions of the skeleton - especially pelvis. The tumor forms atypical primitive cartilage. The tumor cells form clusters of highly pleomorphic and atypical, sometimes stellate cells within lacunae. Stellate forms and multinucleation within the lacunae is present. Multinucleated chondrocytes and giant cells are noted embedded within a myxomatous hyaline matrix. Focal calcifications and/or ossifications might be found. Tumor cells do not form osteiod.
Diff. diagnosis : Osteosarcoma
Prognosis : Slow growing, late metastasizing.
Questions :
What are the following conditions? :
(1) Ollier’s disease
(2) Maffucci’s syndrome
214. Primary muscular dystrophy
The best example of this group of diseases is represented by Duchenne Muscular Dystrophy. To revise this entity briefly, it is a severe, progressive, sex-linked, recessively inherited condition with marked elevation of serum creatinine kinase levels from birth. The clinical features are noted as a proximal muscle weakness, mainly of the pelvic and shoulder girdles, becoming clinically apparent between the third and fourth year of life.
The atypical pathologic change in the muscle consists of scattered foci of degenerating and regenerating fibres together with large hyalinized dark fibres which are overly contracted and in an early stage of degeneration. Some fibres are packed with phagocytes clearing out a degenerated sarcoplasm. Some fibres are smaller than normal and have a granular cytoplasm. Their nuclei are enlarged, vesicular and contain prominent nucleoli - these representing regenerating fibres. Endomysial fibrosis - collagen around the individual fibres - is also a feature. The changes, therefore, are those of a chronic non-inflammatory myopathy.
Questions :
1. What do you understand by the clinical term “pseudohypertrophy”?
2. What is the prognosis of this type of dystrophy?
3. What is the most common cause of death?
4. What isoenzyme is diagnostic of this condition?
5. What other dystrophies are there?
215. Osteogenic sarcoma (osteosarcoma)
The most frequent primary malignant bone tumor, exclusive of hematopoeitic system. Most frequent in the ages 10 – 25 years and being exceptionally rare in preschool children. Another peak incidence occurs after the age of 40, (when associated with other disorders). Slight male predominance. Most tumors occur de-novo, but may be associated with other diseases:
1. Paget’s disease (in patients over 40)
2. Radiation exposure – following latent period of 10-15 years
3. Chemotherapy – in children treated for other malignancies
4. Pre-existing benign bone lesions –(fibrous dysplasia, osteochondromatosis)
Site: Located at metaphyseal area of long bones particularly lower end of femur, upper end of tibia and humerus. Occasionally they are multicentric. Arise in medullary cavity and extend into the cortex.
Gross appearance and spread:
Forms a tumor mass, distorting the bone, with bone, cartilage, hemorrhagic areas and even cystic areas present
May spread along marrow cavity or invade adjacent cortex.
It may be elevated or perforate the periosteum with a resultant radiological typical appearance known as the “Codman’s triangle”.
It may perforate the periosteum and extend into soft tissues.
May extend into the epiphysis (particularly if the epiphysis is closed).
It may invade the joint space or form satellite nodules independent of the main tumor mass.
Metastasis is typically by blood, to distant sites with the lung being most common. Regional lymph node metastasis are so rare that they should be disregarded for therapy purposes.
Microscopic examination:
The key feature in the diagnosis is the detection of osteoid produced directly by tumor cells. Osteoid appears as eosinophilic material with a glassy appearance, with irregular contours surrounded by a rim of abnormal osteoblasts. The osteoid may be easily confused with hyalinized collagen, (that is, however, usually fibrillary).
Fibroblastic, osteoblastic and chondroblastic foci are identified in the cellular components. Many multinucleated forms are generally identified, as too are spindle cell forms. Microscopic variants are : telangiectatic, small cell, fibrohistiocytic, anaplastic and well differentiated varieties.
Immunohistochemistry : Osteosarcomas are generally positive for ALF, S-100 and vimentin.
Differential diagnosis :
Osteosarcoma may be very difficult to differentiate from other benign and malignant lesions from a histologic viewpoint :
Benign lesions : Callus in fractures, myositis ossificants, fibrous dysplasia, osteoblastoma.
Malignant lesions : Fibrosarcoma, chondrosarcoma, giant cell tumor, metastatic carcinoma.
From a clinical viewpoint, osteosarcoma has a similar age and site predilection to Ewings sarcoma
302 Bronchogenic carcinoma (lung, squamous cell type)
The tumor consists of irregular masses of highly atypical and malignant squamous cells. The cells occur in multilayered masses and show typical features of malignancy. The cells are hyperchromatic and contain variably sized, often markedly enlarged nuclei. Mitoses are frequent. Typical keratin pearls are not common, but individual squamous cells do show keratinization. Intercellular bridges (desmosomes) should be easily identified on high magnification. The tumor also shows areas of hemorrhage and necrosis.
Questions :
1. Classify the lung tumors of importance under the headings :
Benign
Malignant
2. What is the clinical setting of squamous cell carcinoma of the lung?
305 Oat cell carcinoma (Small cell carcinoma)
The specimen shows tumor cells in closely packed hyperchromatic deeply basophilic clusters. The individual tumor cells show little cytoplasm. The nuclei are oval and chromatin rich (oat-shaped). Note similarity of tumor clels to lymphocytes. Crush artifact may be very marked and prevent good visualization of cells. The surrounding stroma is hemorrhagic. Carbon pigment may be seen as well.
Questions :
1. What do you understand by the paraneoplastic syndrome?
2. Give some further examples of this syndrome in other conditions.
3. Why is diagnosis of this tumor so difficult on bronchial biopsy?
306 Asthma - lung
There is marked hypertrophy of the muscular coat of the bronchi and bronchioli with a thickened eosinophilic basal membrane. The bronchial epithelium is tall and contains basally situated nuclei. There is apical mucous vacuoles in the cytoplasm. Metaplastic cells (squamous) may also be present. Some areas may show sloughing of the mucosal cells. The bronchial lumen is filled with basophilic, inspissated mucous forming a plug. This mucous may contain neutrophils and desquamated mucosal cells. The bronchial wall has lymphocytes and plasma cells representing a chronic bronchitis. Eosinophils and mast cells, representing the basic hypersensitive process are also noted. The inflammatory infiltrate may extend into the adjacent lung parenchyma. An incidental finding of emphysema, atelectasis and anthracosis may be present.
309. Anthracosis and chronic emphysema of the lungs
A 68-year-old man was found dead on the right side of the road. The medico-legal expertise revealed multiple skull factures, subdural hematoma and laceration of brain. Incidental autopsy findings revealed inflated lungs with black, pigmented linear streaks especially near the hilar region which also showed blackened lymph nodes.
Note the markedly enlarged, almost cystic formation of the alveoli. This is the basic feature of emphysema and is due to rupture of the interalveolar septae. There is peribronchial fibrosis that extends from the bronchial areas into the alveolar septae. Black, carbon pigment is abundant in the lymphatic tissue in the specimen, as well as in type-1 pneumocytes.
Formalin pigment in contrast - representing overfixation artifact presents as fine black granules not as phagocytised material in cells.
310 Edema of lungs (pulmonary edema)
Histologic examination of the lungs shows alveolar capillaries that are engorged with blood. The intra-alveolar space is partially to totally filled with a granular pink precipitate. Alveolar microhemorrhages and hemosiderin laden macrophages (“heart failure cells”), are noted. Such changes as these not only impair normal respiratory function but also predispose to final onslaught to the patient - hypostatic pneumonia. Within the lung tissue anthracosis, emphysema and atelectasis may also be present.
Questions:
4. What are the mechanisms of edema?
5. What do the terms anasarca and ascites mean?
6. What is the difference between an exudate and a transudate?
311 Confluent bronchopneumonia
Affected areas of the lung are in various stages of the disease and therefore, give a patchy non-homogenous overall pattern to the lung parenchyma.
Pathogenesis: Begins in the terminal bronchioles and spreads into the surrounding alveoli. Spread from one alveolus to the next adjacent one is via the pores of Kohn. As a result, different alveoli show different stages of inflammation and repair. Some alveoli have an exudate of PMN’s and fibrin. others may show intra-alveolar edema fluid. Areas of necrosis and abscess formation within the lung parenchyma should be sought. Look for the inflammation within the bronchiolar elements.
Questions :
1. What are the main etiologic agents?
2. What do you understand by the term hypostatic pneumonia?
3. What are the complications of bronchopneumonia?
312 Lobar pneumonia - Gray Hepatization stage
The overall pattern is a homogenous one within one whole lobe of the lung. Pleural surface is covered by fibrin, PMN’s, histiocytes and erythrocytes = fibrinous pleuritis.
All the alveolar lumina in one lobe of the lung are distended and filled with fibrin, PMN’s and karyorrhectic cellular debris (disintegrated PMN’s). Lower the condenser lens to better visualize the fibrinous exudate in H & E sections. Some alveoli are filled with pale eosinophilic exudate free edema fluid. Isolated bronchioles might be destroyed. Inflammation is limited by interlobar fissures. Incidental finding is anthracotic granules near destroyed bronchi.
Questions :
1. What are the uninterfered stages of lobar pneumonia?
2. Who gets this disease?
3. What is the main etiologic agent?
4. What is the usual outcome?
313 Organizing pneumonia
This stage represents the phases of resolution of a lobar pneumonia prior to complete and uncomplicated recovery. The neutrophils and karyorrhectic material noted in the alveolar spaces in the previous stage (see slide 312) are now replaced to a large degree, by macrophages and fibrin, scattered areas of neutrophils may still be discerned.
Questions:
1. If resolution does not occur, what are the complications of pneumonia?
2. What is understood by the term “carnification”?
314 Miliary tuberculosis of lung
Case History
A female foreign worker in Israel, aged 24 years, for 4 months before being hospitalized, had complained of dyspnea, intermittent fever and constipation with abdominal pains. The family physician had treated her with antipyretics for a common cold.
At admission she showed vomiting and mental confusion . Because of a suspicion of meningitis, a lumbar puncture was performed. The laboratory tests showed CSF that was opalescent and contained a mixture of neutrophils and lymphocytes. The protein value was 1.75gr / lt. (normal range 0.15 – 0.40 gr. / lt. No glucose was found. Antibiotic treatment was started but 24 hours later, the woman died.
The post-mortem examination revealed the following main lesions :
4. Congestion of lungs and presence of small nodules (1-2 mm in diameter), pale but firm, randomly distributed under the pleural surface and deep into the parenchyma.
5. The small intestine presented irregular ulcers with undermined edges of the mucosa. The ulcers were situated in the transverse axis of the bowel and contained friable white caseous material. The mesenteric lymph nodes were enlarged and on cut surface they showed a diffuse, soft, cheesy-white material.
6. The meninges at the basal cisternae region contained a gelatinous grey, viscous exudate which penetrated into the regional sulci. Near the blood vessels a few grey tubercles were also found.
Questions :
4. What is the cause of death?
5. Which organ shows the primary lesion?
6. Describe the etiology and pathogenesis of the event.
In the histologic sections two types of granuloma ** are represented:-
Soft tubercle: The hallmark of tuberculosis - caseous necrosis is noted at the centre of the tubercle and appears as eosinophilic areas lacking cellular detail and appearing granular. These areas are surrounded peripherally by the epithelioid histiocytes and giant cells described above typical of a granuloma.
Hard tubercle: The same cellular constituents are present as in the soft tubercle but there is no central caseation.
Questions:
4. What other causes are there for granulomata?
5. What does the term “naked granuloma” denote?
6. How would you confirm your presumptive diagnosis of Tuberculosis?
* The term miliary refers to spread of tuberculosis organisms gaining access to blood and lymphatic vessels with subsequent seeding to distant organs. The term miliary is descriptive of the character of the minute lesions which are small, yellow-white and resemble canary bird seed or millet [milium (Latin)] seeds.
**A granuloma is a collection of inflammatory cells, principally modified macrophages, usually surrounded by a rim of inflammatory cells (lymphocytes). Giant cells that are coalescent and fused macrophages are often part of granulomata, (in tuberculosis these giant cells are called Langhans cells). When used in the context of tuberculosis, the tuberculous granulomata are referred to as Tubercles.
316 Hyaline membrane disease of the newborn (Lungs)
Near total collapse of lung parenchyma. Uninflated alveoli with thick septae alternate with emphysematous areas (hyperinflated area). The respiratory bronchioles and the distended alveoli are lined on their inner aspect by amorphous eosinophilic material - hyaline membranes. There is also congestion and hemorrhage present as well as distended respiratory bronchioles indicating positive pressure ventilation of lungs.
Questions :
1. What is the clinical setting for development of HMD?
2. What complications are there of HMD and its therapy?
321 Interstitial pneumonia
The alveolar spaces are difficult to visualize due to the marked thickening of the alveolar septae. The alveolar septae (interstitial regions) contain numerous inflammatory cells that include lymphocytes, plasma cells and histiocytes. A variable amount of fibrosis is also noted. This represents the basic pathologic finding of an interstitial pneumonia.
The alveolar spaces are partially to totally lined by an eosinophilic, acellular membrane = hyaline membrane. (Not present in all slides). In some of the slides present, giant cells of Measles can be seen - these are the Warthin-Finkelday giant cells (look for inclusion bodies). Other slides have oval enlarged mononuclear cells with an intranuclear inclusion body - being that of Cytomegalic virus.
323 Pneumocystis carinii pneumonia
This is a nonbacterial opportunistic infection. Most cases are seen in individuals who are chronically debilitated and immunosuppressed, such as in AIDS. The diagnosis depends on the microscopic identification of the organism since at present there are no reliable microbiologic or serologic tests available.
The microscopic features characteristic of the infection are :
1. Foamy or honeycombed intra-alveolar exudate appearing as a paleosinophilic exudate in the alveolar spaces.
2. Lymphoplasmacytic interstitial infiltrate that expands the interalveolar septae.
The cysts of the organism appear as round structures 5(m in diameter with a crescentic shape - resembling a steel helmet.
These cysts are identifiable under oil-immersion and best stained by specialized silver stains = Gomori’s methenamine silver.
401 Cardiac hypertrophy
Note : The same slide shows representative sections of infant myocardium; normal myocardium and hypertrophied myocardium.
A post-mortem specimen from a 62 year-old man showed he had died of an intracranial hemorrhage of the right temporo-occipital lobe. He had been known to have a blood pressure of 210-110 mm Hg for the past 5 years but had refused treatment. At autopsy the heart weight was 450gr. and showed marked hypertrophy of the left ventricle, it’s lateral wall measuring 24 mm thickness (normal 13-15 mm). A moderate aortic stenosis was also found.
Microscopy : The hypertrophied myocardium is cut in different planes and shows myocardial fibres of variable thickness, mostly being thicker than normal (cf. normal and infant’s myocardium). The striations are also thickened and increased in number. The chromatin rich nuclei are enlarged and irregular in size and shape. Some are bizarre in shape and may resemble “stag horns”. The total number of nuclei per microscopic field is, due to the increase in size thereof, reduced. Surrounding and adjacent to these enlarged nuclei, in some of the hypertrophied fibres, a granular golden-yellow pigment (lipofuscin) can be found. This is the so-called “wear and tear” pigment (that can be found in normal myocardium too). Scattered areas of fibrosis, in between the hypertrophied muscle fibres can be seen - repreenting areas of hypoxia with resultant fibrosis.
Compare the findings of the hypertrophied muscle with the normal muscle represented.
Question :
324 Chronic passive congestion, lung
Macro The affected lung is heavy, dark red and firm; abundant frothy red fluid can be squeezed from it.
Micro The lung parenchyma shows large inflated alveoli - emphysema - alternating with collapsed ones - atelectasis. The large blood vessels as well as the capillaries in the interalveolar septae look distended and engorged with erythrocytes - congestion. The interalveolar septae look fibrotic at various extends.
The alveolar spaces contain many large round to ovoid cells with small nuclei - histiocytes. In most of these cells dark brown granules are seen - “heart failure cells” or siderophages. In some cases the alveolar lumen is filled with an eosinophobic proteinous material - edema (see specimen 310) and inflammatory exudate of WBC as well as small hemorrhagic foci.
327 Inflammatory polyp of nose
Polypoid tissue fragments lined on the surface by pseudostratified cilliated columnar epithelium of the respiratory tract. Areas of metaplastic change (usually squamous) may be noted. Mucous secreting glands may also be noted near the surface. The stroma of the polyps is edematous and includes congested small arterioles. A diffuse scattering of inflammatory cells is present within the stromal tissue. The infiltrate includes numerous eosinophils and plasma cells. Smaller numbers of lymphocytes and neutrophils are also noted. (acute cells = Neutrophils and ? eosinophils; Chronic cells = lymphocytes, plasma cells, histiocytes and ? eosinophils).
328 Metastasis of Adenocarcinoma in lungs
Variably sized tumor nodules are randomly dispersed within :
(a) alveolar walls and interlobar septae
(b) undefined positions when the tumor nodules are large.
The interface between the tumor and the healthy lung parenchyma is not well defined. The tumor is composed of columnar secretory cells showing small nuclei. The primary tumor is most probably of gastrointestinal or endometrial origin.
Incidental findings of emphysema, edema, chronic passive congestion and macrophages with hemosiderin.
Questions :
1 Where could the possible primary tumor have arisen?
330 Fibrinous pleuritis (organization)
On the surface of the visceral pleura there is an eosinophilic pseudo-membrane consisting of a thick fibrinous network. Admixed within this network of fibres are macrophages, lymphocytes and many capillaries. Some nodules of fibrotic tissue - representing fibrous adhesions between visceral and parietal pleural layers are noted on the surface. The underlying lung parenchyma shows thick walled alveoli with a neutrophilic infiltration - representing resolving underlying bronchopneumonia.
331 Pulmonary emboli
The lung parenchymal histology is normal. The lumina of small arteries are occluded by thrombus - representing the emboli. The emboli lie freely within the lumina, not attached to the vessel wall, indicating origin from a far removed site and not originating within the vessel. The emboli consists of the constituents of a thrombus - fibrin, erythrocytes and debris.
Note: Septic emboli contain basophilic bacterial clusters. Within the sections, adjacent lung tissue may show emphysema, atelectasis and anthracosis.
Questions :
5. What is the most probable origin of the emboli?
6. What is Virchow’s triad?
7. What do you understand by the term “paradoxical emboli”?
8. What are the clinical symptoms and signs of pulmonary emboli?
401 Cardiac hypertrophy
Note : The same slide shows representative sections of infant myocardium; normal myocardium and hypertrophied myocardium.
A post-mortem specimen from a 62 year-old man showed he had died of an intracranial hemorrhage of the right temporo-occipital lobe. He had been known to have a blood pressure of 210-110 mm Hg for the past 5 years but had refused treatment. At autopsy the heart weight was 450gr. and showed marked hypertrophy of the left ventricle, it’s lateral wall measuring 24 mm thickness (normal 13-15 mm). A moderate aortic stenosis was also found.
Microscopy : The hypertrophied myocardium is cut in different planes and shows myocardial fibres of variable thickness, mostly being thicker than normal (cf. normal and infant’s myocardium). The striations are also thickened and increased in number. The chromatin rich nuclei are enlarged and irregular in size and shape. Some are bizarre in shape and may resemble “stag horns”. The total number of nuclei per microscopic field is, due to the increase in size thereof, reduced. Surrounding and adjacent to these enlarged nuclei, in some of the hypertrophied fibres, a granular golden-yellow pigment (lipofuscin) can be found. This is the so-called “wear and tear” pigment (that can be found in normal myocardium too). Scattered areas of fibrosis, in between the hypertrophied muscle fibres can be seen - repreenting areas of hypoxia with resultant fibrosis.
Compare the findings of the hypertrophied muscle with the normal muscle represented.
Question :
314. Name as many conditions as you know that may cause the cardiac muscle fibres to hypertrophy.
404 Recent myocardial infarction
Examine the section to identify normal myocardial fibres with well preserved striations and nuclei. Scan the slide until an area is encountered where there is marked eosinophilia and necrosis of the myocardial fibres. Here striations and cytological detail is lost. The nuclei are pyknotic or even absent. Within this area of infarction, a marked P.M.N. infiltrate is present. The infarcted area of myocardium is surrounded by a hemorrhagic zone or rim. Using the lecture notes on this process (or other references) attempt to date this region of infarction.
Questions :
1. What do the terms transmural and sub-endocardial infarction mean?
2. What are the complications of these lesions ?
405 Organizing myocardial infarction
On microscopic examination, large areas of myocardial fibres are absent and replaced by granulation tissue. This tissue (as described in slide 102) is composed of an admixture of capillaries and inflammatory cells. Histiocytes with large round nuclei are also evident, some with hemosiderin in the cytoplasm (siderophages), representing old areas of hemorrhage. Other areas of more recent hemorrhage are also noted.
As in the case of slide 404, attempt to date this infarction using lecture notes (or other references)
406 Scar of old Myocardial Infarction
(5-8 wks)
The myocardium shows large regions of replacement by hypocellular fibrous scar tissue. Within the scar tissue as well as around the periphery, hypertrophied cardiac muscle fibres can be seen. A chronic inflammatory cell may also be noted in these areas. In some of the slides recurrent infarcts can be seen as fresh areas of necrosis and inflammation.
407 Fibrinous pericarditis
The most common response of the pericardium to various injurious agents, infectious and non-infectious, is an inflammation characterized by a fibrinous exudate with or without serous effusion. The most common causes include uremia, acute bacterial infections, rheumatic fever, myocardial infarction and tuberculosis.
Microscopic examination shows a segment of heart that includes a strip of cardiac muscle and the pericardium. The pericardium shows small areas of adipose tissue and loose connective tissue. On the surface of the connective tissue there is reticulated , deeply eosinophilic, amorphous material which is identified as fibrin. Within the fibrinous material scattered histiocytes may be present. These histiocytes occur in “lacunae” due to degradation of the fibrin by proteolytic enzymes from the histiocytes.
Questions:
1. What has been likened to bread and butter w.r.t. pericarditis?
2. What other types of pericarditis are described?
3. What are the clinical features of pericarditis?
408 Interstitial Myocarditis
The cardiac fibres show essentially normal histologic features with striations present. In small, focal areas, isolated myocardial fibres may show necrosis. The pathologic process is present within the interstitium. In the interstitial areas between cardiac fibres there is edema with an inflammatory infiltrate noted within the expanded area of the interstitium. The infiltrate consists of lymphocytes, plasma cells and histiocytes.
Question :
1. What are the most common causes of this condition?
409 Acute bacterial endocarditis
Macro : Thin sliver of valve tissue with a “crumbling” vegetation on the surface.
Micro : The fibrous valve has a surface vegetation that is composed of fibrin in the form of threads of eosinophilic material in which scattered inflammatory cells (P.M.N.s mostly) are present. Also admixed in this irregular mesh are erythrocytes and clusters of basophilic bacteria (Staph. aureus). An additional finding, within the small amount of myocardium attached to the valve, is the presence within the myocardium of micro-abscesses, representing spread of the infection into the myocardium.
Questions:
1. How do these vegetations differ from those of Rheumatic fever?
2. Which of the above embolise? To where and with what results?
3. Who are those patients predisposed to bacterial endocarditis?
4. What should be sought if culture reveals Strep. fecalis?
411a Aschoff body like granuloma - Auricle of heart
The endocardium is thickened and contains elliptically shaped granulomatous lesions (Aschoff bodies). As the endocardium is devoid of blood vessels, the typical perivascular position of the lesion is not present. The granulomatous lesion shows a central area of fibrinoid necrosis surrounded by macrophages (Anitchkow myocytes). Multinucleated Aschoff Giant cells are also absent usually in the endocardium. The granulomata are surrounded by a rim of lymphocytes.
Quetions.
1. What microscopic phases of Rheumatic fever are there and which phase is the diagnostic one?
418 Thrombosis - (organized) coronary artery
Macro: Cross section of a small artery showing partial to almost total occlusion of the lumen.
Micro : The lumen of the vessel is almost totally occluded by connective tissue that is attached to the vascular wall. The original lumen is reduced to a narrow slit lined by a thickened intima. The connective tissue obstructing the lumen is composed of immature granulation tissue as well as secondary smaller vascular channels representing recanalization.
419 Buerger’s Disease (Thrombangitis obliterans)
Macro : Cross section of a medium sized artery
Micro : The vascular lumen is partially to totally occluded by organizing thrombus with recanalization within the thrombus (small vascular channels in the thrombus lined by endothelial cells and filled with blood). The internal elastic lamina is preserved. The media of the vessel shows a heavy inflammatory cell infiltrate with lymphocytes, neutrophils and giant cells. The inflammatory infiltrate might be noted in the adjacent (thinner) vein as well as in the nerve.
Questions.
1. In what clinical setting is this disease present?
2. What are the complications?
422 Atherosclerosis of coronary artery
Macro : Cross section through a small artery with surrounding connective tissue and in some sections, a thin walled flat vessel (vein).
Micro : The original lumen of the vessel is markedly narrowed and distorted, compressed eccentrically to one side. The lumen is lined by flattened endothelial cells. There is eccentric thickening of the intima which represents the atherosclerotic process. The thickened intima contains an atheromatous plaque in which there are cholesterol clefts (needle shaped spaces where cholesterol has been dissolved in processing), and dust-like calcium granules. More extensive basophilic calcifications are also noted. Interspersed within the plaque are variably sized collagen bundles with few cellular elements.
There is an indistinct border between the intima and the media. The media is atrophic, particularly in the areas immediately below the atheromatous plaque. In the sections that have an adjacent vein note the total absence of pathological changes.
424 Giant cell arteritis
Macro : Cross section through a large sized artery.
Giant cell arteritis is a systemic vascular disease with granulomatous inflammation of medium sized and large arteries. Histologic examination shows a non-specific inflammatory infiltrate throughout the wall of the vessel with both polymorphonuclear and mononuclear cells (neutrophils, lymphocytes, histiocytes and a variable number of giant cells). The internal elastic lamina is fragmented and split. The infiltrate, though transmural, is most notable within the media.
Questions.
1. What are the clinical manifestations of this disease?
2. What are the vessels most commonly affected?
3. What are the vessels most often biopsied to diagnose this entity?
502 Gaucher’s Disease - Spleen
A chronic familial disease in which cerebroside accumulates in reticulum cells of the spleen, liver, lymph nodes and bone marrow.
Microscopically, the distinctive feature in the spleen is the presence of large, pale Gaucher cells which compose the greyish translucent areas within the otherwise atrophic white pulp. These cells have a small eccentric nucleus and abundant pale, eosinophilic cytoplasm containing fine striations or threads - often likened to wrinkled cigarette paper. Multinucleated forms may occur. The cytoplasm of the Gaucher cells stain positive with the P.A.S. stain.
506 Lymphatic leukemia in liver
The lobular pattern of the liver is preserved. Identify the three zones of the liver lobule for orientation purposes (central, mid-zone and portal tract).
On low power there is clear expansion of the portal tract area that appears blue. On higher power, it is clear that this basophilia is due to a massive infiltrate in the portal tract zone, by numerous lymphocytes.
The lymphocytes are uniform and small in size. They contain small, central spherical nuclei and little surrounding cytoplasm. These lymphocytes closely resemble mature, adult lymphocytes and have minimal mitotic activity. (The lymphocytes are of the B cell type).
Diff. diagnosis: Chronic inflammation in the portal tracts.
507 Reactive follicular hyperplasia of lymph node
(In this case - tonsil)
The specimen is of a tonsil removed during tonsillectomy for recurrent tonsillitis. It is utilized here to show the features of hyperplasia in a lymphoid organ and to revise the normal lymph node morphology.
The tonsil in this case is lined on one surface by stratified squamous epithelium that sends invaginating epithelially lined crypts deep into the underlying lymphoid stroma. Some slides may show Actinomyces mycetomata in the deep areas of these crypts.
The deep margins of excision of the specimen show connective tissue, mucous secreting glands and skeletal muscle fascicles.
The lymphoid tissue shows a reactive follicular hyperplasia pattern. The lymphoid follicles are located predominantly in the cortex and around the periphery of the organ. The follicles have large germinal centres showing numerous tingible body macrophages and mitotic activity in the germinal centre cells. The follicles are surounded by well developed mantle zones consisting of small, benign, mature lymphocytes. The interfollicular area is inbetween the lymphoid follicles.
Questions :
1. What is the most important low power microscopic feature that differentiates benign from malignant lymph nodes?
2. What other salient features are sought to differentiate benign from malignant lymph nodes?
3. What are the areas in the nodes that represent the B-cell and T-cell areas?
509 Multiple myeloma, vertebral body
This entity is characterized by a proliferation and accumulation within the marrow of neoplastic cells that usually constitute > 20% of the marrow cells and morphologically resemble plasma cells.
The marrow cavity is infiltrated by plasma cells, some of which closely resemble mature plasma cells. (Mature plasma cells, to revise, have eccentric ovoid nuclei with a “cart-wheel” type pattern. There is a clear perinuclear “halo” zone. The cytoplasm is usually purple.)
Abnormal plasma cells may also be present, binucleated as well as giant cells. Small and atrophic bony spicules may be seen in-between the infiltrate.
Questions:
1. How can this entity be suspected, prior to bone marrow biopsy?
2. What other organs besides the bone marrow can be involved in myeloma?
3. What are other complications of myeloma?
510 Amyloidosis of the spleen
Amyloidosis in its systemic form involves the spleen more frequently than any other organ. The splenic involvement may cause splenomegaly and it may involve the spleen in either a nodular or in a diffuse pattern. The macroscopic examination of such a spleen is described in the nodular form as “sago spleen” and in the diffuse form as “lardaceous spleen”. Macroscopically, the spleen on its cut surface has a characteristic “waxy” nature. The Malpighian bodies appear exaggerated and translucent rather than gray-white. In the diffuse type, amyloid is deposited within the red pulp.
Microscopic examination shows pale pink (Salmon pink) amyloid deposits that have replaced the Malipighian corpuscles. Smaller areas of amyloid are seen in connective tissue trabeculi as well as in the splenic capsule. Note the deposits of amyloid in the arterial vessels.
Questions:
1. What is amyloid?
2. What is the classification of amyloid?
3. What is the most common cause of amyloidosis in Israel?
4. What specific stains are used to identify amyloid?
5. What other organs are affected by amyloidosis?
517 Sarcoidosis, lymph node
(Besnier-Boek-Schaumann disease or Boek’s Sarcoid)
Sarcoidosis is a generalized systemic granulomatous disease in which there is common involvement of lymph nodes, lung, bone marrow (phalanges), spleen, liver and salivary glands. The lymph nodes most commonly involved are particularly the cervical nodes in the head and neck region.
Macroscopic examination shows lymph node tissue that has its normal structure effaced to a large degree due to the presence of multiple, crowded granulomata. The granulomata are of varying size and can show a close resemblance to the granulomata of tuberculosis. Within the granulomata, giant cells of the Langhans’ type are also encountered. Within the centre of the granulomata, laminated concretions may be sought (very rare). These are the “Schaumann bodies”. Other stellate, so-called “asteroid” bodies may also be found in the giant cells.
The granulomata in sarcoidosis are also termed “naked granulomata” as there is no rim or mantle of lymphocytes as is found in tuberculous granulomata.
Further points of differentiation between the two entities are :
4. No caseous necrosis in sarcoidosis
5. No acid fast bacteria are identified on special stains
Questions:
1. What is the Kveim test?
2. What is the etiology of Sarcoidosis?
3. What are the complications and prognosis?
518 Malignant lymphoma (Non-Hodgkin’s, follicullar, small cleaved cell.
(An example of a Low-grade non-Hodgkin’s lymphoma, according to the “Working Formulation” classification system).
This form of lymphoma is most common between the ages of 50-60 years, with an equal sex distribution. It presents usually as an asymptomatic, generalized lymphadenopathy.
On low power, the secretions show lymph node tissue that has a nodular pattern with variation in the sizes and shapes of the follicles, thus giving it the term follicular lymphoma. This type of lymphoma can be difficult to differentiate from reactive hyperplasia of the lymph node, but with careful examination, one can ascertain that the normal lymphoid architecture has been effaced. One can see that the sub-capsular sinus of the lymph node is not “open” and is infiltrated by the same lymphocytes that constitute the lymph node. There is extension of these lymphocytes into and often beyond the capsule of the node into pericapsular adipose tissue.
On higher power, the malignant follicles are surrounded by cuffs or mantles of mostly small lymphocytes and are closely arranged with little interfollicular tissue. The germinal centres of the follicles show a uniform population of cells (c.f. reactive germinal centre). The following cell types are described within the germinal centre:-
Centrocyte - cell with an irregular nucleus showing a prominent indentation or “cleave”, giving this entity its name. Mitotic figures are relatively common in these cells.
Centroblast - Non cleaved nucleus with basophilic cytoplasm, with few mitotes, small in size.
519 Malignant lymphoma (Non-Hodgkin’s, diffuse, mixed small and large cell)
(An example of an intermediate-grade non-Hodgkin’s lymphoma, according to the “Working Formulation” classification system)
This lymphoma type accounts for 5-10% of NHL.
All the features of a lymph node with effaced architecture are present. On low power, this lymphoma shows lymphoid tissue that is diffusely infiltrated by atypical lymphoid cells. No follicular pattern of cell growth is noted,
On high power, two definite populations of lymphocytes can be seen intermingling. The larger cells are typically pleomorphic and show irregular nuclei and usually single nucleolus. The smaller lymphocytes may have cleaved features and have central nuclei with scanty basophilic cytoplasm.
520 Diffuse lymphoma, large cell, immunoblastic type (lymph node)
(Rappaport = diffuse histiocytic lymphoma)
The normal lymph node architecture is effaced. The malignant lymphocytes replace most germinal centres. Various cell types can be identified.
1. Immunoblasts : Large cells with basophilic cytoplasm (high concentration of R.N.A.), large, uniform, round to oval vesicular nuclei with a prominent central nucleolus.
2. Plasmacytoid cells : Abundant amphophilic to basophilic cytoplasm (R.N.A.), ovoid cell with eccentric nucleus.
3. Clear cells : Abundant optically clear cytoplasm with central nuclei.
4. Polymorphous variants : Small lymphoid cells with irregular nuclei, large cells with hyperlobated nuclei - “Reed-Sternberg” like cells.
A vascular stroma is present but vessels lack the arborizing quality seen in angioimmunoblastic lymphadenopathy (T cell lymphoma).
522 Hodgkin’s Disease - mixed cellularity type in lymph node
The lymph node architecture is destroyed due to a heavy infiltration of various cell types. Reed-Sternberg cells are readily identified together with other variants thereof - both mononuclear as well as multinucleated forms. There is a typical “background” of normal lymphocytes, eosinophils and plasma cells. Fibrosis may be present, diffusely or focally . Small foci of necrosis may be found, as well as epithelioid granulomata.
This type of H.D. includes all cases of H.D. that cannot be clearly classified within other types of this disease entity.
524 Hodgkin’s Disease - Nodular sclerosis
Hodgkin’s disease is a unique malignant disorder of the reticuloendothelial system that commonly first involves lymph nodes. The origin of the neoplastic cell in Hodgkin’s disease (H.D.) - the Reed-Sternberg cell (R/S cell) is controversial, but the presence of this diagnostic cell type is a prerequisite for the diagnosis of H.D.
Four histopatholgic subtypes of H.D. are recognized on the basis of specific cellular and stromal fibroblastic components.
(a) Lymphocyte predominant (L.P.)
(b) Mixed cellularity (see slide 522)
(c) Lymphocyte depletion
(d) Nodular sclerosis (N/S)
N/S is determined by the presence of distinctive R/S cell variants - lacunar cells -and by the presence of dense bands of fibrosis within the lymph node. In addition to the R/S cell variants, numerous typical R/S cells and other variants are commonly found within a lymph node of N/S.
Microscopic examination of the lymph node shows a lymph node whose architecture is totally effaced by broad bands of fibrous, collagenous tissue (that even macroscopically) divides the lymph node into smaller and larger nodules of lymphoid tissue. The typical R/S cell is easily identified and is typically described as being a binucleated, very large cell with abundant pale pink cytoplasm. There are two large vesicular nuclei containing very prominent eosinophilic, central nucleoli giving the appearance of an “owl’s eye”. Multinucleated R/s cells may also be commonly found, even more commonly than the classic R/S cell. The lacunar cell - an R/S variant - has abundant, pale cytoplasm with a lobulated nucleus and eosinophilic nucleoli that are intermediate in size. The lacunar cell is so named because in formalin fixed tissue, the cytoplasm artifactually retracts towards the nucleus and the cell appears to lie in a lacuna or lake. In the “background” other inflammatory cells are found. These include normal eosinophils, plasma cells and lymphocytes.
Questions:
1. What is the typical clinical setting for N/S Hodgkin’s ?
2. What is the proposed origin of the R/S cell?
525 Metastatic adenocarcinoma, lymph node
Microscopic examination shows lymph nodes with interspaced loose, adipose connective tissue.
First identify the normal elements of the lymph node - germinal centres, interfollicular areas, subcapsular sinuses etc. Identify highly atypical malignant cells in groups, some forming poorly formed glandular structures. The malignant cells should be found in the sub-capsular sinuses and within the central areas of the lymph node.
Questions.
1. If the lymph node was taken from the axilla of a female patient, what is the most likely diagnosis?
2. In what part of the lymph node does metastasis first appear?
527 Cat Scratch Disease, lymph node
Cat-scratch disease is a form of mixed reactive lymphoid hyperplasia. It most frequently causes a unilateral lymphadenitis in young people, and in most cases, a history of contact, scratch or bite by a cat or other animal is present.
Macroscopical examination shows enlarged lymph nodes with the characteristic granulomatous abscess formation. There are large areas of confluent necrosis and fibrinopurulent debris (neutrophils and necrotic cellular elements). These areas of abscess formation are said to have a typical stellate (star-shaped) pattern. Around the edge of the necrosis and scattered elsewhere are granulomata which contain giant cells of the foreign body or Langhans type. Plasma cells and lymphocytes commonly surround these granulomata.
Questions.
1. What is the differential diagnosis of this entity histologically?
2. What is the etiologic agent for this entity and what special stains can be used to confirm the diagnosis?
603 Acute pancreatitis with fat necrosis
Whatever the etiology of the pancreatitis, essentially four histologic changes occur:
6. enzymatic destruction of pancreatic tissue - (? autodigestion).
7. hemorrhage
8. fat necrosis due to lipolytic enzymes
9. severe inflammatory reaction
In the example examined one can clearly differentiate areas of normal pancreatic tissue - both endocrine as well as exocrine areas. Interspersed between the intact elements are variable areas of necrosis with a heavy acute (neutrophilic) inflammatory cell infiltrate. Hemorrhage is also present. In some areas, basophilic material is present (calcifications.
Questions.
1. What enzymes are the principle culprits in the production of the tissue necrosis?
604 Adenocarcinoma of the Pancreas
The tumor is formed by malignant glandular cells of ductal origin that form irregular malignant acini. The acini vary in size and some are devoid of a lumen. Atypical hyperchromatic adenocarcinoma frequently induces a desmoplastic stromal reaction.
Prognosis : poor - 1% 5yr. survival
Questions :
1. What is the clinical presentation of this disease?
2. What does the urine look like?
3. What does the stool look like?
4. Why?
610 Helicobacter associated Gastritis
Helicobacter pylori (HP) at the present time is generally accepted to be the most common cause of chronic gastritis in Western countries. There is the general agreement that the organism damages the gastric mucosa initiating a progressive disease culminating in atrophy and intestinal metaplasia with possible association with carcinogenesis. It is also agreed that there is a close association of HP with peptic ulceration of the duodenum and stomach too.
The slide you may have, may vary from that of your neighbours as these are biopsy fragments so only a limited number of slides can be sectioned from each block. It is suggested that you exchange slides so that all features described in general are seen.
HP affects the mucosa in a diffuse fashion with identifiable curved or coma shaped bacteria in clusters in the mucous on the surface of the gastric mucosa, (search under high power in the mucous on the surface).
The lamina propria will generally show a polymorphous inflammatory cell infiltrate that will include :
1. Acute inflammatory cells - PMNs that may overrun the mucosal glands (“inflammatory exocytosis”) and even result in microabscesses in the mucosal lumina. This may even progress further to form focal areas of erosion or ulceration of the mucosa with regenerative changes in the adjacent mucosa.
2. Chronic inflammatory cell infiltration that will be shown as the formation of lymphoid aggregates (not normally found) within the lamina propria even with the formation of lymphoid follicles with germinal centres -(so-called “follicular gastritis).
The mucosal lining, depending on a range of factors, may show the features of so-called “intestinalization” or “goblet cell metaplasia”. This feature is the presence of colonic type mucosal goblet cells in the gastric mucosa. This feature is thought to be of particular importance in the progression to dysplasia.
Questions.
1. If HP organisms cannot be clearly seen on H & E stains, what specialized stains may be used to identify the organisms?
2. How would you classify “gastritis” in general terms?
611/A Candidiasis of esophagus
The specimen shows a segment of esophagus that includes only small areas of intact non-ulcerated, stratified, squamous eipthelium. Find these intact areas (which might not be present in all slides); follow these areas until large areas of ulceration of the epithelium are seen. On the ulcerated surface, under high power, identify spores and filamentous hyphae of the fungus. In-between the fungal elements, fibrin as well as small clusters of basophilic bacteria can be found. Below the ulcerated areas inflammation and granulation tissue is found. The muscular coat of the esophagus appears mostly intact.
Questions.
1. Why is the inflammatory reaction less severe than would be expected?
2. What clinical settings predispose to this type of infection?
3. What are the special stains used to identify fungi?
4. How may one identify fungi immediately from oral scrapings?
612 Chronic peptic ulcer (stomach)
The mucosal surface has an ulcerated “crater-like” lesion that extends to variable depths into the muscular coat of the stomach. The ulcerated crater has the following layers from the surface downwards :
- necrotic material on surface
- fibrin and P.M.N.’s
- granulation tissue
- inflammatory cells - lymphocytes, plasma cells and eosinophils
- fibrous scar tissue replacing the muscular coat
The margin of the ulcer shows sudden and abrupt transition to almost normal gastric mucosa with regeneration at the edges. Within the submucosa, endarteritis obliterans might also be present.
Diff. diagnosis : Ulcerated carcinoma of stomach; but here must identify malignant cells. The muscular coat is diverted towards the mucosal surface.
613 Anaplastic carcinoma of the stomach
(Prior to examining this specimen, it is advisable to revise the normal histologic layers of the stomach)
The microscopic description of “linitis plastica” corresponds to this tumor. The histologic carcinomata described as linitis plastica tend to be poorly differentiated tumors and at times can be difficult to differentiate from malignant lymphoma in the stomach. In these instances, mucin stains (P.A.S. and Alcian stains) can be of great assistance.
The secretions show a segment of stomach wall that extends and includes mucosa, lamina propria, muscularis mucosa, submucosa and the muscularis propria. The mucosal rugae are prominent and ulcerations are rare. Originating from the mucosa and infiltrating all layers of the stomach wall, are groups as well as single malignant cells. In areas the tumor may form very poorly defined glandular structures and trabecular forms. The major cell type constituting the tumor is a mucous secreting cell, described as the signet ring cell. These cells have large amounts of cytoplasmic mucous, occupying the majority of the cell and compressing the nucleus to one side, thus giving it the descriptive term.
Questions.
1. What is the prognosis of this type of tumor?
2. What does the term “early gastric carcinoma” mean?
3. What are the premalignant lesions in the stomach?
4. What is Menetrier’s disease?
614 Hemorrhagic infarction of intestine
Macroscopically, the affected bowel segment shows intense hemorrhage of the entire wall of the bowel with hemorrhagic material on the luminal surface, typically showing no evidence of peritonitis.
Microscopic examination of the segment of small bowel shows widely dilated capillaries and extravascated erythrocytes in all layers of the wall. The mucosa is necrotic and there is also marked submucosal venous dilatation. Note that the muscular coat appears viable.
Questions.
1. What is the pathogenesis of this type of lesion?
2. What are the clinical features?
615 Crohn’s Disease - ileum
Crohn’s disease, unlike ulcerative colitis, may involve any portion of the gastrointestinal tract, though it most commonly involves the terminal ileum (regional ileitis). Lengths of normal intestine separate areas of diseased intestine - so-called “skip areas”.
Histologically, areas of ulceration of the mucosa are present where an intense neutrophilic reaction is seen. In the areas where the mucosa is better preserved, the glands are dilated, goblet cells are absent or decreased in number and Paneth cells are more prominent than usual. The muscularis mucosa is hypertrophied and nerves in the involved segment are increased in number, size and prominence. Lymphoid aggregates and follicles are conspicuous in the submucosa and in the subserosa. Noncaseating tubercles, composed of epithelioid histiocytes and occasional multinucleated giant cells may be found. Deep ulcerations of the mucosa may give rise to sinus tracts. These may be followed from the ulcerated mucosa, penetrating deep into the intestinal wall and ending on the serosal surface.
It is pertinent to emphasize that the inflammatory infiltrate in this entity is transmural (c.f. ulcerative colitis).
Suggestion: Make a table comparing the different clinical, macroscopic, microscopic and complication features of ulcerative colitis vs Crohn’s Disease.
621 Ulcerative colitis, colon (U.C.)
In comparison to Crohn’s disease, ulcerative colitis affects the entire colon in the majority of cases. When a limited segment of the colon is involved, it is usually the left side.
Macroscopically, the first lesions appear as tiny erosions that later become deeper and coalesce to form linear ulcers which have the appearance of longitudinal furrows distributed in the long axis of the colon. The ulcers are often undermining, partially freeing ragged remnants of regenerating mucous membrane that is admixed with granulation tissue (pseudopolyps). In the most severe cases the entire colon is extremely friable and bleeds freely. It appears purplish red and velvety. The muscle is thickened and rigid (garden hose). Chronic U.C. is a disease of remissions and exacerbations.
Microscopically, most of the epithelial surface is ulcerated and is lined by an acute inflammatory exudate of neutrophils and debris. Where mucosa can be identified, look for the crypt abscesses that are accumulations of neutrophils in the crypts of Lieberkuhn. These abscesses tend to coalesce to form enlarging, shallow ulcers. Usually there is hyperemia, edema and hemorrhage with an inflammatory cell infiltrate of lymphocytes and plasma cell present in the lamina propria and extending to involve the muscularis mucosa. Eosinophils are frequently also found.
As compared to Crohn’s Disease Ulcerative Colitis is predominantly a mucosal disease with infrequent involvement of the layers beyond the muscularis mucosa.
Suggestion : As mentioned in the description of Crohn’s Disease, it is advisable to compile a table comparing these two entities.
623 Tubular adenoma of colon
Macro : Oval to rounded tissue mass with a stalk = polyp.
Micro : The surface of the polyp is covered by colonic mucosa with normal appearance, containing columnar cells and goblet cells. The mass of tissue forming the polyp is composed of variably sized colonic glands, some of which may be markedly dilated to form cystic structures. Between the glandular elements there is a connective tissue stroma that contains a mild neutrophilic infiltrate. The core of the stalk of the polyp contains myofibrils that are “pushed up” from the muscularis mucosa - peristaltic effect.
Questions.
1. What types of colonic polyps are there?
2. What syndromes are associated with colonic polyps?
3. What grades of dysplasia are there in colonic polyps?
4. On what criteria is dysplasia based?
624 Adenocarcinoma of the colon
* Prior to viewing this slide revise the histologic layers of the colon.
Follow the edges of the section and identify normal colonic mucosa. The colonic mucosa undergoes abrupt ulceration where the ulcerated area may be lined by fibrinopurrulent debris and sloughed off tumor cells and glands. The tumor is formed by malignant cells that form irregular glandular and tubular structures. Individual tumor cells are columnar to cuboidal in shape and show all the cytologic features of malignancy.
In some areas tumor cells form isolated “signet ring” forms and in other areas lakes of mucous may be seen (not in all sections). Note the infiltration of the tumor into the colonic wall.
Questions.
1. What is Duke’s staging of carcinoma of the colon?
2. What are the clinical symptoms and signs of colonic carcinoma?
625 Acute appendicitis
An 8 year-old boy presented a 24 hour history of right sided fosse pain and vomiting. Upon hospitalization tenderness of the abdominal wall with mild fever and leukocyte (17,500 cells/µm3) were noted. Appendectomy wasfperformed.
On macroscopical examination the serosal surface showed acute congestion and yellowish fibrinose exudate.
Macro : Cross section of a tubular structure - can be confused with the ileum of a neonate.
Micro : The mucosa of the bowel is ulcerated. Within the lumen there are fecal remnants present, sometimes occluding the entire lumen. Admixed therein are necrotic epithelial cells and neutrophils. These neutrophils are noted for infiltrating the entire wall of the appendix. Small abscesses are noted within the submucosa and muscularis mucosa (Phlegmonous inflammation). The serosal layer shows fibrinous threads with neutrophils admixed - (peritonitis).
Questions.
1. The histologic diagnosis of acute appendicitis is dependent on what microscopic finding?
2. What is a fecolith?
3. What other causes, particularly in children, are there for acute appendicitis?
627. Melanosis coli – Appendix
Melanosis coli represents the accumulation of a granular brown pigment within macrophages within the colonic mucosa, specifically within the lamina propria. Typically, melanosis coli is caused by excessive usage of laxatives of the anthracene group (cascara, sagrada, alloe, rhubarb, senna, frangula and other anthraquinone derived purgatives).
The sections present show an appendix where the layers of the wall are essentially normal apart from the accumulation of a lipofuscin-like brown pigment in macrophages within the lamina propria.
This specimen represents a further example of “pigmentation” in this case an endogenous pigment induced iatrogenically.
Melanosis coli is not thought to cause any long-term abnormalities in the bowel and the pigmentation subsides following cessation of laxative usage.
Questions:
Classify pigments into the main groups and give appropriate examples for each group.
628 Villous adenoma of the colon
Villous adenomata are of importance as they commonly contain the focus of malignant transformation to invasive adenocarcinoma. (Often polyps of the colon show more than one microscopic pattern resulting in the descriptive term of a tubulovillous adenoma).
In the pure villous adenoma, the mucosa is thrown up into finger-like projections or fronds. The mucosal cells will show stratification, decreased mucous secretion and a variable number of mitotic figures. The villi are supported by a core of fibrovascular connective tissue, in which an increased inflammatory cell infiltrate is common.
629 Pleomorphic adenoma of salivary gland
(Mixed tumor)
This is the most common tumor of the salivary glands. Most occur in the parotid gland, but can be found in other salivary glands as well as in minor glands.
Grossly the tumor is usually surrounded by a fibrous capsule of varying thickness and has an overall bosselated appearance. The tumor is typically clearly demarcated from the surrounding tissues.
Microscopically the hallmark of this lesion is the variety of patterns formed by the constituent tissue - being an admixture of epithelium and mesenchymal-like tissues. The epithelial elements take the form of ducts, sheets of spindle shaped myoepithelial cells and areas of squamous epithelium. In between these epithelial elements hyaline, myxoid or chondroid areas result. At the periphery of the tumor and usually distinctly separated from it, benign salivary gland tissue should be evident.
Questions.
1. What does the term monomorphic adenoma indicate?
2. What are the complications of this tumor, particularly when encountered in the parotid gland?
3. Classify Tumors of the salivary gland under theheadings : Benign and Malignant.
630 Squamous carcinoma of the esophagus
Grossly the tumor which is most common in the middle third of the esophagus, is an ovoid growth with its long axis parallel to the long axis of the esophagus.
Microscopically follow the stratified squamous epithelium of the intact esophagus till a region of ulceration is encountered. This ulcerated area is lined by a fibrinopurrulent exudate - (neutrophils, cellular debris and fibrin). Below this exudate, malignant squamous carcinoma can be identified. The tumor cells show the microscopic features of squamous cells and show the formation of keratin pearls. The tumor can be followed to its infiltration depth into the muscular coat of the esophagus.
Questions.
1. What are the clinical features of this tumor?
2. How is the poor prognosis related to the histologic structure of the esophagus?
650 Fatty change, liver
(Steatosis; Fatty metamorphosis)
Macroscopically the liver may appear enlarged and flabby, yellowish in color and have a greasy cut surface.
Microscopic examination shows liver tissue in which the lobular pattern is preserved. The prominent pathologic change is the swollen appearance of hepatocytes. These distended cells contain many fat vacuoles in their cytoplasm, compressing the nucleus to the periphery of the cell. In some cells, the nucleus may not be visible at all. Kuppfer cells are not affected.
Questions.
1. What is the pathogenesis of fatty change?
3. What are the causes of fatty change in the liver?
4. In which other organs does fatty change occur and what are the causes?
5. What is meant by the term fatty infiltration?
652 Chronic passive congestion of liver
This is seen most commonly in cases of right-sided heart failure or more rarely in hepatic vein or inferior vena caval obstruction.
Macroscopic examination of the liver usually shows an enlarged bloody liver. On cut surface the central veins appear red surrounded by yellowish-brown uncongested liver, resembling the cut surface of a nutmeg - the so-called nutmeg liver.
Microscopic examination shows accumulation of blood with marked congestion in the central veins and extending into the hepatic sinusoids. The hepatocytes in the congested area are atrophic or necrotic. In the mid-lobular and peripheral areas of the liver lobules the sinusoids are less dilated and hepatocytes are unaffected. The portal tracts are normal.
Questions.
1. What do you understand by the term “cardiac sclerosis”?
2. What is the Budd-Chiari syndrome?
656 Viral hepatitis
The lobular pattern is distorted due to irregular patches of necrosis. The necrosis may be centered within the parenchyma or be more extensive, bridging the central to portal tracts and portal to portal tracts. Panacinar necrosis can also occur. In the region of necrosis, necrotic hepatocytes with pyknotic nuclei are noted. An inflammatory infiltrate of P.M.N. s, histiocytes, lymphocytes and plasma cells may be present in the area of necrosis. Isolated large acidophilic (hyaline) cells without nuclei or with a pyknotic nucleus may be found - Councilman bodies. In the less affected areas, or at the edges of the necrotic areas, hepatocytes appear swollen and have a granular eosinophilic cytoplasm. Others show hydropic change with cytoplasmic vacuoles of variable size -Ballooning degeneration. Binucleated or multinucleated hepatocytes, indicative of regenerating hepatocytes are also noted. Kupffer cells are enlarged and contain bile pigment (yellow) or formalin pigment (black granules). The portal tracts show proliferation of small bile ducts with cholestasis and a periportal infiltrate of lymphocytes, P.M.N.s, plasma cells and histiocytes.
659 Postnecrotic cirrhosis : Liver
Macro : Nodules of tissue of varying size (some > 1cm in diameter) separated by fibrotic bands.
Micro : Normal liver architecture is distorted with the formation of nodules of liver tissue separated by broad bands of fibrous tissue. Within the nodules of liver tissue, normal hepatocytes are noted. The fibrous bands which link up portal tract to portal tract contain proliferating small bile ducts, blood vessels and a lymphocytic inflammatory cell infiltrate. These nodules of liver tissue are referred to as regenerative nodules. Isolated clusters of abnormal hepatocytes with granular cytoplasm and multinucleation may still be identified indicating active regeneration.
Incidental finding : Fatty change - (previous or ongoing damage)
Diff. diagnosis : Nutritional cirrhosis
660/A Hemachromatosis, liver (& Prussian blue stain).
A 58 year-old man who suffered for years from diabetes, bronze pigmentation of skin and hepatomegaly (“bronze diabetes”), developed ascites and died of cardiac failure.
Full blown hemochromatosis is characterized by a triad of pigment cirrhosis, diabetes and skin pigmentation (hence the old term “bronze diabetes).
Morphologically hemachromatosis shows pigment cirrhosis (hemosiderin) of the liver and systemic hemosiderin, involving pancreas, endocrine glands, myocardium, skin and any other parenchymal organ.
In the liver, the involvement varies from delicate fibrous scarring around portal tracts to the full blown picture of thick bands of fibrous tissue resulting in cirrhosis.
The cirrhotic liver, macroscopically, shows a nodularity with nodules that vary in diameter from several millimetres to 1cm and are of similar size to those encountered in alcoholic cirrhosis.
Microscopic features show liver architecture distorted and obliterated by broad bands of fibrous tissue that bridge portal tract to portal tract. As a result, regenerative pseudolobules of liver tissue appear, circumscribed by the dense fibrous tissue. These pseudolobules are devoid of central veins. Within the fibrous connective tissue, numerous hemosiderin-laden macrophages (siderophages) are noted. The iron deposits are also noted within hepatocytes as well as within Kuppfer cells.
Note : Compare these features of pigment cirrhosis with the slides 659 and 664 where cirrhosis is also present.
661 Hepatocellular carcinoma
The two main primary tumors arising in the liver are :-
1. Hepatocellular carcinoma - tumor arising from hepatocytes.
2. Cholangiocarcinoma - tumor arising from bile duct epithelium.
This example is of hepatocellular carcinoma. It is advisable to revise the etiology and clinical features of this tumor type.
Macroscopically these tumors arise as nodular growths that may even be multifocal. The liver is often the seat of advanced cirrhosis. The right lobe is more commonly involved and often bulges out beneath the Glisson’s capsule, these nodules being much softer to palpation than are areas of nodular regeneration.
Microscopic examination shows a tumor composed of malignant cells with a close morphologic resemblance to normal liver cells. The individual cells have large, round, hyperchromatic nuclei and abundant granular eosinophilic cytoplasm. They tend to arrange themselves in cords or trabeculi two to eight cells wide. There is a capillary stroma in-between the tumor cells. The excess (desmoplastic) connective tissue stroma, so often present in adenocarcinomata (e.g. pancreas, breast), is absent in this entity. The function of hepatocytes is often maintained by tumor cells and, therefore, bile, fat and glycogen is found in the cytoplasm of the tumor cells.
Questions:
1. What is the most common tumor in the liver?
2. In small biopsy specimens when one is unsure of the diagnosis, what features are suggestive of the lesion being a primary hepatocellular carcinoma?
3. What specialized stains could be used in equivocal cases?
662 Acute and chronic phlegmonous cholecystitis
(Definition: Phlegmon: - Acute suppurative inflammation of connective tissue)
Microscopic examination shows a distorted gall bladder which will only show an intact mucosa focally. Follow the mucosa to where it is interrupted by acute ulceration. The surface will be covered by fibrino-purulent debris. Below the ulcerated area there is marked infiltration of the gall bladder wall, (lamina propria and muscularis), by inflammatory cells that include both acute and chronic inflammatory cells. The inflammation is noted to extend into the connective tissue external to the muscular layer. Irregular areas of fibrosis also distorts the lamina propria and muscular layers. Aschoff-Rokitnasky sinuses may be present.
Questions:
1. What is the etiology of cholecystitis?
2. What is meant by the term “porcelain gall bladder” and what is its significance?
3. What is cholesterolosis and the “strawberry gall bladder”?
4. What is the typical clinical setting of inflammation of the gall bladder?
664/A Laennec’s cirrhosis (nutritional or alcoholic cirrhosis)
This is the end stage in the progression of alcoholic liver disease. This morphologic pattern in the alcoholic patient is a result of continual encroachment of collagen fibers into regenerating nodules that proliferate most exuberantly during periods of improved nutrition and cessation of alcoholic intake. The outcome is a cirrhotic liver usually made up of poorly defined, irregularly sized nodules with thin collagen fibers insinuated between hepatocytes.
Microscopic examination of the tissue shows obliteration of the normal lobular architecture of the liver. Small, irregular islands of liver cells are noted that are surrounded by thick bands of collagenous connective tissue. These nodules of liver cells do not represent normal liver lobules. As can be seen on close examination, they lack the presence of central veins and are not associated with portal tracts. These are, therefore, pseudolobules or regenerating lobules. Although fatty change may still be present (indicating ongoing alcoholic abuse) other examples may not show fatty change (indicating cessation of intake). Focal areas of cholestasis and inflammatory cell infiltration may be found. Small bile ducts can be found and often there is a proliferation thereof.
Questions:
1. What are the signs of portal hypertension?
2. What are the complications of cirrhosis?
3. What other causes of cirrhosis are there?
703 Amyloidosis kidney
(Review slide 510)
A 73 year-old man suffered from heavy proteinuria, hypoalbuminemia and edema (chronic renal failure) and died of myocardial infarct. At autopsy the kidney was slightly enlarged but firm with a pale, waxy appearance. On section a blurring of thecortico-medullary junction typical of amyloidosis was seen
Macroscopically the kidneys are usually pale and enlarged.
Microscopic examination shows involvement of the glomeruli that first appears in the mesangium. The deposits of amyloid are nodular and expansive, ultimately compressing and collapsing the capillaries.
Examine the glomeruli : Amyloid is unevenly distributed and in some, almost the entire glomerulus is replaced by amyloid.
Examine blood vessels : Amyloid is deposited along capillary walls as well as in afferent arterioles and media of arcuate arteries.
704 Lupus Erythematosis, kidney (S.L.E.)
S.L.E. involves the kidney in 60-70% of cases. The renal glomeruli are the prime site of injury in this disease. Acute renal injury tends to correlate with systemic evidence of clinical activity : fever, hypertension, rashes and high titres of antibodies.
Microscopic examination shows hypercellularity of glomerular lobules associated with” fibrinoid” necrosis and nuclear karyorrhexis. The fibrinoid immune complex material is deposited as a thick coat in the mesangium and inside the glomerular basement membranes producing the thick-walled capillary loops - the so-called “wire loops”. Other glomeruli show a diffuse proliferative pattern with “crescent formation”. These crescents represent proliferation of parietal epithelium from the Bowman capsule that fill the glomerular space, sometimes forming adhesions with the glomerular tuft. The interstitium often shows a lymphocytic inflammatory cell infiltrate.
706 Recent infarct, kidney
Examination of the slide using the naked eye shows two distinct areas :
1. the central area, being wedge shaped - the area of infarction
2. the areas around it representing intact renal parenchyma
Microscopic examination shows a central area of infarction bordered clearly by normal renal tissue. The infarcted area shows shadows of glomeruli that are still clearly identifiable. The tubular epithelium is eosinophilic and nuclei are barely recognized. At the border between the normal and infarcted areas, neutrophilic infiltration is present.
708 Diabetic kidney
In diabetes mellitus, glomeruli, arterioles and tubules are directly involved. Indirect effects include an increased incidence of pyelonephritis, necrotizing papillitis and atherosclerosis of muscular arteries (e.g. arcuate vessels). There are four main glomerular changes with nodular glomerulosclerosis - as the pathognomonic lesion of D.M.
1. Diffuse glomerulosclerosis : not limited to diabetics; comprises an overall thickening of the basement membranes of the capillaries throughout their entire length, associated with the proliferation of mesangial cells and deposition of excess amounts of mesangial matrix (which is P.A.S.+). Eventually the entire glomerular tuft undergoes sclerosis.
2. Nodular glomerulosclerosis - (intercapillary glomerulosclerosis = Kimmelstiel Wilson Disease) . The glomerular lesions take on the form of ovoid or spherical, often laminated, hyaline masses situated at the periphery of the vascular tufts.
3&4. Exudative lesions : (fibrin caps and capsular drops). These are deeply eosinophilic, P.A.S. positive, crescentic deposits at the periphery of the glomerular tuft that on high power is seen to lie trapped between endothelial cells and basement membrane of the visceral epithelial cells.
Another finding which may be sought in the tubular epithelial cells is the accumulation of glycogen - giving rise to glycogen nephrosis or the Armanni Ebstein lesion
Interstitial inflammation in the specimen and atherosclerotic changes within the blood vessels may also be present but are not pathognomonic for D.M.
711 Acute, diffuse, proliferative glomerulonephritis
(Post-streptococcal glomerulonephritis)
Although many causes are known to be involved with this renal entity, the most common cause is streptococcal infection. This is an example of such a case.
Glomeruli appear large and the lobular structure thereof appears slightly accentuated. All glomeruli are hypercellular due to proliferation of endothelial cells and mesangial cells. P.M.N. infiltrate is present in glomerular tuft and Bowman’s capsule.
Incidental finding : Vascular congestion in the medulla
Hyalinised glomeruli
Intimal fibrosis of medium sized arteries
712 Rapidly progressive glomerulonephritis
(Sub-acute glomerulonephritis)
Glomeruli are hypercellular and show varying degrees of proliferation of endothelial and mesangial cells resulting in disorganization of the normal glomerular structure. The proliferative process affects both the visceral epithelium and the capsular layer. There is fibrosis and variable adhesions between the capsular epithelium and the glomerular epithelium. The proliferative lesions appear as crescents that obscure the glomerulus. There is periglomerular, concentric fibrosis with a PMN infiltrate. The tubuli mostly appear normal but some may appear atrophic. These atrophic tubuli contain intracytoplasmic granules (protein). The tubular lamina are filled with hyaline casts. Some tubuli may have basophilic cytoplasm, indicating regeneration. The interstitium is expanded and may also show a white cell infiltrate.
713 End stage kidney
(following chronic glomerulonephritis)
The lobular structure of the glomeruli is recognizable. Some glomeruli are enlarged and congested and have variable degrees of adhesions to the capsule. Other glomeruli are hyalinized almost entirely and the thickened capsule is surrounded by concentric fibrosis. Tubuli show atrophic epithelium with enlarged lumina and hyaline casts therein. The interstitium is thickened and expanded and has a lymphocytic infiltrate.
Incidental finding : Arteries show intimal fibrosis and medial hypertrophy - (reflecting superimposed arterial hypertension).
Diff. diagnosis : Vascular contracted kidney
716 Chronic pyelonephritis
Macro : “U” shaped cortical scars on surface of kidney being the indented, retracted area corresponding with the inflammatory process.
Micro : The glomeruli may appear quite normal or may show variable degrees of hyalinization and sclerosis. The hyalinized glomeruli are those which are in association with the interstitial process. The interstitium of the cortex shows dense interstitial inflammation consisting of chronic inflammatory cells. Lymphoid aggregates may be seen forming lymphoid follicles. Arcuate and interlobular blood vessels disclose obliterative endarteritis in the scarred areas within the interstitium. The tubules show atrophy in some areas and dilatation of their lumina is common. The dilated tubules may be filled with colloid casts, a pattern referred to as thyroidization.
719 Renal cell carcinoma (Hypernephroma; Grawitz tumor)
“Clear Cell Carcinoma”
Macro : Tumor mass present adjacent to compressed uninvolved kidney.
Micro : The tumor cells are large and polygonal and typically have a clear cytoplasm. Other tumor cells may have an eosinophilic granular cytoplasm. The nuclei of the tumor cells are typically central, small and round. The cytoplasm of the clear cells (glycogen “washed out” during tissue processing) may also contain lipid droplets. Tumor cells have distinct cell membranes and have an overall “plant-like” pattern. Other variants of tumor cells are common - a glandular pattern with tumor cells arranged in nests and rows. A sarcomatous pattern is also common wherever tumor cells are spindle shaped and occur in a desmoplastic stroma.
Note large vascular supply and hemorrhage in the tumor.
Questions:
1. Name some common and some rarer ways that this tumor may present.
2. What has this tumor got a tendency to infiltrate into?
3. What do you understand by the term “renal cell adenoma”? Is there such an entity?
722 Transitional cell carcinoma of the bladder
This tumor type appears as single or multiple, finely fronded, papillary or sessile structures within the bladder. The tumors may occur anywhere within the bladder urothelium but have a predilection for the trigone, the ureteral orifices and the posterolateral walls.
Microscopic examination of the tumor shows an epithelial tumor composed of finger-like papillary structures with a delicate vascular stalk. The multilayered epithelium has a resemblance to the normal epithelium of the urinary tract, but the most obvious feature present is the increase in cell numbers and the multilayered appearance. (It is pertinent to remember that the normal urothelium consists of up to 7 cells in thickness).
The tumor cells within the papillary structures are atypical. Most have large hyperchromatic nuclei and nucleoli. There is still a degree of surface maturation of the urothelial cells forming somewhat triangular cells at the surface.
To fully assess a bladder tumor one needs to determine four specific features :
1. Pattern of growth - (e.g. Papillary or solid)
2. Cell type - Transitional, squamous - metaplastic or malignant, and adenocarcinoma
3. Degree of differentiation = Grade
This grading description depends on how closely the tumor resembles the normal, benign urothelium. This is usually described as Grade 1, 2 or 3. The example present in this example corresponds to a grade -2 tumor.
4. Depth of invasion of the bladder wall = Stage.
Questions:
1. What are the proliferative and metaplastic lesions of the bladder?
2. In what setting is squamous carcinoma of the bladder most common?
723 Schistosomiasis, bladder (Bilharziasis)
A review of the life cycle of Bilharzia is in order to place the features in this slide into perspective.
Ova passed in urine (S. haematobium) ( into water ( free swimming miracidia(penetration into freshwater snails ( numerous cercariae are liberated from the mollusk( enter through intact skin (“swimmer’s itch) ( lymphatics ( regional lymph nodes ( pulmonary circuit( systemic circulation ( intrahepatic portal veins ( male and female worms mature - travel into mesenteric plexuses and female deposits ova ( urinary bladder submucosa.
Microscopic examination shows abundant ova within the lamina propria of the bladder wall. The adjacent mucosa may appear thickened and hyperplastic. Foci of squamous metaplasia may be seen in the mucosa. The ova occur in granulomata surrounded by fibroblasts and many eosinophils.
Questions:
1. How can one differentiate between the various species of Schistosomiasis, using the morphology of the ova?
2. What are the long term complications of S. Haematobium in the bladder?
3. What is Loeffler’s syndrome?
724 Seminoma of the testis
These tumors constitute the most common germ cell tumor of the testis and occur at a peak incidence in the young male between ages of 15 and 35.
The tumor usually causes a painless enlargement of one testis, causing a unilateral often very large mass that may reach several times the size of the normal testis.
Macroscopically the typical seminoma consists of a homogenous grey-tan tumor mass that if not totally replacing the testicular stroma, compresses the non-neoplastic testicular stroma to one side. The typical seminoma is uniformly tan and fleshy and shows very little hemorrhage and necrosis (compared to other germ cell tumors).
Microscopically the tumor in the typical form consists of uniform large polyhedral tumor cells with clear cell borders and often watery clear cytoplasm with prominent nuclei and one to several very prominent eosinopnilic nucleoli.
Mitotic activity is variable from one tumor to the next but in all typical seminomas the tumor cells are grouped into large lobular aggregates, separated by delicate fibrovascular trabeculae or septae that classically show a prominent lymphocytic inflammatory cell infiltration.
Questions:
1. Classify the tumors of the testis into the main groups.
2. How many forms of seminoma are there?
3. Which are they?
4. What are the main differences with regards to age incidence, clinical presentation, biochemical markers, macroscopic appearance and microscopic appearance between seminoma and embryonal carcinoma of the testis.
5. What biochemical markers are used to diagnose and monitor testicular neoplasms?
6. Which markers are used for which tumor?
7. What are the most important predisposing factors in the development of testicular malignancies?
726 Adenomatous hyperplasia of the prostate
(Benign prostatic hyperplasia)
A 71 year-old man who complained of nocturia, dysuria and dribbling at the end of micturition. On digital palpation per rectum a large, tender but symmetrical enlargement of the gland was detected. Retropubic prostatectomy was performed.
Macro: The prostate wieghed 150gr (normal 20-30gr in adult patients) and measured 8x6x5cm. In transverse section multiple well circumscribed, solid nodules of varying sizes are seen.
The normal prostate weighs ± 20gr. The enlarged prostate can weight up to 4-5 times the normal.
Note: Prostatic hyperplasia occurs in the inner zone of the prostate, whereas carcinoma is usually found in the outer portion.
Macroscopically, the prostate is enlarged and often nodular. On section, the nodularity may be seen as several smaller to larger gray-white nodules of firm rubbery tissue. Cystic areas are common. These nodules usually represent the hyperplastic glandular areas and are surrounded by firm, pearly white stromal tissue, representing the hypertrophic fibromuscular stromal tissue.
Microscopic examination. The classic pattern of benign prostatic hyperplasia is due to changes in both the glandular elements as well as in the fibromuscular stroma. The glandular elements show hyperplasia as indicated by marked proliferation of the acini forming a “back-to-back” pattern of crowded glands. Many of the glands show infoldings of the columnar epithelium forming papillary structures. Note that the epithelium is usually vacuolated with basal nuclei and has a distinct myoepithelial layer at the periphery. Centrally, in the lumina of some glands, inspissated secretion may be found as eosinophilic corpora amylaceae. Usually, there is a moderately severe chronic inflammatory cell presence (lymphocytes) around the glandular structures.
The fibromuscular stroma shows hypertrophy as indicated by an increased amount of fibrous tissue in-between stellate and spindle shaped stromal cells (fibroblasts as well as smooth muscle cells).
Questions:
1. What are the clinical features of prostatic disease? (see slide 727)
2. Is this condition regarded as premalignant?
727 Adenocarcinoma of the prostate
The tumor is composed of small, crowded acini with empty lumina, lined by a single layer of cells. The acini lack a peripheral myoepithelial cell layer. The tumor cells are low columnar to cuboidal cells and have hyperchromatic or clear nuclei with nucleoli visible. Clusters of tumor cells are noted to infiltrate into the stromal tissue which may contain a lymphocytic infiltrate. Tumorous areas can be seen abutting onto adjacent zones of benign prostatic hypertrophy.
Questions:
1. What are the clinical features of prostatic disease?
2. What laboratory tests are screening tests of prostatic disease?
3. Where does prostatic carcinoma spread to?
4. What is the system used internationally in grading this tumor?
732 Rejected kidney, (acute phase)
The renal capsule is thickened and edematous with foci of hemorrhage. There is almost universal affectation of nephrons with cystic dilatation of the space of Bowman. The glomerular tufts are atrophic as too are the tubuli. The tubular epithelial cells show hydropic changes and pyknotic nuclei. The tubular lumina contain hyaline casts and desquamated epithelial cells. There is edema and hemorrhage in the interstitium with an inflammatory cell infiltrate of many neutrophils, as well as lymphocytes, plasma cells and macrophages. Surrounding medullary blood vessels, a neutrophilic infiltrate is also seen. These vessels may be occluded by thrombus. The muscular media of some arterioles may show fibrinoid necrosis.
Some glomeruli show crescent formation, indicating proliferative glomerulonephritis - unrelated to the rejection process, but related to the original underlying disorder that caused the original renal failure in this patient.
751 Carcinoma in situ - cervix
Prior to examination of this slide, a review of the normal histology of the cervix is in order.
The cervix is divided histologically into ectocervix, (stratified, non-keratinizing squamous epithelium) endocervix (single layer of columnar, mucous secreting epithelium) and an abrupt transitional zone between the two. Nabothian follicles represent dilated cystic structures in the endocervical canal and at the transitional zone.
The staging of cervical intra-epithelial neoplasia (C.I.N.) is as follows :
C.I.N. - 1. Undifferentiated dysplastic cells involve the lower 1/3 of the thickness of the squamous epithelium.
2. Dysplatic cells involve the lower third and middle third (2/3) of the squamous epithelium.
3. Undifferentiated dysplastic cells involve all layers of the cervical epithelium.
Microscopic examination of the slide shows an example of C.I.N.-3 that, in this case, is synonymous with carcinoma in situ. Identify the endocervix, transitional zone and focus on the ectocervical epithelium. This epithelium shows basophilic pleomorphic cells that occupy the entire thickness of the epithelium. Mitotic figures are noted in all layers of the epithelium. There is no evidence of surface maturation of the cells composing this area. Note that the basal lamina is intact. The stromal tissue has a lymphocytic inflammatory cell infiltrate. The same dysplastic cells noted on the surface of the epithelium may be found within endocervical glands, and do not indicate invasion of the stromal tissue.
Questions:
1. What conditions are thought to predispose to C.I.N.?
2. What simple tests are used to screen for cervical pathology?
752 Dermoid cyst of the ovary (Benign cystic teratoma)
Definition: Teratomas are tumors composed of recognizable tissues of ectodermal, mesodermal and endodermal origin in any combination. They are common and usually benign. They are of germ cell origin.
Macroscopically these lesions vary in size but are usually unilocular and lined by a firm fibrous capsule. The lumen is usually filled with desquamated keratin that forms a mass of yellow cheese-like material admixed with masses of hair. Calcified areas, bone as well as teeth, may be present. If a remnant of ovarian tissue is present, it is usually compressed to the periphery of the cystic mass.
Microscopic examination of the slide shows a section of the cyst wall which is lined by stratified keratinizing epithelium as would be seen in normal skin. Below the epithelium, sebaceous glands, apocrine glands and hair follicles are seen. In some slides respiratory type or gastro-intestinal type of epithelium is noted. In some slides neural elements may also be seen.
Questions:
1. What is struma ovarii?
753 Mucinous cystadenoma of ovary
This is an example of one of the common epithelial tumors of the ovary. These tumors are typically unilocular or multilocular cystic masses. These cystic masses can attain great size.
Microscopic examination shows glandular spaces that are lined by tall columnar cells with basal nuclei and large apical mucin vacuoles. The epithelium rests on a thin connective tissue stroma. There is no stratification or mitotic activity in the mucin secreting cells.
Questions:
1. What is the classification of mucinous tumors of the ovary?
2. What does the term “pseudomyxoma peritonei” mean?
3. What is Meig’s syndrome?
754 Papillary serous cystadenoma of the ovary
&
755 Papillary serous cystadenocarcinoma of the ovary
These tumors represent common epithelial tumors of the ovaries. In the same specimen an example of the two extremes of the spectrum of this tumor type are given.
Serous cystadenoma : These cysts form single or multiple loculations lined by low columnar epithelium which is sometimes ciliated, (thus resembling epithelium of the Fallopian tube). The cyst fluid is watery or viscous. Papillary processes are common and may be numerous and complicated. It is common to find calcific concretions - “psammoma bodies”- in the stroma of the papillary processes. The single epithelial lining shows no stratification or mitotic activity and lines a fibrous stroma.
Serous cystadenocarcinoma : Again this tumor may be formed by single or multiple locules lined by columnar epithelium. The epithelium is, however, highly atypical and shows stratification, mitotic activity and evidence of invasion by tumor cells into the fibrous stroma. Psammoma bodies may also be detected.
Questions:
1. In what other conditions are psammoma bodies identified?
2. What tumor markers are used in the diagnosis of ovarian tumors?
756 Chronic salpingitis
The naked eye appearance of the slide shows a tubular structure with a thick muscular wall and a central folded lumen.
Microscopic examination shows areas of normal mucosal folds of the Fallopian tube lined by ciliated columnar epithelium. Some of the cells appear more flattened and are devoid of cilia. In some areas, the mucosal folds appear fused together forming pseudoglandular formations. In the submucosa, there is an infiltrate of lymphocytes as well as neutrophils. This inflammatory infiltrate is noted to extend into the muscular coat and even onto the serosal aspect. In some areas, the aggregates of lymphocytes forming lymphoid follicles may be seen. Serosal blood vessels are congested.
Questions:
1. What do you understand by the clinical term - pelvic inflammatory disease?
2. What is salpingitis istimica nodosa?
3. What do the terms pyosalpinx, hematosalpinx and hydrosalpinx mean?
762 Glandular cystic hyperplasia of endometrium
(Mild or simple hyperplasia)
Macro : Tissue fragments admixed with hemorrhage - curettage specimen.
Micro : Endometrial glands are increased in number as well as showing marked variation in their size. Some may appear of normal size but there are glands that are cystically dilated and dispersed within a compact, tightly packed stroma. This pattern of stroma and dilated glands give the overall pattern referred to as “Swiss-cheese”. Glandular lining cells are columnar and may show mitotic activity.
Questions:
1. Classify the hyperplasia of the endometrium.
763 Leiomyoma of uterus
Benign tumor of myometrium composed of fascicles, irregular whorls and rows of benign smooth muscle cells. The typical smooth muscle cells are spindle shaped and tapering and contain a central “cigar” shaped nucleus. Interspersed in between the muscle cells there is a variable amount of collagenous connective tissue. Mucinous degeneration, necrosis and calcification may be seen.
Questions:
1. What are the complications of leiomyomata of the uterus?
764 Adenocarcinoma of endometrium
Macro : Area of tumor appearing nodular within endometrium and myometrium.
Micro : A tumor composed of glandular structures showing component cells with all the features of malignancy. The cells are hyperchromatic, show loss of polarity and frequent mitoses. Areas of necrosis of the tumor may be seen. The most superficial layers are friable and appear to be breaking down. Variable areas of infiltration by the tumor into the myometrium are noted.
Questions: :
1. In what clinical setting is this lesion common?
2. Name the “variations” on the theme of adenocarcinomata of the endometrium.
3. What is the most important determining factor in the prognosis ?
766 Squamous cell carcinoma of the cervix
Review slide 751 - Carcinoma in situ of the cervix and revise the histologic features of the cervix.
Identify the ectocervical, endocervical and transitional zone on the slide. In some of the slides, residual carcinoma in situ may be found in the ectocervical epithelium that lines the specimen. Note how in this slide (cf. 751) nests of malignant squamous cells are noted to have infiltrated and penetrated throughout the basement membrane into the cervical fibromuscular stromal tissue. The tumor is composed of irregular nests of squamous cells showing evidence of central keratohyalin production (pearls). The squamous nature of the cells can further be identified by the presence of desmosomes. Note the marked pleomorphism and mitotic activity of the tumor cells.
Questions:
1. What other tumors are found in the cervix?
2. How is cervical carcinoma staged?
767 Products of conception
Macro : Fragments of tissue admixed with blood clot.
Micro : The tissue fragments present correspond to tissue from
1. the maternal endometrium
2. the foetal placenta.
The maternal tissue is composed of decidual tissue. This tissue shows large polygonal stromal cells with well defined borders, round central nuclei and abundant eosinophilic cytoplasm. Endometrial glands admixed in this area show marked secretory activity (vacuolation of cytoplasma). The glands are stellate in shape and are referred to by the descriptive term of Arias Stella.
The foetal placental tissue is composed of chorionic villi . The villi are composed of :
(a) Outer layer of multinucleated cells with no visible cellular borders - syncitiotrophoblast. In some areas these cells form a conglomeration referred to as a syncitial knot.
(b) Inner layer of cells with distinct cellular border - cytotrophoblast.
(c) Stroma of the chorionic villi is a loose connective tissue network which contains primitive mesenchymal cells, Hofbauer cells and small blood vessels containing nucleated foetal erythrocytes.
Questions :
What do you understand by the terms .....
1. Missed abortion
2. Blighted ovum
3. Incomplete abortion
4. Inevitable abortion
5. Habitual abortion
6. Threatened abortion
768 Hydatidiform mole, placenta
A hydatidiform mole is actually a placenta composed entirely of immensely swollen chorionic villi. Macroscopically the villi appear as grape-like structures of varying sizes, often enabling macroscopic diagnosis.
Microscopic examination shows markedly swollen and edematous chorionic villi that show abundant hyperplasia of syncitiotrophoblast, cytotrophoblast or both elements. Large anaplastic looking nuclei are often present simulating a malignant neoplasm. The villi are devoid of central vascular spaces. Often internalization of the epithelial elements is noted forming secondary lumina within edematous villi.
Questions :
1. What biochemical markers are used to monitor pregnancy and what are the findings in a molar pregnancy?
2. What do the following terms mean?
(a) Incomplete hydatidiform mole
(b) Invasive mole
3. What tumor complicates a hydatidiform mole?
4. What is the incidence of this complication?
5. Where does this tumor spread to and how is it treated?
802. Multiple colloid adenomatous goiter of thyroid
(Nodular colloid goiter)
The variably sized nodules present in the thyroid tissue comprise small and large acini filled by colloid. The follicle lining cells appear tapered and flattened. Some acini are compressed and have an empty lumen. The crowded acini are grouped in a back-to-back fashion. In-between the nodules there is variable amounts of connective tissue conferring the nodular pattern to the thyroid. Secondary degenerative changes due to hypoxia are reflected by extensive fibrosis. Areas of hemorrhage and hemosiderin pigment (indicating old hemorrhage) are seen.
Questions :
1. What is Plummer’s syndrome?
803 Hashimoto’s thyroiditis (diffuse lymphocytic thyroiditis)
This entity is characterized by thyroid enlargement, lymphocytic infiltration of the gland and occurrence of thyroid autoantibodies. The disease is common in women, especially around menopause. It is an autoimmune disease that is immunologically closely related to Grave’s disease - HLA-DR5 related.
Macroscopically the thyroid is enlarged (40-50gr) and is firm and rubbery.
Microscopic examination has the most prominent feature of a very marked lymphocytic infiltrate in the thyroid gland with the formation of lymphoid follicles with germinal centres. The thyroid gland may be so heavily infiltrated as to almost efface all recognizable normal thyroid follicles. The follicles that can be discerned are generally small and are often devoid of colloid. The epithelial cells have an abundant oxyphilic and faintly granular cytoplasm (Ashkenazy cells, oxyphilic cells or Hurthle cells). In most cases there is fibrosis of the septae and evidence of recent and old hemorrhage (hemosiderin laden macrophages). Foci of squamous metaplasia may also be found.
Questions :
1. What serious complications are there of this entity?
805 Papillary carcinoma of thyroid
Acini are present, some with colloid and some without colloid. In the dilated acini papillary finger-like projections are noted. The cells lining the papillae are atypical, tall and cuboidal in form. Nuclei are large and ovoid with central clearing -referred to as “Orphan Annie” nuclei. Some nuclei have grooves giving them a “coffee bean” appearance. Spherical calclified bodies with a concentric pattern of calcification - Psammoma bodies are noted. A fine connective tissue stroma present confers a lobular pattern on the specimen.
Questions :
1. Which other tumors show Psammoma bodies?
2. How does this tumor type spread?
806 Follicular carcinoma, thyroid
This tumor comprises ± 25% of all thyroid tumors, most found in middle aged female patients. Regional lymph node metastases are rare whereas distant metastases are common (cf. papillary carcinoma).
Macroscopically follicular carcinoma is usually circumscribed and macroscopically resembles an adenoma. It is usually surrounded by a fibrous capsule.
Microscopic examination shows a tumor of the thyroid comprised of a follicular arrangement of cuboidal cells. This tumor mass is surrounded by a fibrous capsule and peripherally by normal thyroid gland tissue. The follicular tumor shows a closely packed arrangement of follicles with very little or no central lumina with colloid. From a purely histologic basis, the differentiation between a follicular adenoma and a carcinoma may be exceedingly difficult and depends on extensive sampling of the tissue and identification of vascular and/or capsular invasion by tumor cells.
807 Medullary carcinoma of thyroid
Tumor cells show markedly variable morphology from tumor to tumor. The tumor presents as sheets and nests of neoplastic cells separated by an amyloid containing stroma. Occasionally the stroma might be calcified. The individual tumor cells might be polygonal with faintly eosinophilic cytoplasm, or in other instances, the cells may be spindle-shaped and sometimes even may form glandular structures resembling a carcinoid. Bizarre, extremely anaplastic tumors may also occur.
812 Parathyroid Adenoma
The slide shows an encapsulated proliferation of glandular elements of the parathyroid, with total absence of interspersed adipocytes. Cellular atypia is totally absent.
Peripherally to the primary lesion (adenoma) normal parathyroid tissue is present that shows the intermingled pattern of parathyroid glandular tissue and adipocytes.
Questions :
1. Classify the forms of hyperparathyroidism.
2. What lesions occur in the bones associated with hyperparathyroidism?
3. How do patients with hyperparathyroidism present?
4. Which familial diseases are associated with hyperparathyroidism?
833 Pheochromocytoma of adrenal
Normal adrenal tissue is not present and therefore tissue of origin cannot be stated.
The tumor comprises markedly pleomorphic cells showing marked variation in size and shape. Amphophilic abundant cytoplasm is the rule and the cells contain pleomorphic vesicular nuclei with multinucleated cells as well. The presence of intracytoplasmic granules gives the chromatin reaction. Mitotic figures are very, very occasional. In-between tumor cells there is a fine fibrous stroma with numerous branching capillaries and evidence of recent and old hemorrhage (hemosiderin).
Questions :
1. What are the possible sites where such a lesion can be situated?
2. How could you “tie up” slides 801 and 833 in one patient?
862 Fibroadenoma of the breast
This is a benign tumor of the breast with its peak incidence during the productive period and most common in women younger than 30 years old. It is the most common cause of a breast mass in a woman under 30 years of age. Clinically, fibroadenomas are usually well circumscribed, mobile masses in the breast tissue - (“breast mouse”).
Microscopically the tumor shows anastomosing, epithelial lined ducts compressed into slit-like spaces by proliferation of surrounding connective tissue. Stromal cells show no pleomorphism or mitoses. In some areas the ductal elements may show piling up of epithelial cells with focal papillary structures. The tumor is surrounded by a fibrous capsule.
Questions :
1. What is a cystosarcoma phyllodes?
863 Fibrocystic mastopathy of breast
(Cystic mastopathy, fibrocystic disease of breast)
The changes in the breast tissue vary from case to case but include the following :
1. Fibrosis : Dense connective tissue replaces the stromal tissue of the breast. The connective tissue is hypocellular and collagenous.
2. Cystic change : The ductules show a varying degree of cystic dilatation. Some of the “cysts” are lined by tapered and flattened cells. The normal bi-layered nature of the epithelium is still maintained.
3. Apocrine metaplasia : Within smaller “cystic” areas cells with a marked eosinophilic cytoplasm are noted. These cells show apical snouts - referred to as decapitation secretion.
4. Adenosis : There are hypoplastic changes in the lobules with an increased number of lobules in focal areas.
5. Epitheliosis: (England) Hyperplasia (USA). The epithelium of the ducts and acini show piling up of cells referred to as epitheliosis. The epitheliosis can be of three sub-types :-
(a) Solid ducts filled to varying degrees by polygonal cells
(b) Papillary intraductal projections
(c) Cribriform intra-acinar pattern without stroma.
Questions :
1.What portions of fibrocystic mastopathy are thought to have possible association with malignancy?
864 Infiltrating duct carcinoma of the breast
In order to place this entity within the correct perspective, it is advised to revise the classification of carcinoma of the breast.
1. Ductal carcinoma
(a) intraduct & (Comedo carcinoma as one variant) = in-situ
(b) infiltrating (Scirrhous carcinoma is an example)
2. Lobular carcinoma
(a) in situ lobular carcinoma
(b) infiltrating
3. Rarer types (e.g. medullary carcinoma, tubular carcinoma, colloid etc.)
This slide shows ductal carcinoma with areas of both in-situ as well as infiltrating tumor.
The in-situ (intraduct) areas show dilated elements packed with pleomorphic and highly atypical ductal cells. Mitotic activity with atypical forms may be seen. The ductal cells that fill the lumina may form a solid mass or may have a cribriform pattern to them. Search for a region of intraductal carcinoma where central necrosis of tumor cells can be seen - these ducts would represent areas of Comedo carcinoma.
The infiltrating areas of carcinoma show malignant epithelial cells that infiltrate into the stroma and fatty tissue of the breast. The tumor cells may form poorly formed ductal structures or may infiltrate into the stromal tissue as islands or trabeculi of tumor cells. When a dense desmoplastic stromal reaction is elicited by the tumor, this same tumor type is termed scirrhous (macroscopically, when this tumor is processed and cut, it cuts with the consistency of an “unripe pear”).
Questions :
1.What are the prognostically important findings of breast tumors which the pathologist refers to following mastectomy for breast carcinoma?
865 Scirrhous carcinoma of the breast
(See description of slide 864)
The slide shows a densely fibrotic connective tissue stroma in which malignant epithelial elements are found. The stroma is termed desmoplastic and is thought to be induced by the presence of the tumor itself.
The tumor cells from irregular ductal structures, rows, clusters and irregular aggregates of cells. At the periphery of the sections, fatty tissue may be visible infiltrated by the smae tumor cells. Individual tumor cells show all the cytologic features of malignancy viz : hyperchromacia, anisocytosis, pleomorphism, mitotic activity with atypical forms.
866 Paget’s disease of the nipple
(Described by Sir James Paget in 1874 as an eczematoid lesion of the nipple in patients with carcinoma of the breast)
The nipple lesion that bears Paget’s name is caused by tumor cells invading the basilar layers of the epidermis of the nipple after having migrated through lactiferous sinuses from an underlying carcinoma (mostly of ductal type) of the breast.
Microscopically these cells can be sought in the abovementioned site in skin that shows hyperkeratosis and acanthosis. The tumor cells occur between normal epithelial cells and appear as pale stained nests or as single cells with typically hyperchromatic nuclei and nucleoli. The dermis may have a chronic (lymphocytic) inflammatory cell infiltrate.
Questions :
1. What are the clinical features of carcinoma of the breast?
901 Purulent meningitis
A 15 year-old mentally retarded girl suffered recurrent episodes of upper respiratory infection. On admission to hospital she showed photophobia, irritability and neck stiffness.The lumber puncture revealed a cloudy CSF with high protein and very low glucose levels.
Macro : The cerebral hemispheress show congestion of leptomeningeal vessels with a white-yellow thick exudate over the flattened gyrii.
The subarachnoid space and the leptomeninges themselves are extensively infiltrated by a marked inflammatory cell infiltrate that consists of abundant neutrophils and monocytes with karyorrhectic material. In-between the cells fibrin and edema fluid are present. The meningeal vessels are congested. The inflammatory press frequently penetrates into the cerebral cortex through the Virchow-Robin space with resultant meningo-encephalitis. The brain cortex is edematous.
Questions :
1. What organisms are the etiologic agents most commonly causing meningitis and in what age groups?
2. What is the mechanism of spread to the mininges?
903 Meningioma
This tumor occurs chiefly in adults over 30yrs. of age and accounts for up to 15% of intracranial tumors. The most common sites for these tumors are the frontal parasagital area, lateral cerebral convexity, base of cerebrum and spinal cord. The majority are encapsulated, slowly growing neoplasms that compress rather than invade the adjacent neural parenchyma.
Microscopic examination shows an encapsulated tumor composed of slightly elongated to plump cells with vesicular nuclei and poorly defined cytoplasm. The cells are arranged in fascicles running in various directions and often form whorls and concentric layers of cells. These latter structures may degenerate and calcify giving rise to psammoma bodies. The tumor may have a marked vascular component.
Questions :
1. How do meningiomas present clinically?
2. How do meningiomas behave biologically?
909 Infantile Amaurotic Idiocy (Tay-Sacks Disease)
(Syn: Amaurotic familial idiocy -1880)
A lysosomal storage disease resulting in accumulation of a sphingolipid - due to the absence of the enzyme Hexoaminidase A. (Sphingolipid = Gm2 ganglioside). This disease has a high incidence among Jews of eastern European extraction. The ganglion cells of the macula are involved in the process and this causes a characteristic cherry-red spot evident on funduscopic examination of the eye. Death ensues before the end of the third year from infection after loss of mental function, seizures and severe spasticity. Fortunately the disease can be averted by testing for the carrier state in potential parents.
Examination of the sections of brain tissue shows enlarged Purkinje cells with a balloon or pear shape. The Nissl substance and nucleus are pushed to the periphery of the cell. The cytoplasm is granular, eosinophilic and foamy and contains round globules. With the destruction of neurons - gliosis ensues.
911 Glioblastoma multiforme (Malignant or anaplastic astrocytoma)
This tumor is the most common malignant astrocytoma. It occurs in adults over the age of 40 years and is associated with a dismal prognosis. In some cases, the dedifferentiation is so great the an astrocytic origin cannot be established unless specialized staining techniques are utilized. The majority occur in the cerebral hemispheres of adults. Areas of necrosis are always encountered. Cystic degeneration and hemorrhage may be present.
Microscopically the tumor has two main components :
1. Round, polygonal, oval and markedly elongated cells with giant cells and abundant eosinophilic cytoplasm. These are the malignant astrocytes with some cells bearing the term gemistocytes (ovoid to round cells with eosinophilic cytoplasm).
2. Vascular components - interspersed in-between necrotic areas. Note how tumor cells collect in a perivascular pattern around the blood vessels. Another constant microscopic feature of undifferentiated gliomas is represented by the marked proliferation of the endothelium in the capillary network.
Questions :
1. Which of the intracranial primary tumors metastasize?
913 Polyomyelitis - Spinal cord
The main lesion is located in the anterior horn of the spinal cord. The posterior horn is not affected. The lower motor neurons are those mostly affected and they exhibit different stages of destruction :
1. Chromatolylsis - disintegration of the granules of Nissl’s substance in the nerve cell body.
2. Satellitosis - marked accumulation of neuroglia cells around neurons.
3. Shrunken neurons
4. Neuronaphagia
5. Gliosis
There is a perivascular cuffing of the vessels in the leptomeninges by inflammatory cells in particular - lymphocytes.
914 Amputation “stump” neuroma
Following amputation of a peripheral, myelinated nerve, the proximal fibres attempt to recanalize and often results in this entity. Microscopically one sees whorls and well defined lobules and nodules of variable sizes, of regenerating nerve fibres and nerve bundles surrounded by perineurium. These nodules of fibres are embedded in a loose connective tissue stroma. Note the irregular criss-cross pattern of the nerve fibres as opposed to the linear parallel arrangement of an intact nerve. The original nerve might be seen in some of the sections present.
Diff. diagnosis - Neurinoma and neurofibroma.
Questions :
1. What do the terms neuropraxia, axonotmesis and neurotmesis mean?
2. What is the clinical significance of each of these processes?
3. What are the names of benign tumors of peripheral nerve cells and malignant ones?
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