A 42-year-old male in previously good health presented to ...
Pathology Dr. Mira
Friday, March 30, 2001 10a.m. Denton/Gragoski
In response to a question Dr. Mira received from one of us (he didn’t know who)…re: colon innervation. The colon receives both parasympathic (PS) and sympathic innervation. One works to stimulate peristalsis (PS), the other works to inhibit peristalsis (sympathetic).
Case 1
A 42-year-old male in previously good health presented to his physician for evaluation of headache and "problems seeing." The patient indicated that over the past year he had developed headaches that were generally worse while reclining. While aspirin or acetaminophen had provided symptomatic relief during the first six months, his pain had become more persistent over the last six months. Over the last six months, in addition, the patient noted the development of "blind spots" (bi-temporal, hemianopia) involving his lateral fields of vision, particularly on the right side. Physical examination revealed slight blurring of the optic discs. An asymmetrical, bitemporal visual field deficit was present, involving the right temporal visual field somewhat more than the left.
CT and MRI scans of the head revealed a large midline mass associated with erosion of the sella turcica (Slide 1). The mass extended into the suprasellar space and into the right cavernous sinus. Laboratory evaluation revealed a prolactin level of 90 ng/ml (normal < 14 ng/ml). The patient was taken to the operating room, where the sellar mass was exposed via frontotemporal craniotomy. The mass obliterated the diaphragma sella and the lateral walls of the sella turcica; it compressed the optic chiasm superiorly and extended bilaterally into the cavernous sinuses. A small biopsy of the mass consisted of soft, almost gelatinous, tan tissue. Histologic examination of the biopsy revealed a monomorphous population of cells with uniform, round-to-ovoid nuclei and amphophilic cytoplasm (Images 2 and 3). The mass was resected as completely as possible. The patient made an uneventful postoperative recovery and was discharged, to be followed in neurosurgery and endocrinology clinics. Removal of this mass, if large enough can lead to empty sella syndrom.
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1. Magnetic Resonance Image (MRI), Coronal Plane
This MRI demonstrates a large lesion involving the sellar and suprasellar regions. The patient has been injected with contrast material, which causes this particular mass to enhance as a bright (white) lesion. Compare this image to the coronal section of the pituitary adenoma in image #6 in this folder.
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2. Biopsy of Suprasellar Mass - Low Power
Note the monomorphic cellular proliferation. The cells are growing in a diffuse pattern and lack the characteristic nesting architecture of the normal anterior pituitary gland. For comparison, you may wish to review the microscopic features of the normal anterior pituitary in image #7 in this folder.
Q: What additional studies might be done to further characterize this patient's tumor?
A: Other studies that might be done would include immunohistochemical staining for the anterior pituitary hormones. An immunostain for prolactin, in particular, is probably the most significant one in this case. A negative prolactin stain would confirm that the elevated prolactin level was due to stalk effect, rather than secretion of hormone by the neoplasm. If prolactin was present within the neoplasm, however, postoperative treatment with bromocriptine (which inhibits prolactin secretion and shrinks prolactin-producing cells) might also be indicated.
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3. Biopsy of Suprasellar Mass - High Power
At higher magnification, the comparatively uniform, amphophilic ("amphophilic" means that the color is somewhere in no-man's land between eosinophilic and basophilic) staining pattern of the neoplastic cells is apparent. Once again, this monotony contrasts with the mixed cell population seen in the normal anterior pituitary.
Q: What is your diagnosis in this case?
A: Pituitary adenoma.
Q: What processes need to be considered in the differential diagnosis of the patient's sellar mass?
A: The differential diagnosis of sellar-region masses would include pituitary adenomas of all flavors, tumors of the meninges, and primary suprasellar neoplasms (e.g., craniopharyngioma, germinoma, and pilocytic astrocytoma). The presence of extensive sellar erosion in this case would weigh against a primary suprasellar lesion, but would not completely exclude them from consideration. Endocrine evaluation and surgical exploration is usually necessary to make the definitive diagnosis. Remember, these are supra sellar tumors (in origin), size is important. Also, calcification is helpful in identifying.
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4. Pituitary Adenoma at Autopsy, Brain - Gross, Ventral Surface
This specimen demonstrates a pituitary adenoma (adenoma is the most common form of pituitary tumor) discovered incidentally in a patient who died of unrelated causes. Pay special attention to the relationship between the adenoma and adjacent structures in order to better understand some of the presenting clinical manifestations of mass lesions in the pituitary region. The right olfactory nerve is pointing at the tumor. The adenoma has been removed en bloc with the brain, and is invested superiorly by the diaphragma sella, a portion of which is visible anterior to the tumor. Note the proximity of the tumor to the optic nerves.
Q: How would you explain the patient's visual field deficits? Why are the deficits present in a bitemporal distribution?
A: The patient's visual field deficits are caused by expansion of the sella-region mass superiorly, with compression of the optic chiasm at the base of the brain. The temporal visual fields are visualized via activity of the medial (nasal) areas of the retina. Fibers emanating from the medial retina, in turn, decussate (cross) at the optic chiasm. If the chiasm is compressed, these decussating fibers are compromised, resulting in loss of images from the medial retina in both eyes and, hence, a bitemporal field cut. In real life, this is often a bit asymmetrical, as in this patient. The medial (nasal) visual fields are visualized by the temporal area of the retina, whose fibers do not decussate.
Stalk Effect – The stalk that connects the hypothalamus to the pituitary gland may be compromised by pressure from a mass in the sella turcica. This loss of communication results in the pituitary gland releasing excess amounts of prolactin leading to prolactinemia.
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5. Pituitary Adenoma, Pressure Effect - Gross
The pituitary adenoma has been removed to demonstrate local changes due to the mass effect of the tumor. Note the depressed area just anterior to the mammillary bodies, which marks the site of the adenoma. As noted in the previous slide, as pituitary adenomas expand, compression of the visual pathways and resultant visual field deficits are fairly common. The textbooks frequently mention a bitemporal hemianopsia, as was present in our patient, occurring due to compression of fibers in the optic chiasm coming from the nasal aspect of the retina. In practice, however, the visual field deficits may be quite variable. If untreated, pituitary adenomas may grow far beyond the immediate vicinity of the sella, as is illustrated in the next image.
Q: What is the cause of the patient's elevated prolactin level? What other endocrine studies might be of interest in this patient?
A: The mildly elevated prolactin level is a common phenomenon, related to the so-called "stalk effect" rather than to the direct secretion of prolactin by the tumor. Any mass in this site can cause a mild elevation in prolactin by interfering mechanically with hypothalamic-hypophyseal connections and disrupting the steady state inhibitory effect of the hypothalamus on prolactin secretion by the anterior pituitary. Mild hyperprolactinemia in the presence of a pituitary region mass does not justify a diagnosis of a prolactin-secreting pituitary adenoma. Patients with functional prolactinomas generally have a serum prolactin level over 200 ng/ml. Other endocrine studies might include assays of the other anterior pituitary hormones (GH, TSH, ACTH, LH, FSH). Pituitary adenomas may be associated with secretion of excessive amounts of these hormones, singly or in combination. In addition, nonsecretory adenomas may compromise the native anterior pituitary sufficiently to produce hypopituitarism.
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6. Pituitary Adenoma - Coronal Section through Cerebral Hemispheres
This specimen demonstrates the advanced pituitary adenoma,similar to the scan in image one. The lesion was from an elderly woman who presented for evaluation of weakness and altered mental status, and it is comparable in size to that noted in the radiographic imaging studies from our patient. The adenoma has grown far beyond the confines of the sella turcica, has markedly distorted the left lateral ventricle, and encases the internal carotid artery. The neoplasm contains several small areas of hemorrhage. In some cases, pituitary adenomas may undergo extensive spontaneous hemorrhage, causing a substantial, rapid increase in the size of the mass. Ancillary studies in this autopsy case revealed no evidence of hormone production by this adenoma.
Q: Why would nonfunctional pituitary adenomas (i.e., adenomas that do not secrete an active hormonal product) typically be larger than hormonally active tumors at the time of diagnosis?
A: Nonfunctional tumors will come to clinical attention only by mass effects or panhypopituitarism, whereas small functioning tumors produce enough hormone to produce typical end-organ effects to suggest the diagnosis. Easier to detect in young, non-pregnant women due to the presence of amenorrhea and galactorrhea.
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7. Normal Anterior Pituitary (Pars Distalis) - High Power
This slide illustrates the normal constituents of the anterior pituitary. Note the mixture of cell types, including the red-staining acidophils, purple-staining basophils, and the chromophobes, whose cytoplasm stains only weakly. The variability in staining reflects the presence of different hormonal secretory products (prolactin or growth hormone in acidophils; TSH, ACTH, or gonadotrophins in basophils). Immunohistochemical staining, demonstrated in the next image, may be used to identify the hormone secreted by a given cell. The cells are grouped into small nests by the normal connective tissue framework of the anterior pituitary. (In adenoma you will see essentially a single population.)
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8. Immunohistochemical Stain of Normal Anterior Pituitary for Growth Hormone (hGH) - Medium Power
In this section, somatotrophic (hGH-secreting) cells have been labeled with an antibody to hGH. The antibody, in turn, has been linked to a chromogen that stains the somatotrophic cells brown.
Case 2
A 28-year-old woman notices while attempting to button her shirt collar that her neck is enlarged. She is not gaining weight; rather, she is losing a small amount of weight in spite of having a voracious appetite. She feels well and active and in fact, whereas she formerly suffered from constipation, she now notes that she has bowel movements twice daily. On physical examination her pulse is 86 beats per minute with blood pressure 125/70.
On visual inspection, she appears to have a wide-eyed stare with a slight lagging of the upper lid on slow downward gaze. The thyroid is asymmetrically enlarged and estimated to weigh 40 grams (normal 10 to 20 grams), with a firm 1.5 cm nodule in the middle of the left lobe. The initial impression is that of moderate thyrotoxicosis with a single prominent goitrous nodule. Although the lid retraction suggested increased sensitization of the adrenergic system, the absence of proptosis (protrusion of the globe) indicates absence of significant clinical autoimmune ophthalmopathy at this time.
Lab data included fasting glucose 105 mg/dL, free T4 2.2 ng/dL (reference range 0.76-1.8), and TSH zero (undetectable) by a highly sensitive assay. A radioiodine scan was performed. The diffuse gland had a marked uptake, well above the upper limits of normal. The left lobe had a decreased functional uptake corresponding to the palpable nodule. Fine needle aspiration biopsy of the left lobe nodule was performed, which revealed papillary clusters of epithelial cells with enlarged irregular nuclei, some thyroglobulin, and several psammoma bodies.
Surgical treatment was suggested to treat her illness.
Psammoma bodies: concentric laminar calcification seen eventually in any papillary lesion, whether malignant or benign. Suggestive of a papillary carcinoma, not just thyroid if in appropriate background of neoplastic cells.
Graves Disease = #1 cause of hperthyroidism.
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1. Diffuse Hyperplasia of Thyroid (Graves' Disease) - Gross
The thyroid is symmetrically moderately enlarged and would show beefy red parenchyma on cut sections.
Q: What are other causes of thyroid enlargement? A: Goiter, Hashimoto's thyroiditis, neoplasms.
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2. Graves' Disease - Low Power
Thyroid parenchymal lobules are separated by thin fibrous septa. The gland shows diffuse hyperplasia, which is not uniform in all areas (note sparing of the lower left corner in the photomicrograph). Hyperplastic papillary infoldings replace much of the luminal colloid in the follicles in this photograph. There may be a patchy lymphoid infiltrate, which may include rare germinal centers as well as prominent vascularity (not pictured).
Q: What are the other causes of thyroid hyperplasia?
A: TSH-producing pituitary adenoma (rare), goiter (hyperplasia is patchy).
Q: Is thyroid gland hyperplasia always associated with hyperthyroidism?
A: No. In many patients goiter develops in response to some factor that limits the synthesis of T3, T4. Such compensatory hyperplasia is a response to TSH stimulation, and the patient is generally euthyroid.
Q: What are other causes of hyperthyroidism?
A: An adenoma that secretes thyroxine (toxic adenoma), a hyperactive nodule in a goiter (toxic goiter), and excess exogenous hormone intake. Toxic adenoma and toxic goiter would show a different thyroid scan from this patient, namely a hot nodule and relatively low uptake in the rest of the gland.
Q: How do the papillary infoldings of Graves' disease compare and contrast with papillae of papillary thyroid cancer?
A: Graves' papillae are generally within a follicle, small, with preserved nuclear polarity, and are present diffusely in the gland. Papillary carcinoma papillae are localized to the tumor, usually larger, with disturbed nuclear polarity, and frequently a more prominent vascular core. The nuclear characteristics of papillary carcinoma (clear chromatin, pseudoinclusions) are not features of Graves' disease.
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3. Graves' Disease - High Power
The hyperfunctioning follicular epithelium is tall columnar, representing cellular hypertrophy. Papillary infoldings into the follicular lumens result from epithelial proliferation and overcrowding, representing hyperplasia. Peripheral scalloping of the colloid within follicular lumens represents active pinocytosis by the hyperfunctioning epithelium.
Q: What is the stimulus to hyperfunction in Graves' disease?
A: Autoantibodies bound to TSH receptors on the cell membranes.
Q: What is the most important screening test to determine the functional status of the thyroid?
A: A sensitive TSH assay is the best screening test because its levels are exquisitely tuned to that of free T4. In the absence of pituitary disease, TSH levels are elevated in patients with hypothyroidism and close to zero in patients with hyperthyroidism.
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4. Radionuclide Scans of Thyroid
Radioactive iodine is concentrated by thyroid follicular cells from the blood, allowing correlation of anatomic features with thyroid function. Decay of radioactive iodine is detected as dark spots on the scan. Normal thyroid shows diffuse moderate iodine uptake in the right and left lobes and isthmus. Graves' disease is characterized by diffuse increased uptake. Multinodular goiter most often shows patchy irregular uptake, with some nodules being hyperfunctional compared to normal (dark, or "warm," on scan), and other nodules being hypofunctional (pale, or "cold"). The focal rounded defect lacking uptake ("cold nodule") is characteristic of thyroid neoplasms and cysts. A focal rounded area of increased uptake that suppresses the remaining thyroid gland ("hot nodule," not pictured) is most often a hyperfunctional follicular adenoma or goiter nodule.
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5. Papillary Thyroid Carcinoma - Gross
There is a lobectomy of thyroid showing normal parenchyma, within which is a 2 cm, white, slightly irregular expansile tumor mass. No grossly discernible papillae are present on the cut surface. The neoplasm is not encapsulated, but is well-demarcated from adjacent beefy red thyroid parenchyma, and it appears to distend and distort the capsule of the thyroid gland without penetrating through.
Q: Why would the lesion appear as a cold nodule on radioactive iodine scan?
A: Carcinoma is less efficient than normal tissue in taking up iodine.
Q: What would be the most likely sites of metastases for this neoplasm?
A: Regional lymph nodes in the neck.
Q: Exposure to which mutagenic agent is known to increase the incidence of this tumor?
A: Radiation.
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6. Papillary Thyroid Carcinoma - Low Power
Into clear spaces, numerous papillary fronds protrude, showing a delicate branching architecture with central fibrovascular cores.
Q: Can papillary thyroid carcinomas form follicles?
A: Yes, most do.
Q: Can they lack papillary architecture?
A: Yes, they can lack papillary architecture; hence the nuclear features, shown later, are important for diagnosis. The follicular variant of papillary carcinoma forms follicles and lacks papillae, but has characteristic nuclei of papillary carcinoma and behaves like papillary carcinoma.
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7. Papillary Thyroid Carcinoma - Medium Power
Papillae are present within a clear space representing a cystic cavity. The neoplastic papillae are lined by a single row of fairly uniform columnar epithelial cells and have central delicate fibrovascular cores. Examine Image 8 to see nuclear features, which are large, crowded, and overlapping, with loss of polarity, vesicular chromatin, small nucleoli, and infrequent mitotic figures. Chromatin clearing (ground-glass "Orphan Annie" nuclei) and irregular nuclear contours with grooves and cytoplasmic pseudoinclusions are hallmark features of papillary thyroid carcinoma. Papillary carcinomas may also show numerous concentric lamellated calcospherites (psammoma bodies).
Q: Which usual histologic criteria for malignancy do not apply to papillary carcinoma?
A: Cellular and nuclear pleomorphism, hyperchromatic nuclei, and abundant mitoses. These features, seen in many malignant tumors, are not seen in this cancer.
Q: Name other neoplasms that contain psammoma bodies.
A: Meningioma, ovarian papillary serous carcinoma, and rarely in many other types. Psammoma bodies are thought to represent calcification of a nidus of a necrotic cell, especially in papillary neoplasms.
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8. Papillary Thyroid Carcinoma - High Power and FNA biopsy
At high power, several papillae are shown, covered by cuboidal epithelium showing characteristic nuclei of papillary thyroid carcinoma, including chromatin clearing ("Orphan Annie" nuclei). Shared features between histopathology and cytology of papillary thyroid carcinoma are nuclear enlargement, intranuclear inclusions, nuclear grooves, small nucleoli, and nuclear overlapping. Unlike tissue sections, cytologic smears of papillary thyroid carcinoma show finely granular chromatin (inset). Normal follicular cells are roughly the same size as a mature lymphocyte nucleus or a red blood cell. Note that the insert shows nuclear detail, but the cytoplasm of the tumor cells is pale.
Q; What is the significance of papillary carcinoma in this patient with Graves' disease?
A: There is no known association between papillary carcinoma and Graves' disease. Both are common diseases and their occurrence together is coincidental.
(Hashimoto thyroiditis, lymphoma patients are at increased risk for cancer.)
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9. Graves' Exophthalmos - Clinical Presentation
Although this patient in our scenario did not have exophthalmos, it may be found in Grave's disease, as pictured here. The eyes protrude from the orbit due to increased glycosaminoglycan deposition in the fibrofatty tissue and extraocular muscles, as well as a marked lymphocytic infiltrate.
Q: Does therapy of Graves' disease cause regression of exophthalmos?
A: Not necessarily. The treatment of Graves' disease is focused on reducing thyroxine secretion. This does not affect the exophthalmos because the proptosis is not caused by excess thyroxine.
Q: Do other forms of hyperthyroidism also show exophthalmos?
A: No. Exophthalmos is probably caused by autoimmunity itself, and hence is not present unless Graves' disease is the cause of hyperthyroidism.
PS. Thanks to Brian Gill for allowing us to borrow his copy of ROBBINS CD-ROM !!!
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