Thursday, January 18, 2001



Thursday, January 18, 2001 Scribe: Anita Sandhu

Pathology 10 AM Proof: Melissa Chan

Dr. Graham

Lung Cancers (continued)

Adenocarcinoma (continued)

➢ Unusual variant: Bronchiolo-alveolar carcinoma-- the confusing lung cancer.

o Presents as a small nodule, which is incidental, pneumonia, or is complicated by pneumonia

o May have obstructive or restrictive pulmonary function testing (PFT)

o Ubiquitous in its presentation and in its x-ray pictures

Slide 1: Gross specimen, bronchiolo-alveolar carcinoma

➢ Wide differential; Lots of little white nodules, which could be metastatic cancer, extensive bronchopneumonia that is becoming confluent, tuberculous bronchopneumonia, etc.

➢ You would have to use everything you have to make the diagnosis before it comes off the autopsy table.

Slide 2: Cytology of bronchiolo-alveolar carcinoma (see Figure 16-43 in Robbins)

➢ Well-differentiated tumor, abnormal alveolar sacks lined by tall columnar cells snaking their way down.

➢ Called bronchiolo-alveolar tumors because they are thought to derive from bronchial lining cells, or Clara cells, lining alveolar walls.

Slide 3: Histological section, bronchioalveolar carcinoma

➢ Alveolar walls with some low columnar cells with atypical nuclei.

➢ Looks like Type 2 pneumocyte proliferation during organizing diffuse alveolar damage. Type 2 pneumocytes are some of the cells that are thought to be the originators of alveolar carcinoma.

➢ Difficult to distinguish from an interstitial lung disease (ILD) if we were talking about functional changes—restrictive problems on PFTs or diffusion problems. This tumor is confusing for everyone.

Large cell undifferentiated carcinoma

➢ Appearance: lots of pink cytoplasm, no distinct squamous or glandular differentiation.

➢ Garden basket for all the large tumors with lots of cytoplasm that we can’t tell a lot about.

➢ Smoking associated (notes say 90-99%)

➢ Usually central

➢ Primary treatment is surgical. Chemotherapy is sometimes used in these cases.

Slide 4: Large cell undifferentiated tumor (see Figure 16-41D)

➢ Looks similar to a poorly differentiated squamous cell carcinoma except cannot see intercellular bridges or keratin.

➢ Large nucleoli with high mitotic activity. You can also see this on cytology.

Slide 5: Higher power of mitoses

➢ More chromosomes in here than in most people, show very abnormal mitosis; highly malignant, aggressive tumor

Small cell undifferentiated carcinoma

Slide 6: Small cell undifferentiated carcinoma or “o cell” carcinoma (see figure 16-41C)

➢ Lots of small cells without much cytoplasm. Cells tend to stick together because they are epithelial cells.

➢ The major differential at the cytological level is between these and lymphocytes.

➢ 99%+ smoking associated, usually with active smokers

➢ Most occur centrally. Some present as Pancoast tumors, or tumors in the apices of the lung.

➢ Presents with early metastasis—classically, 50% present with metastasis, ex., CNS changes.

➢ Classically associated with paraneoplastic syndrome involving ACTH or ADH.

o Results in Cushing’s syndrome

o Can also produce corticotropin releasing factor (CRF)-like substances, so can present with excess ACTH for other reasons, Cushing syndrome, or syndrome of inappropriate ADH (SIADH).

o Although ADH is a pituitary hormone, most problems related to excess ADH release are due to diseases not related to the pituitary. In this case, it is associated with small cell undifferentiated carcinoma. It can occur in other lung cancers, but the 2 A’s-- ACTH and ADH-- are classic for small cell.

➢ Rapidly- proliferating, small round blue cell tumor— nuclei have very little cytoplasm.

➢ Chemotherapy is first line because the tumors are aggressive with rapid turnover. Surgery is being used more.

Slide 7: X-ray, Lateral view

➢ Tumor—area of increased density-- is difficult to see and can be easily missed. Could easily be clouded by the clavicle.

Slide 8: Poor chest x-ray

➢ Tumor is hidden, so again, it can be easily missed unless someone is looking for it.

Slide 9: Excised pneumonectomy from one of these tumors from the apex of the lung

➢ Could be any tumor, therefore we cannot differentiate grossly. We need histological evidence.

Slide 10: Histological section

➢ Instead of having cells with big ugly nuclei and lots of pink cytoplasm, you have lots of small blue cells.

➢ First thought may be of lymphoma with lots of little blue cells, and this may actually be in the differential in some cases.

Slide 11: Higher power view

➢ Lots of nuclei with very little pink cytoplasm. They tend to mold together, something that lymphocytes do not do.

Slide 12: EM level

➢ Intercellular connections or bridges

➢ Can usually tell these apart more simply with immunoperoxidase (IP) stains.

o IP stains exist that separate a variety of cell lines, not to 100%, but most of the time.

o Stain for epithelial markers, like cytokeratin, but not for leukocyte common antigen or lymphocyte-related markers, so we could easily differentiate small cell carcinoma from lymphocytes.

➢ Small cell cancers are also notable for their positivity or association with neuroendocrine cells. Some of them stain as if they were derived from neuroendocrine cells.

➢ Bronchial carcinoid: predominantly GI tumor associated with carcinoid syndrome of the heart, but neuroendocrine lesions can originate in the lung.

o 3 grades

▪ Carcinoid: low grade tumor malignancy

▪ Atypical carcinoid: a little worse

▪ End stage: small cell lung cancer

➢ Many small cell carcinomas will stain for neuroendocrine markers, and we can use the brown (IP) stains to see these.

o We attach an antibody to an Ag that we think is going to be on these cells.

o Then we add a dye, in this case DAB, which is a brown dye that precipitates and produces brown with Ag +

o Stains for chromogranin and synaptophysin, which are both markers for neuroendocrine differentiation.

➢ This tumor could also be negative for the lymphocyte related markers, which may be in the differential. Can be difficult to tell, so you may have to use this for small biopsies when you have a wider differential.

Slide 13: Gross specimen, small cell tumor

➢ Starts as a small lung primary, with huge regional lymph nodes. Snakes down the lymphatics of the bronchial cells and spreads along the bronchial area.

➢ On biopsy, will not see a fungating tumor like squamous cell. Will see subepithelial lumps and bumps. The epithelium will look good, but it will be involved in epi-lymphatics. Sometimes it is hard to get these cells on biopsy, which is the main reason we look at cytology and biopsy.

➢ Completely surrounded the bronchus, which is still intact and spreading centripetally, hard to get as a biopsy.

➢ Can see in local lymph nodes, may be a resectable tumor or an autopsy specimen.

Slide 14: Gross specimen, small cell tumor

➢ Tumor spreading along bronchioles with white patches-- lymphatic involvement. So it can spread in the lung.

Hamartomas

➢ Benign tumors--a solitary lung nodule could turn out to be a benign lesion; occurs in both young and old people.

Bronchial carcinoid (bronchial adenomas)

➢ Neuroendocrine tumor, classically presents as a polyploid bronchial lesion

➢ Presents with obstruction of a bronchus with any or all of the complications

➢ Low-grade glandular tumor with low-grade malignancy. Can go to local lymph nodes, but does not upstage (to N1, N+).

➢ Does not affect the prognosis because you can usually go in and get it out and get the lymph nodes, too.

➢ It is rarely functional, which is good. Good long-term prognosis.

Slide 15: Gross, bronchial carcinoid mass

➢ White, firm, and uniform with no areas of discoloration or hemorrhaging.

➢ Higher-grade malignancies tend to have a lot of necrosis and fall apart. If you have a nodule that is relatively firm and uniform, you are hoping that it is not a cancer or that it is a lower grade malignancy or benign.

➢ Tumor is obstructing a bronchus. Obstruction can cause:

o Bronchiectasis – huge dilated bronchi reaching toward the pleura; it is a necrotizing infection from obstruction

o Atelectasis

o Partial obstruction of the bronchus can produce air trapping or pneumonia. Obstruction is bad.

Slide 16: Histological section, carcinoid (see figure 16-44B)

➢ Nests and sheets of relatively bland cells.

➢ Glandular tumor, looks like some benign glandular tissue from other organs; ‘weed’ growing where it shouldn’t be

➢ We can stain for markers, using chromogranin, synaptophysin, or some other special stain, and see if it is neuroendocrine in origin from an EM.

➢ Diagnosis of carcinoid is made using cytology, which can differentiate small cell from large cell cancer.

Slide 17: High power view of cytology, small cell carcinoma of the lung

➢ Group of cells molded together like little vertebral bodies, not separate like lymphocytes. Often 2-4 times larger than lymphocytes, but have very little cytoplasm.

Slide 18, 19: Large cell carcinoma

➢ Nucleus has plenty of pink cytoplasm, large cells—much larger than lymphocytes.

➢ Cytoplasmic ratios as well as size helps. If you can see significant cytoplasm, then you have a large cell tumor.

Clinical manifestations Lung Cancer:

➢ Local

o Cough, hemoptysis

o If it extends beyond the lungs and/or involves local lymph nodes, can have superior vena cava (SVC) syndrome—compression of the SVC. These people come in with extended neck veins.

o Can invade the brachial plexus, producing Horner’s syndrome (not expected to know what it is) and producing changes because of the invasion of the cervical sympathetic ganglion.

o Obstruction

▪ Can treat with chemotherapy or remove tumor with surgery, even if it is only palliative.

▪ Often die from complications of obstruction, pneumonia, septicemia, etc.

➢ Metastatic disease

o Can die of metastasis anywhere, most commonly die of metastasis to brain.

o Can die if it metastasizes to the bone from complications of pulmonary embolism (PE)

▪ Ex., after having a fractured hip and being immobile in bed.

▪ Become more susceptible to complications of immobility, which includes PE.

o Multiple direct and indirect causes of death from cancer.

o Sometimes metastases are removed surgically, if there is only one, and it is under control in other ways.

o Can and does respond to chemotherapy.

➢ Paraneoplastic syndrome can be treated, but hypercalcemia can be fatal if untreated.

➢ Weight loss for a variety of unknown reasons; some people die of cancer cachexia, even with a small tumor nodule.

Q: What causes the weight loss?

A: Don’t know. Sometimes it’s from hypermetabolism caused by a local tumor; the body is fighting all kinds of infection. Or it’s from lack of appetite. Sometimes it’s not clear why people lose 60-80 lbs. Clinicians and nutritionists may have better ideas.

Pleura

➢ Effusions

o Transudates-- leaky vessels caused by:

➢ CHF, pulmonary edema for a variety of reasons—some not infectious, don’t have very many cells in them-- essentially serum in blood seeping out.

o Exudates-- microvascualr damage due to infection or tumor-- PUS.

➢ The worst-case scenario is that you collect huge amounts of pus with the empyema, for instance in low-bar pneumonia or in a very bad necrotizing pneumonia.

➢ Hemothorax-- blood from blood trauma, frank blood, blood clot from any kind of traumatic event, a broken rib, etc.

➢ Chylothorax-- due to obstruction of the thoracic duct, often for tumorous reasons.

➢ Pneumothorax

o Ex., Dr. Jumper showed a great case from yesterday of a lady who blew a bleb and ended up with air in her pleural cavity, which essentially produced a restrictive or compressive atelectasis. This resulted in an atelectatic lung, which was subject to infection. You need to get rid of that air.

o Can also be associated with any kind of chest cavity wound.

Slide 20: Chest X-ray, pleural effusion

➢ Appears relatively normal, but you have a pleural effusion, which is producing an air fluid level.

➢ The dome of the diaphragm is lower than would be expected.

➢ About 300 cc of fluid in the recesses of the diaphragmatic infolds can be seen in an AP x-ray. Can see more with CT…

Slide 21: CT scan, pleural effusion

➢ The person is lying on their back, so the fluid has pooled.

➢ See multiple pleural plaques-- squamous cell cancers.

➢ First thought was of metastasis from somewhere else, but it turned out to be a malignant pleural effusion.

o We mentioned before that with bloody or pink tinged effusions in the pericardial sac, we worry about TB and malignancy. This is also true in the pleural cavity where we worry about cancer primarily.

Q: Would a patient be able to describe the feeling of something sloshing in their chest?

A: Don’t know. Ask Dr. Jumper. Most people would probably present with shortness of breath due to restrictive compression of the lungs, which is perhaps the underlying cause of their pleural effusion…

Slide 22: X-ray, pneumothorax

➢ Air is compressing an otherwise normal lung, but has produced atelectasis.

Malignant mesothelioma (“the one tumor that I want you to know about”)

➢ Primarily (>90%) due to asbestos exposure

➢ Primary tumor arising in the mesothelial lining primarily of the lung and sometimes the abdominal cavity.

➢ Can detect fibrotic lung disease

o 20% of pleural tumors and 50% of peritoneal tumors.

o A mesothelioma may not relate directly to the degree of fibrotic lung disease.

➢ Can develop neoplastic proliferation of cells in the pleural cavity that encases the lung, producing a restrictive lung abnormality.

➢ Present with dyspnea, chest pain, and also end up with unsympathetic pleural effusions.

➢ Essentially untreatable, and most people die within one year. (This is what Steve McQueen died of.)

Slide 23: Malignant mesothelioma (see figure 16-46) 

Slide 24: Gross, malignant mesothelioma

➢ The tumor has completely filled the pleural cavity. The pleural effusion is contributory but not important in this case.

➢ It often mimics an adenocarcinoma, which tends to be peripheral anyhow. The pattern and the history help you.

Slide 25: Histological section, malignant mesothelioma

➢ Can use special stains to help differentiate these cells from others.

➢ Looks like a spindle cell-- a mesothelial or mesenchymal tumor-- i.e., spindle cells forming fascicles or bundles rather than the epithelial round cells.

➢ Can be very easy to diagnose when you have an epithelial component that looks almost glandular and a mesothelial component because then it will be “biphasic”. Mimics everything. Difficult to tell from the other primary lung tumors.

Pattern recognition (see notes p. 74-76)

These are low-tech drawings of chest x-rays. (Suggestion from Dr. Graham: take full advantage of any radiology you come across, get up front and look at them, don’t sit in the back, go through many differentials, you will learn very quickly.)

AP: Right Left

[pic]

(Gray = less dense areas on radiograph)

P. 74, upper right:

➢ Pattern: solitary lung nodule

➢ Differential: (assume dealing w/ adults) TUMOR—especially w/ a smoker—deal with the possibility of tumor right away

➢ Infections-- abscess, TB, histoplasmosis, aspergillus fungus ball, pneumonia; COPD; asthma

➢ ILD—sarcoid, silicosis possibly, but the fact that it’s only in one spot, and ILDs are more diffuse, puts it way down the list; hemorrhagic lung diseases-- Wegener’s granulomatosis

➢ Bronchiolitis Obliterans-Organizing Pneumonia (BOOP)—presents as one or more nodules, can mimic almost anything

Middle right:

➢ Pattern: Solitary nodule w/ enlarged lymph nodes

➢ Differential: TUMOR; TB, histoplasmosis, pneumonia, but in bacterial pneumonia, lymph nodes aren’t usually enlarged

➢ Sarcoid and silicosis (but mostly found in upper lobes, and more diffuse, so found way down on the zebra list)-- need clinical history: smoker, age, race, etc.

Middle left:

➢ Pattern: Gohn’s complex

➢ Differential: Primary TB

Bottom Left:

➢ Pattern: gray nodules

➢ Differential: Bronchopneumonia—caused by bacteria, TB bronchopneumonia (TB can mimic anything), bronchioalveolar carcinoma, metastatic tumor (but normally seen both sides), BOOP, bronchiectasis, but not asbestos (bilateral lower lobe, diffuse ILD, would expect fibrosing honeycomb pattern rather than multiple nodules)

Bottom Right:

➢ Pattern: bilateral gray nodules

➢ Differential: Metastatic tumor, bronchopneumonia, especially with an alcoholic who could be aspirating things into his lungs, BOOP…

P. 75, Contrast upper left and right

➢ Right: bilateral apical nodule, fibrocaseous TB or histoplasmosis

➢ Left: unilateral, solitary apical nodule—pancoast tumor

➢ Unilateral vs. bilateral helps to differentiate TB from tumor

Bottom left:

➢ Lobar pneumonia-- made bronchi prominent in left drawing to simulate air bronchograms— sometimes when you have a lot of pus in the alveolar sacs, the bronchi are filled w/ air, so you’ll actually see the bronchial tree as contrast

Bottom right:

➢ Abscess

p. 76 (Do the top 4-- ILDs on your own, will answer questions later)

Mediastinal regions:

➢ Can tell a lot from simple x-rays/CTs, by being able to say whether a mass is in the anterior, superior, posterior, or middle portion of the mediastinum of the chest cavity. Can make a major differential shift.

➢ See diagram, but not tested on exam. Will be helpful when evaluating a lateral chest x-rays for mediastinal tumors.

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Heart

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