Articles on Medical Diseases and Conditions

Various diagnostic modalities are available. Some genetic disorders involve chromosomes. Many chromosomal abnormalities are autosomal (not involving the sex chromosome); others are sex-linked (inherited through the sex chromosomes). In some cases there may be total or partial deletion of a chromosome, presence of an extra chromosome attached to a chromosome pair (trisomy), or translocation, when a portion of a chromosome breaks off and attaches to another chromosome. These disorders require chromosome analysis. Other genetic disorders are due to a defective or missing enzyme and are diagnosed by measurement of the enzyme responsible. Sometimes it is necessary to demonstrate that a normal quantity of enzyme does not produce its expected degree of activity. Finally, genetic abnormalities may be due to a gene defect not shown by standard chromosome analysis. In some of these cases, diagnosis can be made by methods using nucleic acid probes. This technique is described in Chapter 14. Briefly, a specific amino acid sequence is obtained from ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) using an enzyme known as “restriction endonuclease.” This probe fragment is spliced into a DNA strand (recombinant DNA) using an enzyme called “reverse transcriptase.” The probe is then used to identify patient DNA that contains the same amino acid sequence as the probe. It is also possible to construct a probe for certain gene deletions (chromosome regions where part of a gene area has been deleted) and for certain mutations (if the mutation has eliminated a restriction endonuclease cleavage site). In some cases the gene can be detected directly. This is generally the most sensitive and accurate technique. When this cannot be done, a technique known as gene linkage analysis using restriction fragment length polymorphism can be used. This refers to abnormal length of a DNA fragment produced by an enzyme (restriction enzyme) that cuts the DNA chain at a specific location near to the gene in question (an area closely linked to the gene location). This technique is said to be 94%-99% accurate.

Genetic diagnosis has been extended to the fetus by means of amniotic cells obtained through amniocentesis. This is usually carried out at 16-18 weeks’ gestation. It is also possible to obtain a small sample of chorionic villi from the fetal side of placenta at 9-12 weeks’ gestation (before the amniotic sac completely fills the uterine cavity) using suction from a catheter introduced through the cervix into the uterine cavity and then into the placenta with the guidance of ultrasound. There appears to be about a 2%-4% (range, 1%-6.4%) incidence of fetal death after the procedure. An impressive and continually increasing number of conditions can be diagnosed prenatally.

Neonatal genetic diagnosis is being increasingly mandated by state governments. Currently, for example, the state of Illinois requires neonatal screening for phenylketonuria (PKU), galactosemia, biotinidase deficiency, sickle cell hemoglobinopathy, congenital adrenal hyperplasia, and hypothyroidism. All of these disorders can be diagnosed using heelstick blood spotted on filter paper.

Serum lactic dehydrogenase. Serum LDH levels are sometimes elevated in extensive carcinomatosis, often without any obvious reason. This is especially true in lymphoma, where it may be abnormal in up to 50% cases. However, LDH levels can be elevated in many conditions, which considerably lessens its usefulness in cancer diagnosis.

Carcinoma antigen 19-9. CA 19-9 is a carbohydrate antigen segment of a glycoprotein that appears to be a sialylated derivative of the Lewis A blood group. It is detected by monoclonal antibody immunoassay and is reasonably (but not highly) specific for GI tract origin (Table 33-14).

Table 33-14 CA 19-9 in various conditions

Currently, although there is considerable research activity, CA 19-9 assay is not being widely used. Although it has reasonably good sensitivity in pancreatic carcinoma, it does not detect these tumors early enough to improve their current dismal prognosis, and it is not specific for pancreatic neoplasms. It might be useful in the workup of patients when pancreatic or gastric carcinoma is a possibility and more informative diagnostic procedures (e.g., ultrasound or CT) are not available or do not provide a definite answer. A definitely elevated CA 19-9 level result would favor carcinoma of GI or GI accessory organs. The specimen has to be sent to a reference laboratory in most cases, and the results would not be available for several days. The CA 19-9 assay could be used to follow pancreatic carcinomas after surgical resection to detect recurrence, but the question then arises as to what could be done if it does recur. Finally, CA 19-9 has been used in addition to CEA in order to detect recurrence of colon cancer. In some cases, CA 19-9 values become elevated before CEA, and the combination of the two tests is said to be more reliable than either test alone. However, at present CA 19-9 is not widely used for this purpose. As noted in Table 33-14, CA 19-9 may be elevated in some persons who do not have cancer. Also, 5%–10% of the population is Lewis A (blood group) negative and will not react with CA 19-9, even if they have cancer.

Centocor CA 15-3 and Hybritech CA 549. CA 15-3 detects membrane antigens against human milk globules. It is said to be elevated in 57% of preoperative breast cancer patients, 75% (68%–80%) of patients with breast cancer with metastases, 3%–9% of patients with benign breast tumors, 4.5%–10.5% of patients with various nonmalignant conditions, and 1% of clinically normal persons. It is said to correlate with the clinical course of about 75% of patients with metastatic breast cancer, more frequently correlating with tumor progression than tumor regression. CA 549 detects any antigen present both in milk fat globule membranes and also in tumor cytoplasm. CA 549 is reported to be abnormal in 53%–90% of patients with metastatic breast cancer and 1%–13% of patients with benign breast disease. Certain other metastatic tumors are also detected.

Flow cytometry test for bladder cancer. One study reports that standard urine cytology detected 58% of high-grade bladder carcinomas and 33% of low-grade bladder carcinomas. Flow cytometry methods detected 76% of low-grade tumors and 100% of high-grade tumors. However, one study suggests that the technique is not reliable when intravesical chemotherapy is given (which is also the problem with standard urine cytology).

These syndromes have been mentioned in the discussion of certain tumors that may be associated with MEN. These syndromes are familial, with types I and II being inherited as an autosomal dominant disorder. About one half of type III cases are sporadic. Some cases of incomplete or overlapping organ tumor patterns have been reported.

Although carcinoid tumors are not considered part of the MEN syndromes, carcinoid of foregut origin (bronchial and gastric) may be associated with MEN I. Gastrinomas of the Z-E syndrome may be associated with MEN I, which includes pancreatic islet cell tumors (these tumors may produce insulin, gastrin, or vasoactive intestinal polypeptide). About 5%–10% of pheochromocytomas are associated with MEN types II and III.

Many patients with the MEN syndromes do not have all the tumor types considered part of the syndromes.

In general, when an effusion occurs, the problem is differentiation among neoplastic, infectious, and fluid leakage etiologies. Effusions due to neoplasms or infection are frequently termed exudates and those due to hydrostatic leakage from vessels are called transudates. Several criteria have been proposed to separate transudates and exudates and to differentiate among the three major diagnostic categories. Most work has been done on pleural fluids. The significance of tests performed on pleural fluid may not be the same if the tests are performed on ascitic fluid.

Etiology. The two most common causes of pleural effusions are congestive heart failure and neoplasm. Infection (tuberculosis or pneumonia) is the third most frequent etiology. In some cases it is necessary to establish the diagnosis of chylous effusion. Chylous effusions usually have a triglyceride content of 110 mg/100 ml (1.2 mmol/L) or greater and are usually more than twice the serum triglyceride value. Centrifugation does not clear a supernate area, and it may be possible to demonstrate fat droplets with a fat stain such as Sudan III. Another problem that occasionally arises is to differentiate urine from effusion fluid. Urine almost always has a creatinine concentration twice that of serum or more, whereas effusion fluid usually has the same creatinine concentration as the patient’s serum or at least is not elevated as much as twice the serum level. Rarely, recurrent fluid in or draining from the nose or ear has to be differentiated between cerebrospinal fluid (CSF) leakage from the central nervous system (CNS) subarachnoid space versus a serum transudate or local mucosa secretion. The usual diagnostic test is injection of a radioisotope into the CSF and subsequent analysis of a specimen of the draining fluid. Some other tests may be the ratio between serum and CSF total protein (which is usually more than 100), serum albumin/CSF albumin ratio (which is usually over 200), and serum prealbumin/ CSF prealbumin ratio (which is usually over 14).

Specific gravity. Exudates typically have a specific gravity of 1.016 or more and transudates less than 1.015. One study found about 25% error in misclassification of either transudates or exudates.

Protein content. Pleural fluid total protein levels higher than 3 gm/100 ml (30 gm/L) are characteristic of exudates. Transudates have total protein content of less than 3 and usually less than 2 gm. Two studies found that 8% of exudates and 11%–15% of transudates would be misdiagnosed if 3 gm/100 ml were used as the dividing line. Most exudates that were misdiagnosed as transudates were neoplastic. A pleural fluid/serum protein ratio of 0.5 may be a slightly better dividing line; exudates usually have a ratio greater than 0.5. With this criterion, accuracy in identifying transudates improved, but 10% of the exudates, mostly of malignant origin, were incorrectly classified as transudates. Pulmonary infarct, rheumatoid-collagen diseases, acute pancreatitis, cirrhosis with high-protein ascites (12%–19% of cases), and other conditions may produce effusions with protein content compatible with exudates.

Several investigators report that the albumin gradient between serum and ascitic fluid differentiates between transudate or exudate nature of ascites better than total protein content. In one study, total protein ascitic values produced 64% overlap between etiologies of the exudate and transudate groups, whereas the serum albumin-ascitic fluid albumin gradient (SA-AFAG) produced 38% overlap. Another study produced only 7% overlap. The SA-AFAG consists of subtracting the ascitic albumin value from the serum albumin value. A SA-AFAG value of 1.1 gm/100 ml (11 gm/L) or more suggests a transudate, usually caused by portal hypertension due to cirrhosis. A SA-AFAG value less than 1.1 gm suggests an exudate but will not differentiate malignancy from infection or inflammation and occasionally may occur in nonmalignant, nonalcoholic cirrhosis. Another problem may arise when two conditions coexist such as liver metastases in a patient with cirrhotic ascites.

Patients with ascites due to cirrhosis develop bacterial infection of the ascitic fluid without known cause (“spontaneous bacterial peritonitis”) in about 15% of cases (range, 4%–20%). Spontaneous ascitic infection typically has an ascitic total protein less than 1.0 gm/100 ml (10 gm/L). Other types of ascitic fluid infection (“secondary peritonitis”) usually have an ascitic fluid total protein level greater than 1.0 gm/100 ml, ascitic fluid glucose less than 50mg/100 ml (2.78 mmol/L), and more than one organism obtained by culture. Gram stains of ascitic fluid are said to be positive in only 10% of spontaneous peritonitis, but more frequently in peritoneal fluid due to intestinal perforation.

Effusion lactic dehydrogenase. A pleural fluid to serum lactic dehydrogenase (LDH) ratio greater than 0.6 is reported to be typical of exudates. One study found that most transudates were correctly identified but that nearly 30% of exudates were misclassified.

Combinations of criteria. The more criteria that favor one category as opposed to the other, the more accurate the results become. One study found that the combination of pleural fluid/serum protein ratio and pleural fluid/serum LDH ratio correctly identified most transudates and exudates.

pH. An effusion fluid pH higher than 7.40 usually is associated with a transudate, whereas a pH of less than 7.40 is more likely to be an exudate caused by infection, inflammation, or tumor.

Glucose. A pleural fluid glucose level more than 10 mg/100 ml below lower limits of normal for serum, especially when the actual pleural fluid value is less than 20 mg/100 ml, is reported to be suggestive of neoplasm or infection. Possibly 15%–20% of malignant effusions have decreased glucose levels. Patient hypoglycemia, rheumatoid arthritis, and infection are other etiologies.

Cell count and differential. In ascites, a total WBC count of 250 mm 3 or more strongly suggests infection, especially when neutrophils exceed 50% of total WBCs (some use 500 WBCs as the cutoff point). In any body fluid, presence of many segmented granulocytes suggests infection (empyema); many mononuclear cells raise the question of lymphoid malignancy, carcinoma, or tuberculosis. However, several investigators state that sufficient exceptions occur to severely limit the usefulness of differential counts in the diagnosis of individual patients. One study reported that peripheral blood WBCs did not affect ascitic fluid WBC counts.

Culture. Culture is frequently performed for tuberculosis, fungus, and ordinary bacteria. Pleural fluid culture for tuberculosis is said to be positive only in approximately 25% of known cases of tuberculosis effusion. Some believe that tuberculosis culture should be limited to high-risk patients or patients who have a positive skin test result. Whereas tuberculosis is an important cause of idiopathic pleural effusion, although less common in the United States than in the past, fungus is an uncommon cause of pulmonary infection except in patient groups with compromised immunologic defenses. Studies have shown about 85% sensitivity of culture in ascitic infection using blood culture bottles inoculated at the time of paracentesis versus only 50% sensitivity when ascitic fluid is streaked on agar plates or inoculated onto broth media in the laboratory.

Cytology. About 30%–40% (literature range, 25%–52%) of all pleural effusions are associated with neoplasms. About 35%–40% are caused by lung carcinoma (most often adenocarcinoma), and about 20%–25% are due to breast carcinoma, with lymphoma or leukemia, ovary, or unknown primary in third place. Cytologic study is reported to detect tumor cells in about 50%–65% (literature range, 30%–98%) of patients with malignant pleural effusions. One problem that sometimes occurs is poor cytologic preparations due to blood in the pleural fluid. We have obtained better results by using cytologic spray fixative when the cytologic slides are prepared rather than fixing the slides by the usual technique of dipping them in alcohol.

Pleural effusion carcinoembryonic antigen (CEA) CEA is discussed in detail elsewhere. Pleural fluid CEA levels may be elevated in various malignant and some benign conditions. When a cutoff level approximately 4 times the upper reference limit (corresponding to 10 ng/ml with the Hansen technique, whose upper normal limit is 2.5 ng/ml) is used, most elevations due to nonmalignant cause are eliminated (< 5% false positive results; literature range, 1%–12%). About 35%–50% of malignancies are detected (25%–89%). Therefore, CEA by itself is less sensitive than cytology. Addition of CEA to cytology (using a CEA cutoff value sufficient to exclude benign disease) improves detection of malignancy about 10%–15% over cytology alone. Carcinoembryonic antigen assay can also be used for ascitic fluid, with similar results.

Tests for cancer-related ascites Among many tests proposed to detect malignancy causing ascites or accumulation of peritoneal fluid are the serum albumin-ascitic albumin gradient (SAAAG), ascitic fluid cholesterol, ascitic fluid fibronectin, cytology, CEA, flow cytometry (FCM), CA 125, and the monoclonal antibody immunohistochemical stains. In general, SAAAG less than 1.1 appears to be the best single overall relatively simple test, with sensitivity in detecting malignancy about 93% (range, 85%–100%) and accuracy of about 95% (range, 93%–97%). The main drawback is inability to detect those cases of ascites due to liver metastases or hepatocellular carcinoma without peritoneal implants (since the intrahepatic malignant cells are infrequently in direct contact with ascitic fluid) or differentiate these cases from ascities due to cirrhosis. Ascitic fluid cholesterol greater than 45 in two reports had 90%–100% sensitivity, but not enough studies are available, and patients with cardiac or pancreatic-origin ascities may in some cases have elevated ascitic cholesterol. Fibronectin had sensitivity of about 90% (range, 86%–93%) in three studies, but specimens usually would have to be sent to a reference laboratory. Serum CEA has been discussed earlier. Ascitic fluid CEA has a reported sensitivity of about 50% (range, 36%–80%). Cytology of ascitic fluid has sensitivity of about 60% (range, 40%–70%). Adding CEA assay to cytology increases cytologic sensitivity about 10%–20%. FCM estimates the amount of nucleic acid in cell nuclei; in general, an abnormal quantity of nucleic acid (aneuploidy) suggests malignancy. In one study, FCM aneuploidy increased the number of patients found to have malignancy by 39% over results of cytology alone. However, not all aneuploid cells are malignant, and not all malignant cells are aneuploid . Therefore, flow cytometry has been reported to produce about 30% (range, 0%–43%) false negative results and some false positive results. CA 125 assay in serum is discussed earlier in this chapter. It has much less often been applied to ascitic fluid. In a few reports, CA 125 has been reported to increase detection of ovarian carcinoma (and occasionally, uterine or fallopian tube carcinoma) over detection rates from cytology with or without CEA. Disadvantages of ascitic fluid CA 125 assay is frequent elevation of the antigen in ascities due to cirrhosis and to some extent with endometriosis. Monoclonal antibody stains against various tumor antigens have been applied to cell blocks or smears or by FCM in body cavity fluid specimens. The most useful antibodies in peritoneal fluid appear to be CA 125 and B72.3 for ovarian carcinoma, and EMA and CEA for adenocarcinoma in general. In one representative study, peritoneal washings from patients with stage I and II ovarian carcinoma were positive by cytology in 41% of patients and by immunohistology in 56%. In stage III and IV ovarian carcinoma, immunohistology also added an additional 14% positive patients to results from cytology.

Peritoneal lavage for traumatic injury. Although this subject does not involve cancer, it does fit with discussions on tests for effusions, and thus it is included here. The standard criteria leading to high expectation of intraabdominal bleeding are one or more of the following: aspiration of gross blood (the quantity required is not uniform, but at least 10 ml or 20 ml are most often mentioned), fluid with an RBC count greater than 100,000/mm 3, or a WBC count greater than 500/mm 3. Other criteria that have been proposed but that are not widely accepted are abdominal fluid bilirubin or creatinine values higher than serum values or elevated effusion amylase. In most series the standard criteria detect significant intraabdominal bleeding in about 90% of cases and falsely suggest significant bleeding in about 10%–15% of cases (some of these patients may have bleeding that retrospectively is not considered sufficient to warrant laparotomy). CT scanning has proved extremely useful in trauma patients, with a sensitivity equal to that of lavage and a false positive rate significantly less than that of lavage. In addition, CT can often demonstrate what organs are affected.

General considerations. Three anticoagulated tubes of effusion fluid should be sent to the laboratory, one tube containing ethylenediamine tetraacetic acid (EDTA) anticoagulant, one tube containing 0.05% sodium polyanetholesulfonate (SPS; Liquoid), and the third containing heparin. The EDTA tube is used for cell count and differential, the SPS tube for culture, and the heparinized tube for cytology. Without anticoagulant there may be sufficient protein in the specimen to induce spontaneous clotting, which can trap WBCs and bacteria and produce erroneous cell counts and falsely negative cultures. Some use of the heparinized tube both for culture and for cytology, but too much heparin may inhibit bacterial growth. Nonanticoagulated effusion fluid should also be sent to perform biochemical tests. As noted previously, when the effusion is ascites it is better to inoculate blood culture bottles when the ascitic fluid is obtained rather than to perform routine culture methods.

About 27% of all cancer patients have some metastases at autopsy. Any carcinoma, lymphoma, or sarcoma may metastasize to bone, although those primary in certain organs do so much more frequently than others. Prostate, breast, lung, kidney, and thyroid are the most common carcinomas. Once in bone they may cause local destruction that is manifested on x-ray film by an osteolytic lesion. In many cases there is osseous reaction surrounding the tumor with the formation of new bone or osteoid, and with sufficient degree of reaction this appears on x-ray films as an osteoblastic lesion. Prostate carcinoma is usually osteoblastic on x-ray film. Breast and lung carcinomas are more commonly osteolytic, but a significant number are osteoblastic. The others usually have an osteolytic appearance.

Hematologic. About one half of the carcinomas metastatic to bone replace or at least injure bone marrow to such an extent as to give hematologic symptoms. This must be distinguished from the anemia of neoplasia, which appears in a considerable number of patients without direct marrow involvement and whose mechanism may be hemolytic, toxic depression of marrow production, or unknown. The degree of actual bone marrow replacement is often relatively small in relation to the total amount of bone marrow, and some sort of toxic influence of the cancer on the blood-forming elements has been postulated. Whatever the mechanism, about one half of patients with metastatic carcinoma to bone have anemia when first seen (i.e., a hemoglobin value at least 2 gm/100 ml [20 g/L] below the lower limit of the reference range). When the hemoglobin value is less than 8 gm/100 ml (80 g/L), nucleated red blood cells (RBCs) and immature white blood cells (WBCs) may appear in the peripheral blood, and thrombocytopenia may be present. By this time there is often extensive marrow replacement.

Therefore, one peripheral blood finding that is always suspicious of extensive marrow replacement is the presence of thrombocytopenia in a patient with known cancer (unless the patient is on cytotoxic therapy). Another is the appearance of nucleated RBCs in the peripheral blood, sometimes in addition to slightly more immature WBCs. This does not occur in multiple myeloma, even though this disease often produces discrete bone lesions on x-ray film and the malignant plasma cells may replace much of the bone marrow.

Alkaline phosphatase. Because of bone destruction and local attempts at repair, the serum alkaline phosphatase level is often elevated. Roughly one third of patients with metastatic carcinomas to bone from lung, kidney, or thyroid have elevated alkaline phosphatase levels on first examination. This is seen in up to 50% of patients with breast carcinoma and 70%–90% of patients with prostate carcinoma.

Bone x-ray film. If an x-ray skeletal survey is done, bone lesions will be seen in approximately 50% of patients with actual bone metastases. More are not detected on first examination because lesions must be more than 1.5 cm to be seen on x-ray films, because parts of the bone are obscured by overlying structures, and because the tumor spread may be concealed by new bone formation. Almost any bone may be affected, but the vertebral column is by far the most frequent.

Bone radionuclide scan. Bone scanning for metastases is available in most sizable institutions using radioactive isotopes of elements that take part in bone metabolism. Bone scanning detects 10%–40% more foci of metastatic carcinoma than x-ray film and is the method of choice in screening for bone metastases. A possible exception is breast carcinoma. Although bone scan is more sensitive for breast carcinoma metastasis than x-ray film, sufficient additional lesions are found by x-ray film to make skeletal surveys useful in addition to bone scanning. Also, in cases in which a single lesion or only a few lesions are detected by scan, x-ray film of the focal areas involved should be done since scans detect benign as well as malignant processes that alter bone (as long as osteoblastic activity is taking place), and the x-ray appearance may help to differentiate benign from malignant etiology. Bone scan is much more sensitive than bone marrow examination in patients with most types of metastatic carcinoma. However, tumors that seed in a more diffuse fashion, such as lung small cell carcinoma, neuroblastoma, and malignant lymphoma, are exceptions to this rule and could benefit from marrow biopsy in addition to scan.

Bone marrow examination. Bone marrow aspiration will demonstrate tumor cells in a certain number of patients with metastatic carcinoma to bone. Reports do not agree on whether there is any difference in positive yield between the sternum and iliac crest. Between 7% and 40% of the patients with tumor in the bone have been said to have a positive bone marrow result. This varies with the site of primary tumor, whether the marrow is tested early or late in the disease, and whether random aspiration or aspiration from x-ray lesions is performed. The true incidence of positive marrow results is probably about 15%. Prostatic carcinoma has the highest rate of yield, since this tumor metastasizes to bone the most frequently, mostly to the vertebral column and pelvic bones. Lung small cell (oat cell) carcinoma, neuroblastoma, and malignant lymphoma also have a reasonable chance of detection by bone marrow aspiration.

Several studies have shown that marrow aspiration clot sections detect more tumor than marrow smears and that needle biopsy locates tumor more often than clot section. Two needle biopsies are said to produce approximately 30% more positive results than only one.

The question often arises as to the value of bone marrow aspiration in suspected metastatic carcinoma to bone. In this regard, the following statements seem valid:

1. It usually is difficult or often impossible to determine either the exact tumor type or the origin (primary site) of tumor cells from marrow aspiration.
2. If localized bone lesions exist on x-ray film and it becomes essential to determine their nature, a direct bone biopsy of these lesions using a special needle is much better than random marrow aspiration or even aspiration of the lesion area. In this way, a histologic tissue pattern may be obtained.
3. If a patient has a normal alkaline phosphatase level, no anemia, and no bone lesions on bone scan (or skeletal x-ray survey, if bone scan is not available), and in addition has a normal acid phosphatase level in cases of prostatic carcinoma, the chances of obtaining a positive bone marrow aspirate are less than 5% (exceptions are lung small cell carcinoma, lymphoma, and neuroblastoma).
4. If a patient has known carcinoma or definite evidence of carcinoma and x-ray lesions of bone, chemical studies or bone marrow aspiration usually have little practical value except in certain special situations in which anemia or thrombocytopenia may be caused by a disease that the patient has in addition to the carcinoma.

Thyroid carcinoma seems to have generated a considerable number of misconceptions. About 20% of these tumors are “pure” papillary, about 10% pure follicular, about 50% mixed papillary and follicular, and about 5% (range, 2%–10%) are called medullary. However, the pure papillary carcinoma usually has a few follicular elements if enough histologic sections are made, and the reverse is sometimes true in follicular tumors. In addition, some pathologists classify the tumors according to the predominant element unless the proportions of each element are very similar. If this were done, about 65% would be called papillary and about 20% follicular. There is enough diversity in classification methods to create difficulty in relating pathology reports to statistics in the literature. Papillary and most mixed papillary-follicular carcinomas metastasize primarily to regional lymph nodes. Prognosis is excellent in young adults but less so in older persons. Follicular carcinoma tends to produce hematogenous metastases, most often to lungs and bone. About 15% (range, 4%–30%) of single palpable nodules not selected by thyroid scan or fine-needle aspiration are malignant when excised.

Thyroid radionuclide scan. A major screening test is the thyroid scan. The characteristic appearance of thyroid carcinoma is a single nonfunctioning nodule. A gland that is multinodular on scan has less chance of containing carcinoma than one with a solitary nodule. On occasion, a palpable nodule may represent metastatic carcinoma from another primary site in a lymph node close to the thyroid.

Radionuclide scanning of thyroid nodules can be done with radioactive iodine (RAI) or technetium 99m pertechnetate. Results from comparison studies usually agree, but occasionally carcinomas that appear to have some function on technetium scan but not on iodine scan have been found. About 20% of single thyroid nodules without demonstrable function on scan are malignant (literature range, 3%–58%). About 6% of nodules with some function (reduced, but present) and about 6%–8% of nodules with apparent normal function (literature range, 0%–38%) are reported to be malignant. In some of these cases, normal thyroid tissue above or below the nodule creates a false impression of nodule function. Hyperactive nodules are very rarely malignant, although occasionally a malignancy is found unexpectedly in the same gland.

A minority of investigators believe that radioiodine or technetium scanning is not helpful in evaluation of thyroid nodules for possible malignancy. As noted previously, a single nodule without demonstrable function on scan has roughly a 20% chance of malignancy, which means that 80% of such nodules will be falsely positive for malignancy. On the other hand, some reports indicate that 6%–8% of nodules with apparently normal function may actually be malignant and thus represent false negative results. Therefore, some investigators rely on criteria other than thyroid scan to determine which patients with thyroid nodules should receive operative therapy. The criteria that have been used include patient history, characteristics of the nodule on physical examination, fine needle aspiration, or response of the nodule to thyroid hormone suppression. In the suppression test, failure of the nodule to diminish at least 50% in size during 3 months of suppression would increase the chance of malignancy.

A significant number of patients are referred for thyroid scan while thyroid uptake of radionuclide is being suppressed by administration of thyroid hormone or by x-ray contrast media. This frequently produces unsatisfactory or even misleading results.

Thyroid scan to detect thyroid carcinoma metastases. A different problem may arise when thyroid cancer is discovered and patients are referred for scanning to detect metastases, either before or after initial therapy. Unless all of the normal thyroid tissue is removed or is ablated by radioiodine therapy, enough of the scanning dose will be taken up by normal tissue to make such attempts useless in most cases. In addition, replacement thyroid hormone administration must cease for 2-4 weeks before scanning, so that the pituitary will once again produce thyroid-stimulating hormone (TSH), which, in turn, will help stimulate the tumor to take up the radioiodine. The dose of (RAI (1–5 mCi; SI, 0.037–0.185 MBq) for a metastatic tumor scan is more than 10 times the usual thyroid scan dose, and the optimal time to scan is 72 hours after administration of the dose. Some prefer a technetium phosphate bone scan to an iodine 131 (131 I) tumor scan. Most bone metastases detected by iodine are also detected by technetium phosphate, and the remaining thyroid tissue does not have to be ablated. However, a few bone metastases are detected by radioiodine and not by technetium. Lung metastases or recurrent neck tumor would be missed using technetium bone scan agents.

Serum thyroglobulin (TG) assay. Serum thyroglobulin (TG) assay has been advocated to follow patients after treatment of thyroid carcinoma. TG is synthesized by thyroid epithelial cells. It is present in measurable amounts in the serum of normal persons on immunoassay (using antibodies against TG) and is increased following TSH stimulation. Elevated values are found in active thyrotoxicosis (diffuse or nodular), thyroiditis, iodine deficiency, benign thyroid adenomas, and differentiated thyroid carcinomas. Therefore, TG elevation is too nonspecific to use for diagnosis of thyroid carcinoma. In thyroid carcinoma, the TG level is usually elevated in papillary, follicular, and mixed papillary-follicular neoplasms. Some anaplastic thyroid carcinomas produce elevated values and some do not. Medullary carcinomas do not produce measurable serum levels of TG. The TG assay can be used to monitor the progress of differentiated thyroid carcinomas after treatment. The half-life of circulating TG is said to be 8-22 hours, so circulating levels should be absent in 7-14 days after total destruction of all normal thyroid tissue and tumor tissue by surgery. Ablation by radioactive iodine is much more gradual and variable. TG values that are nondetectable or nearly so following therapy signify that no residual thyroid or tumor remains, and future elevations mean tumor recurrence or metastasis. Thyroglobulin values that are within the reference range following therapy could either be tumor or could be remnants of normal thyroid, and a thyroid tumor scan with 131 I is required to differentiate these possibilities.

One advantage of TG monitoring is less need for 131 I scanning. This avoids both additional radiation and the need to temporarily stop thyroxine replacement therapy to perform the scan. Also, occasionally patients with metastases associated with elevated TG levels but not detected on 131 I tumor scan have been reported. Disadvantages include a small number of patients with metastases detected on 131 I tumor scan but TG values within the reference range. This occurs in about 4% of cases (literature range, 0%–63%). TG levels are more likely to be normal with pure papillary tumors or those with only lung metastases. Also, the presence of patient anti-TG autoantibodies may interfere with the TG assay.

Fine-needle aspiration cytology. Fine-needle aspiration of thyroid nodules with cytologic smear examination of the aspirate has been advocated to aid diagnosis and, when possible, to replace surgical biopsy. Results in the literature vary rather widely, partially depending on experience with the technique, patient selection, and method of reporting positive results (for example, “definitely malignant” would detect fewer cases of carcinoma than the combination of “malignant” and “suspicious for malignancy”). Some centers report a false negative rate of less than 5% and a false positive rate of less than 2%. Most hospitals could not expect to achieve such good results. The average false negative rate for malignancy with experienced cytologists is about 5%–10%, and the average reported rate overall is about 10%–15% (literature range, 0%–50%). Follicular carcinoma is more difficult to diagnose than papillary carcinoma. The average false positive rate for experienced cytologists is about 2%–4%, and the average reported rate overall is about 5% (range, 0%–14%). Most pathologists without special interest or extensive experience in fine-needle aspiration cytology are better able to interpret needle tissue biopsy material than thyroid aspiration cytology, because thyroid cytology takes special training and experience. However, well-differentiated follicular carcinoma is difficult to diagnose on needle biopsy as well as on aspiration. Needle biopsy is also useful to diagnose thyroiditis.

Thermography and B-mode ultrasound have been used to help evaluate thyroid nodules for malignancy. Results of thermography to date have been rather disappointing. Ultrasound has been used to differentiate cystic thyroid lesions from solid ones. About 15%–20% of thyroid nodules that fail to concentrate radioactive iodine are cystic. Typical completely cystic lesions are rarely malignant (about 2%; literature range, 0%–14%). Ultrasound accuracy in differentiating pure cystic lesions from solid or mixed cystic-solid lesions is usually quoted as about 95% (80%–100%). The procedure in many clinics is to perform aspiration with cytology on ultrasonically pure cysts.

Medullary carcinoma of the thyroid. Medullary carcinoma constitutes 5% (range, 2%–10%) of thyroid carcinomas. It is derived from certain stromal cells known as “C-cells.” The tumor has an intermediate degree of malignancy. It may occur sporadically or in a hereditary form. The sporadic form comprises 80%–90% of cases and is usually unilateral. The familial variety is transmitted as an autosomal dominant trait, is usually present in both thyroid lobes, and is frequently associated with other neoplasms (phenochromocytoma, mucosal neuromas) as part of MEN II (Sipple Syndrome,Table 33-13) or MEN III. This also includes some degree of association with other endocrine abnormalities, such as parathyroid adenoma and Cushing’s syndrome. The tumor may have a variety of histologic patterns, but the classic form is solid nests of cells that are separated by a stroma containing amyloid. These tumors have aroused great interest, since most secrete abnormal amounts of the hormone calcitonin (thyrocalcitonin). Calcitonin has a calcium-lowering action derived from inhibition of bone resorption; therefore, calcitonin acts as an antagonist to parathyroid hormone. Thyroid C cells produce calcitonin as a normal reaction to the stimulus of hypercalcemia. About 70%–75% of medullary carcinomas produce elevated levels of serum calcitonin; this includes most sporadic (nonfamilial) cases. About 25%–30% of familial medullary carcinoma (MEN type III or IIB) have normal basal calcitonin levels. In patients with normal basal calcitonin levels, elevated calcitonin values can be induced by stimulation with calcium infusion or pentagastrin. Glucagon also stimulates calcitonin secretion but not as effectively. A few medullary carcinomas are reported to secrete serotonin or prostaglandins. About 30% of patients experience diarrhea. Besides medullary thyroid carcinoma, calcitonin secretion has been reported in as many as 60% of patients with bronchogenic carcinoma (small cell and adenocarcinoma tumor types).

Table 33-13 Multiple endocrine neoplasias

AFP and beta subunit chorionic gonadotropin (hCG) levels by EIA methods are elevated in certain gonadal tumors. In general, pure seminomas fail to produce AFP, whereas hCG production in seminoma ranges from 0%–37%. Some 70% or more of patients with embryonal cell carcinoma and malignant teratoma have elevated AFP levels, and 40%–60% or more have elevated hCG levels. Eighty-five percent or more patients have elevated levels of one or both. Elevation of AFP by immunoassay occurs in hepatoma (70%–90%,Chapter 20) and has also been reported in up to 18% of patients with gastric carcinoma, up to 23% of those with pancreatic carcinoma, and occasionally in patients with lung carcinoma or other tumors, mostly in low titer. Elevated AFP level is also reported in up to 30% of patients with acute and chronic active hepatitis. Elevated hCG level is found in choriocarcinoma or hydatidiform mole (Chapter 32) and has also been reported in low titer with a small number of various other neoplasms, notably gastric, hepatic, pancreatic, and breast carcinoma. It has even been detected in a few patients with melanoma and myeloma (again, usually in very low titer).

Neuroblastoma. Neuroblastoma is the most common nonhematologic extracranial tumor of childhood and is the most frequent abdominal malignant mass lesion except for Wilm’s tumor between ages 1-4 years. Treatment by combined radiation and chemotherapy produces excellent results in sufficient patients that diagnosis has become of more than academic interest. It usually presents as an abdominal mass, and frequently the only method of definitive diagnosis is abdominal exploration with biopsy. Urine vanillylmandelic acid (VMA) levels have been found elevated in more than 90% of patients (literature range, 61%–100%), although some elevations were not present on initial specimens. Homovanillic acid (HVA), a metabolic product of the catecholamine precursor dopamine, has been reported to be abnormal in about 80% (53%–93%) of patients. Combined VMA and HVA positive results include nearly 100% of patients. Bone marrow aspiration has been reported abnormal in up to 50% of patients. Therefore, some investigators recommend that bone marrow aspiration be done on all patients, since the finding of marrow metastases rules out surgery alone as a curative procedure.

Neuroblastoma discovered during the first year of childhood has a much better prognosis than cases found afterward. DNA analysis by FCM has shown that aneuploid neuroblastomas have in general a better response to chemotherapy and a better prognosis than diploid ones, the opposite of usual circumstances. In addition, 30%–40% of patients have detectable n-myc oncogene (located on chromosome 2), and in those patients in whom the n-myc molecule is amplified (increased in number) over 3 times, there is a worse prognosis. There is also a very high incidence of other chromosome abnormalities, such as deletion of chromosome 1, but this has less prognostic value. Other prognostic tests include serum ferritin, where normal values (less than 150 ng/ml, but reference range is age related) are associated with early stage and less aggressive tumors. Ferritin can also be used to monitor the effect of chemotherapy. Serum neuron-specific enolase has also been reported to have prognostic value, with levels over 100 ng/ml being associated with poor prognosis; but the enzyme cannot be used to monitor therapy.

In primary brain tumor, cerebrospinal fluid protein level is elevated in up to 70% of patients and cell count in about 30% of cases. One or the other is abnormal in 65%–80% of cases. Electroencephalogram (EEG) is abnormal in about 70%–75% of patients (literature range, 70%–92%), brain scan in about 80%–85% (65%–96%), and CT in about 90%–95% (85%–100%). Therefore, CT scan (or magnetic resonance imaging [MRI]) is clearly the best single test for primary brain tumor (or any space-occupying brain lesion), whereas EEG adds little, if anything, to CT or brain scan information. About 15%–25% (range, 4%–37%) of brain tumors are metastatic (“e condary”). The most common site of origin is lung (about 40% of metastatic brain tumors; literature range, 35%–60%). Next is breast (about 25%; range, 20%–30%); third is probably melanoma (about 10%–15%) or kidney (about 10%). The GI tract (including pancreas) contributes about 5%, and the remainder is shared by various primary sites.

Tumor in the liver is most often metastatic. The liver receives metastases more frequently than any other organ, since 25%–50% of all metastasizing cancers reach the liver. The GI tract (including the pancreas), breast, kidney, lung, melanomas, and sarcomas are especially apt to produce hepatic metastases.

Tests for detection include alkaline phosphatase, gamma-glutamyltransferase, liver scan (radionuclide, ultrasound, CT), and liver biopsy. Primary liver cell carcinoma (hepatoma) is more common in cirrhosis. On liver scan, it typically appears as a large, dominant, space-occupying lesion. The alpha-fetoprotein (AFP) result is often positive. Liver biopsy is essential to verify a diagnosis of cancer in the liver, since nonneoplastic diseases may produce abnormalities identical to those of neoplasia in any of the tests.