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(" a-\",LZKbԲ-t0 (ZFV̱G*b!X!yъz%Y !ȫ!{,.= - *F$䴋8q"<Y 8ŧ0Ci l C SBe0D yf>m@C\Tw ׁćD*`F2r= e85@gET!txɊ / 1p|C+v2 , ) ՀOQO (@EǤI"J(0c"$)8UF810>5G)Cڊx!%Ѩ"KqCfCyr< ;31u #j(R9-PPkNOBOp>qǫr&d4C 8x*[:;Q{D+"@P0'A*@|$( BЁ`@'ȁ aE0P Vif4 $g9̢@&hX1=6 JX20G9x<<x8YgCϴ(fⓄЂO j bO, Qa`hN+h$( 8 =8 'O Ї FP@d](~b|AS6A@2 i|Jjb1ĕC>w YBTA qPZԆtF@'= b"IC-jAhv4UK"cC "e CfXKpj$kd L) 9OQxԔP:CAn.ڷ"r,F e.^I*Ró:!V H@0$b8@~qb 9<A@ȃA B0;(EChHH>0P" ϲG3q Nb8 y`\3 Ds *{%[aDsxPm [p ° Hf `b W |p Wp& `@ JTP>w9KQ d# Gհ >aذ zX-e2,` iA qs#t+]0 `Q@Lan ~ 0> } "HdQ` 5?  |$ _b0X Xf,@T0 >APRx($ ADRENOCORTICOTROPIC HORMONE

Adrenocorticotropic hormone (ACTH) is the most frequently observed ectopic hormone produced by neoplasms. In 1928, the first instance of ectopic production of ACTH in a patient with small-cell carcinoma of the lung was reported [n118]. Ectopic production of ACTH has been subsequently associated with other malignant diseases, including adenocarcinoma and squamous cell carcinoma of the lung, carcinoid, pancreatic islet cell tumors, carcinoma of the breast, carcinoma of the colon, pheochromoctyoma, thymoma, medullary carcinoma of the thyroid gland and carcinoma of the ovaries. Elevated levels of ACTH have been observed in numerous benign conditions, including chronic obstructive pulmonary disease, obesity, hypertension and diabetes mellitus.

Carcinoma of the lung, particularly small-cell carcinoma, is the most common cause of ectopic production of ACTH; however, most carcinomas of the lung secrete "big" ACTH, a prohormone with 3 to 5 per cent of the biologic activity of native ACTH. Because of the relative inactivity of this prohormone, clinical manifestations of Cushing's syndrome are uncommon. Ectopic secretion of ACTH can be differentiated from ACTH that originates in the pituitary gland by the dexamethasone suppression test: Failure to suppress plasma cortisol levels with high does dexamethasone suggests ectopic secretion of ACTH.

ACTH has no value in screening for carcinoma, and pretreatment levels demonstrate no correlation to patient survival time or stage of disease. The usefulness of serial measurements of ACTH to monitor response of tumor to therapy remains controversial. ACTH lacks the sensitivity and specificity to be clinically useful for screening, staging or predicting response to therapy.

ANTIDIURETIC HORMONE

Small-cell carinoma of the lung is the malignant disease most commonly associated with ectopic secretion of antidiuretic hormone (ADH). Secretion of ADH may be detected biochemically or may present clinically as the syndrome of inappropriate ADH (SIADH). Approximately 80 per cent of the instances of SIADH associated with malignant disease occur with small-cell carcinoma of the lung; however, SIADH occurs in less than 10 per cent of patients with small-cell carcinoma of the lung.

Other malignant disease found to secrete ectopically ADH include carcinoma of the pancreas, bronchial carcinoid tumors, carcinoma of the adrenal cortex, thymomas, carcinoma of the bladder and prostate. Benign causes of ADH production include pulmonary disease, disorders of the central nervous system, anesthetics and ingestion of drugs. ADH is not a useful marker for screening of carcinoma, staging or monitoring response to therapy.

POLYAMINES

The polyamines consist of a group of organic cations, including putrescine, spermidine and spermine. Levels of polyamines increase in response to growth of tissue, cellular replication and numerous benign and malignant conditions. Benign diseases associated with elevated levels of polyamines include rheumatoid arthritis, polymyositis, psoriasis, tuberculosis, chronic obstructive pulmonary disease and pernicious anemia. Elevated urinary excretion of polyamines has been documented in patients with a variety of malignant diseases, including leukemia, lymphoma, melanoma, carcinoma of the colon and rectum, pancreas, bladder, prostate and lung and primary tumors of the brain.

In patients with malignant disease, levels of polyamines seem to correlate with tumor burden, activity of the disease and cell loss. In 1979, higher levels of polyamines were observed in patients with actively progressive disease and in patients with large tumor burdens. Other studies have documented higher urinary levels of polyamines in patients with metastatic carcinoma of the breast compared with patients with localized carcinoma of the breast. Furthermore, recurrence of disease may be preceded by increasing urinary levels of polyamines. In patients with medulloblastoma, increasing levels of putrescine in cerebrospinal fluid have accurately predicted recurrence.

Response of hematologic and solid tumors to chemotherapy has been associated with an immediate increase and subsequent decrease in levels of polyamines. An immediate twofold or greater increase in urinary levels of spermidine correlated with objective response of tumor to chemotherapy in one study. In patients with no significant increase in excretion of spermidine, no response to therapy was observed. These findings are preliminary, however, and require confirmation by subsequent clinical investigation.

ADDITIONAL MARKERS

A number of enzymes, proteins, hormones and antigens are currently being investigated as potential markers of tumors in the future. The recent development of monoclonal antibodies has lead to the discovery of numerous tumor-associated antigens in the serum and tissue of the tumor in patients with malignant disease. Chromosomal changes, including deletions, segmental duplications and trismony, have been documented in human malignant disease and may provide important diagnostic and prognostic information. These markers require further study to determine the role in screening for carcinoma, assessing tumor burden and monitoring the response of the tumor to therapy.

SUMMARY

This state-of-the-art review identifies the clinical usefulness and limitations of currently available tumor markers. The role of specific tumor markers in screening, assessing extent of disease and monitoring the response of the tumor to antineoplastic therapy is discussed. Recent technologic advances, including monoclonal antibodies and genetic analysis, may identify additional tumor markers and provide insight into the developmental process of neoplasia by characterizing the biologic changes associated with malignant disease.

SUPPLEMENTARY INFORMATION: From the Department of Surgery, Division of Surgical Oncology, University of Pennsylvania School of Medicine, Philadelphia.

Reprint requests:  Dr. Michael H. Torosian, Hospital of the University of Pennsylvania, 4th Floor, Silverstein Pavilion, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.