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Home , Paraneoplastic syndrome

[ RESEARCH 34, 2088-2091, August 1974] Ectopie Synthesis and Paraneoplastic Syndromes1

Thomas C. Hall2

Los Angeles County-University of Southern California Cancer Hospital and Research Center, Los Angeles, California 90033

Summary

Paraneoplastic are clinically important dis The second major histological anlägefrom which tu turbances of function in distant organs of the human cancer mors arise to produce "ectopie" products is the foregut. patient. They appear to arise because partially differenti Here we find hepatoblastomas producing gonadotrophins ated cells in specific tissues, when transformed, retain some and pancreatic tumors producing and . Not specialized synthetic capacities of their tissues of origin, all glandular foregut are functioning, however. The while expressing others which result in rapid growth, stomach and lining epithelium have rarely been described as mobility, broaching of the basement membrane, and lack of involved in such syndromes, although cancer of the lower feedback inhibition. The result is the production and release may be associated with distant effects into circulation of unusual amounts and/or varieties of upon the skin, such as . The nephro- macromolecules, which may result in unphysiological over- genic ridge "cancers," e.g., of , ovary, and uterus, or underactivity of a number of distant host target organs. commonly produce erythropoietic substances which resem The products involved should be studied as possible onto- ble those normally produced by the anoxic normal kidney. genic-phase-specific tissue macromolecules. Occasionally, a kidney tumor will be associated with hypercalcemia in the absence of bone métastases,or a prostatic cancer will produce Cushing's , or Introduction hypokalemic alkalosis, suggesting the synthesis of parathy The "paraneoplastic syndromes" are disease entities roid or ACTH of pituitary type. This emphasizes found in cancer patients, in whom clinical disorders of that the tumor product is usually, but not invariably, similar function are found in host organs at a distance from the to a normal product of a tissue derived from the same cancer (7). It has been calculated that, at any one time, 15% embryogénieanlägeas the tumor. of cancer patients will be suffering from such distant The neuroectodermal tumors do not often give rise to metabolic effects of the cancer, as opposed to the symptoms metabolic derangements of other host organs. This may be and signs that the cancer causes by direct of host because most brain tumors are of connective tissue or glial organs. The incidence and severity of such systemic mani origin, or because the material "ectopically" produced festations increase with the severity of the neoplastic would resemble that of normal neurons, which do not have process; it is believed that three-fourths of all uncured endocrine functions and, accordingly, would be difficult to cancer patients will suffer from such a syndrome during the detect. However, certain cells of neuroectodermal origin do course of their disease. wander into other areas during embryogenesis and come to represent an "organ" which is widely dispersed throughout Classification the other parenchymatous organs. These cells are neuro- secretory, commonly producing one or more amines with The tumors that are found to be associated with distant powerful systemic effects. Such cells include the Kul- host effects can be grouped into 4 major types, character schitsky cell of the lung, and the argentaffin cells of the ized by the embryological origin of the tissue from which the gastrointestinal tract. Because of their characteristic histo- tumors arise. The commonest cancer of branchial cleft chemical staining properties, they have been called by origin is that of the lung. Such tumors give rise to many Pearse (8) the "amine precursor uptake and decarboxylat- syndromes caused by the cancer producing the polypeptide ing (APUD) cells." Tumors derived from this 3rd embryo- which are normally produced by other branchial logical anlägeinclude of the gastrointestinal cleft derivatives such as the parathyroid and the anterior tract, lung, and pheochromocytomas, which may produce pituitary. Parathyroid cancers continue to produce their a wide spectrum of catechols and polypeptide hormones. own normal product, , but in excessive The final embryological anlägefrom which physiologi amounts; this is true of both adenocarcinomas and medul cally active cancers arise is the chorion itself; choriocar- lary tumors. The neoplastic synthesis of hormones is not cinomas of the placenta and those of the gonads commonly complete, however, since lung cancers rarely make TSH.3 produce large amounts of chorionic gonadotrophins and, in some cases, TSH. 1Presented at the Third Conference on Embryonic and Fetal Antigens In addition to classification by the tissue of tumor origin, in Cancer, November 4 to 7, 1973, Knoxville, Tenn. 2American Cancer Society Research Professor PRP-47. syndromes can also be grouped pathophysiologically ac 3The abbreviations used are: TSH, thyroid-stimulating hormone; cording to the mediators which are produced by the tumors ACTH, adrenocorticotrophic hormone. and which then alter the function of noncancer tissues of the

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1974 American Association for Cancer Research. Ectopie Synthesis and Paraneoplastic Syndromes host. These can be considered as short-range substances because of the production by distant tumors of amyloid which act only upon the cells quite close to the , (myeloma), excess uric acid (), or antigen- and long-range mediators which have their major action complexes (, colon cancer). The bone matrix can upon an organ other than that in which the tumor originates be stimulated to produce osteoid by the local action of or is found as a metastatic deposit. We shall pay little at métastasesfrom mucus- and phosphatase-secreting tumors, tention to the short-range effectors here, except for the few with resulting increased density of bone cortex, crowding cases in which a direct effect so alters the function of an out of marrow, and leukoerythroblastic . Increased organ that a "secondary" re cortical calcification of bone can also be induced by the sults. Examples of short-range mediator effects include the distant production of thyrocalcitonin by medullary parathy intravascular coagulation produced around small tumor roid cancer. Analogously, decreased bone matrix can be emboli by direct activation of clotting factors, proliferation induced by local tumor cell osteolysis, with resulting of endothelium by angiogenesis factors, and osteoblastic hypercalcemia; this is the usual mechanism by which breast and osteolytic changes immediately around the tumor. Each cancer causes hypercalcemia. Parathormone-like sub of these can, in some instances, also produce distant system stances produced by can also produce hypercal effects. In the cases cited above they produce, respectively, cemia by acting to dissolve bone. It is interesting to note disseminated intravascular coagulation, "clubbing," and that although we have considered these syndromes as hypocalcemia or hypercalcemia. manifestations of over- and underactivity of the bone The long-range factors include: (a) normal active secre matrix, if one focuses on the action of the mediators at a tory endocrine products of the tissue from which the tumor cellular level, both osteolysis and osteoblastosis may be derived, e.g., steroids produced by ovarian, testicular, and produced by a tumor mediator stimulating to physiological adrenal tumors, in excess of physiological need, apparently overactivity the osteoclasts and the osteoblasts, respectively. because of an inoperative negative-feedback loop. a-Feto- In general, there appear to be more syndromes recognized globulin fits this class, although it is a normal product of the in conjunction with mediators that stimulate organs to embryogénieorfetal liver, rather than of the adult tissue. In overactivity than with mediators that are inhibitory. This this case an ontogenetic repressor seems to be lost; (b) may be more apparent than real, since in many instances cytoplasmic constituents of the tumor, some of which are tumor-induced underfunctions of a host organ would be shared with the normal adult tissue of origin, e.g., prostatic hard to detect clinically. acid phosphatase, or are shared with fetal cells of the An example of tumor-induced hypofunction of bone corresponding tissue, e.g., fetal hemoglobin production in marrow is the pure red cell aplasia that is sometimes seen in acute childhood leukemia (?); (c) immunologically active conjunction with . Here there is evidence of a membrane or cytoplasmic tumor cell constituents which circulating immunoglobulin (1). Another, short-range effect produce antibody or cellular immune reactions in the host, may be the inhibition of normal hematopoiesis by products e.g., , nephrosis, and ulcerative colitis; (d) of nearby cells of myelogenous leukemia. Generally, how tumor-produced excesses of trophic hormones which in turn ever, the bone marrow is stimulated, in the case of produce overfunction of a target organ, whose products then -secreting tumors of kidney and ovary, to produce systemic effects, e.g., a secreting ACTH produce red cells, as is true in the case of the hemolytic which induces Cushing's syndrome. of and lymphoma. The leukocytosis The clinical manifestations seen ultimately involve over- seen in lung cancers may in time be found to be due to the function or underfunction of certain organs that are affected effect of a lung cancer-produced mediator. by these tumor-produced substances. Not all organs are When the immunological system is "depressed" by involved and, usually, malfunction of a single organ system tumors, the depression is usually either the result of local predominates clinically. The skin as an overreactive target replacement of the immune system by a tumor of those organ is represented by the occurrence of acanthosis organs, i.e., a lymphoma, or is due to circulating products nigricans, and atrophie dysfunction is suggested by sclero by a distant tumor. In the 1st instance, the effects must be derma. The nervous system can be overstimulated, as considered to be due to the short-range factors which permit manifested by the mania and induced by some tumor cells to compete successfully with the normal cellular cancers, principally of the lung. Underfunction of the inhabitants of node or spleen. In the 2nd case, immune central nervous system appears to be involved in the hypofunction is seen as depressed reactivity to recall and peripheral neuropathy and myasthenia-like syndromes ob neoantigens. This is commonly and erroneously attributed served with many cancers. Depression of the gustatory to a generally depressed state of immune reactivity whereas, functions of the brain or cranial nerves is apparently in fact, it is usually due to selective impairment of immune involved in the loss of appetite and taste so common in response by the production of excess amounts of tumor- patients with advanced cancer and results in cachexia of an associated tissue antigens. This is a long-range type of extreme degree due to poor nutrition of organs not directly effect. Overactivity of the immune system is much more involved by tumor. The kidney is an organ that can be common, and is most frequently seen with epithelial can stimulated to produce angiotensin and hypertensin by cers, presumably secondary to their release during invasive- renin-producing tumors, and erythropoietin by cerebellar ness of epithelial material into the mesenchymal im- tumors with resulting erythrocytosis. Lung tumors com munocompetency system. The frequency of hyperergic monly produce antidiuretic hormone, with resulting autoimmune syndromes seems proportional to the fre Schwartz-Bartter syndrome. Renal function can deteriorate quency of incidence of tumors—lung, colon, and breast

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1974 American Association for Cancer Research. T. C. Hall being most frequent. The secondary target organs of Biochemically, many of the tumor-associated mediators autoimmune damage include connective tissue (der- are comparable or identical to normal products of normal matomyositis), epithelia (ulcerative colitis and regional tissues. Their production by tumors has been called "ec enteritis), brain (cerebellar degeneration), and kidney topie," "inappropriate," and "derepressed." The first sug (glomerulopathic nephrosis). gests that some materials produced are ectopie in place The term "oncocognitive autoimmunity" has been coined (since, for example, a lung cell should not be making to suggest that many other "autoimmune" diseases may ACTH) or are ectopie in time, since a liver cell should not occur as the unavoidable yet undesirable consequences of be making a-fetoglobulin after fetal life. From the point of immune recognition of small cancer foci and their successful view of the partially differentiated lung or liver cell that is rejection by the host. Many tissue-specific antigenic mate producing the product, however, such functions may not rials have been shown to be present in tumors derived from be ectopie to that cell; nevertheless, the lack of turnoff of those tissues (6), whereas no convincing evidence for human synthesis in the presence of lack of need for the product tumor-specific antigens exists. Thus, immunological surveil suggests "irresponsible" production. Similarly, it may ap lance directed toward small foci of epithelial cancer could pear inappropriate for a lung tumor cell to make , well result in destructive lesions in the nearby normal tissue. but not if the cell is a Kulschitsky cell; it is still an irrespon This is suggested by the high frequency of reactivity of sive tumor, however. Derepressed synthesis has also been lymphocytes from patients with ulcerative colitis against used to describe the function of such cells. To date, return normal colon tissue. Other antigens shared between tumor of previous functions to a previously repressed mature cell and normal epithelia have been described for has not been shown to occur. A more reasonable hypothesis by Caspari and Field (4) and reactivity of multiple sclerosis to explain the syndromes that induce excess production sera against human malignant tissues by Burns et al. (3). of a recognizable trophic product is to consider them Thus, cancer can be likened to infections or trauma which to result from tumefaction of those histological ele disrupt the basement membrane and release antigenic ments which are usually in prolonged partial ontogenic epithelial material into the mesenchyme, giving rise to, for diapause. Repair after injury is always organ specific: example, thyroiditis or sympathetic ophthalmitis, respec the damaged fingernail does not grow a liver back, tively. Since the initiation of tumor growth is not a clinically and liver regeneration does not result in bone marrow noted event, a minute colonie tumor could go through many islands in the portal spaces. There are, accordingly, years of antigenic warfare with the host, resulting in resting cells in each organ which are undifferentiated prolonged ulcerative colitis before the tumor finally broke enough to be able to respond to growth and repair stimuli, through. Seen this way, the high incidence of autoimmune but differentiated sufficiently to develop into functioning diseases preceding cancer may have been the first evidence mature cells of the organ in which they lie. These cells of carcinomatous transformation. should also be those within each tissue, with DNA most The endocrine organs are the commonest sites of sympto easily available to the carcinogenic action of viruses, matic paraneoplastic functional alterations. In most in radiation, and chemicals. However, in humans they are stances, there are, clinically, overactivity syndromes. Thus, much more like their normal tissue counterparts than they sexual precocity can occur secondary to gonadotrophin are like the immature cancer cells of other tissues. This fact production by lung or liver cancer, and occasionally by was not properly appreciated by Greenstein (5), who stimulation of the gonads by a direct . worked with a narrow special group of rodent tumors. Overfunction of the adrenal cortex secondary to ACTH When such cells, which are reasonably well differentiated, production by lungs, liver, prostate, and other tumors has become transformed, they can express many normal tissue been described. Excess thyroid hormone secondary to TSH functions but are nonresponsive to the negative physiologi production has been noted in patients with choriocar- cal controls for rates of growth and secretory capacities. cinoma, but actual clinical hyperthyroidism is uncommon. Therefore, tumors that are uncontrolled for growth and product synthesis result in local masses and distant endo Pathogenesis crine syndromes. In most instances of , the ease of transforming a more immature cell should be The histological basis for the paraneoplastic syndromes greater, hence most cancers should arise in diapausal cells seems based upon the fact that tumor cells are invasive, and too undifferentiated to make physiologically active pro thus epithelial cancers carry usually forbidden cell compo ducts, so that we find paraneoplastic endocrinopathics in nents to beneath the basement membrane and into the a minority of cancer patients. Although not differentiated mesenchyme. When in the mesenchyme, the tumor vessel enough to produce a physiological product, most tumor displays a faulty and discontinuous endothelium which cells can be differentiated morphologically by tissue of permits ready access to the bloodstream of tumor-derived origin microscopically. It is interesting that the major dif steroids, amines, polypeptides, and antigens. This is com ferences between fully normal trophic hormones and those pounded by the fact that many tumor daughter cells die produced by tumors are in the state of differentiation of while in the mesenchyme and release more foreign mate the hormones themselves. Thus, it appears that there are rials. Epithelial cells normally are prevented from entering many more cancer patients who have circulating proinsu- the mesenchyme by an impenetrable barrier; when they die lin, big gastrin (5), or big ACTH than have tumors making they are shed onto a surface and conveyed to the environ the final hormone. This suggests that the immature tumor ment, their antigens never being seen by the mesenchyme. cell lacks the steps by which the final differentiated product

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1974 American Association for Cancer Research. Ectopie Synthesis and Paraneoplastic Syndromes is made by cleaving the precursor polypeptide. In the case study of the progress and pitfalls involved in differentiation of glycoprotein hormones such as the gonadotrophins, there of the somatic cell. is good evidence that many more patients have circulating inactive subunits than have TSH or human chorionic go- REFERENCES nadotrophin (2). This again suggests that these tumors 1. Al-Mondhiry, H., Zanjani, E. D., Spivack, M., Zalusky, R., and lack the enzymes required to combine the subunits into Gordon, A. S. Pure Red Cell Aplasia and Thymoma: Loss of Serum the final product, another example of undifferentiated but Inhibitor of Erythropoiesis following Thymectomy. Blood, 38: specialized cells producing a specialized but not com 578-582, 1971. pleted product. 2. Braunstein, G. D., Vaitukaitis, J. L., and Ross, G. T. The In-Vivo These latter examples suggest that there are probably a Behavior of Human Chorionic Gonadotrophin after Dissociation into large number of unrecognized subclinical states to be found Sub Units. Endocrinology, 35. 1030, 1972. in association with tumors in which large numbers of 3. Burns, L. P., Armentrout, S. A., Gross, S., Van den Noort, S., and precursor molecules of secretory products or partially Stjernholm, R. L. The Effect of a Lymphotoxic Factor in the Sera of Patients with Multiple Sclerosis and Acute Leukemia on the Metabo catabolized fragments of cell constituents will be found in lism of Normal and Leukemic Lymphocytes. J. Lab. Clin. Med., 78: the plasma of tumor patients. Such products might offer 508, 1971. new vistas for early diagnosis, following responses to 4. Caspari, E. A., and Field, E. J. Specific Lymphocyte Sensitizaron in therapy, seeking métastases,and even treatment. The Cancer: Is There a Common Antigen in Human Malignant Neoplasia? concept that the tumor-susceptible cells are ones that are Brit. Med. J., 2: 613, 1971. partially differentiated and tissue committed suggests that 5. Greenstein, J. P. The Biochemistry of Cancer, New York: Academic Press, Inc., 1954. the patterns of paraneoplastic syndromes vary because of 6. Gregory, R. A., and Tracy, H. J. Isolation of Two "Big " from differences in the characteristic ontogenic stages at which tissue cells rest in diapause. Hence, the nature of their Zollinger-Ellison Tumor Tissue. Lancet, 3: 797, 1972. secretory products or the characteristics of their cytoplas- 7. Hakamori, S.-l., and Jeanloz, R. W. Glycolipids as Membrane Antigens. In: D. Aminoff (ed.). Blood and Tissue Antigens, pp. mic constituents may be specific to various phases in the 149-153. New York: Academic Press, Inc., 1970. ontogeny of normal tissue cells. A study of the frequency at 8. Hall, T. C. (ed.) The Paraneoplastic Syndromes. Ann. N. Y. Acad. Sci., which occur in relation to the functional state of 230: 576, 1974. the tumor cell, the relative polymorphism of the mediators 9. Pearse, A. G. E., and Polak, J. M. Neural Crest Origin of the Endocrine involved in the paraneoplastic syndromes, their structures, Polypeptide (APUD) Cells of the Gastrointestinal Tract and Pancreas. and antigenicity may provide an important tool for the Gut, /2/7S3, 1971.

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1974 American Association for Cancer Research. Ectopic Synthesis and Paraneoplastic Syndromes

Thomas C. Hall

Cancer Res 1974;34:2088-2091.

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