Document X75NeLaG6abjkQar53OqZV26J
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
Medical Syndromes Associated With Malignant Tumors David Schottenfeld
CA Cancer J Clin 1970;20;35-43 DOI: 10.3322/canjclin.20.1.35
This information is current as of October 18, 2010
The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://caonline.amcancersoc.org
To subscribe to the print issue of CA: A Cancer Journal for Clinicians, go to (US individuals only): http://caonline.amcancersoc.org/subscriptions/
CA: A Cancer Journal for Clinicians is published six times per year for the American Cancer Society by Wiley-Blackwell. A bimonthly publication, it has been published continuously since November 1950. CA is owned, published, and trademarked by the American Cancer Society, 250 Williams Street NW, Atlanta GA 30303. (American Cancer Society, Inc.) All rights reserved. Print ISSN: 0007-9235. Online ISSN: 1542-4863.
Medical Syndromes AssociatedWith
Malignant Tumors
David Schottenfeld,M.D.
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
Careful and persistent study is need
ed to distinguish the clinical and bio
chemical features of malignant tumors
that do not arise from the mechanical
effects of metastatic or locally invasive
disease, nor from the iatrogenic effects
of therapeutic manipulation. In some
instances, these multisystemic mani
festations dominate the clinical pres
entation of the cancer so that aware
ness and recognition of their signifi
cance and degree of specificity will
facilitate earlier diagnosis and proper
treatment. These symptom complexes
and metabolic aberrations do not neces
sarily signify dissemination or mop
erability, except for those syndromes
which are usually associated with a
predominately
undifferentiated
and
rapidly proliferating tumor.
Apart from their clinical signifi
cance, these syndromes have profound
biologic implications. In regard to the
endocrine syndromes, there is pre
sumptive evidence that a tumor arising
from nonendocrine tissue synthesizes
peptides and proteins with hormonal
activity. These paradoxical hormonal
effects are believed to arise from the
derepression or activation of latent
coding functions in the DNA of tumor
Dr. Schottenfeld is Chief, Clinical Epidemiology and Statistics, and Associate Attending Physician, Memorial Sloan-Kettering Cancer Center, New York, New York.
cells. In regard to the association with
diseases of connective tissue, neuro
myopathies, and multifocal leukoen
cephalopathy, it has been suggested
that these conditions develop from
auto-immune or altered immune re
sponses to organ-specific
antigens
which are elaborated by the malignant
tumor. The association of auto-immune
diseases and congenital immunologic
deficiency syndromes* with lymphore
ticular malignancy emphasizes the
pathogenic significance of immunologic
dysfunction in lymphoma patients. The
following tables list some of the multi
systemic abnormalities associated with
cancer.
* Examples
of inherited
diseases
which
are characterized by immunologic defi
ciency and the predisposition for malig
nancies of the reticuloendothelial system
include:
1. Wiskott-Aldrich
syndrome charac
terized by sex-linked recessive inher
itance, recurrent infections, chronic
eczema and thrombocytopenia;
2. Congenital sex-linked agammaglob
ulinemia of Bruton; and
3. Ataxia telangiectasia of Louis-Bar,
which is a chronic and progressive
multi-system disease with autosomal
recessive inheritance, recurrent in
fections, oculocutaneous telangiec
tasia, mental retardation, progres
sive ataxia, choreo-athetosis and
nystagmus.
35
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
EXAMPLES OF MEDICAL SYNDROMES AND DISORDERS ASSOCIATED WITH MALIGNANT TUMOR
Associated Diseases
A. Cutaneous ConnectiveTissueand Osseous Diseases 1. Dermatomyositis
Tumor Sites
Lung, Breast,Stomach, Ovary.Colon and Rectum, and Lymphoma
2. Scleroderma(SystemicSclerosis)
AlveolarCell(TerminalBronchiolar)
3. DisseminatedLupus Erythematosus
Hodgkin'sDisease,Lymphosarcoma, Chronic Lymphocytic Leukemia
4. HypertrophicPulmonary Osteoarthropathy with or withoutSynovitis
Bronchus.Pleura(Mesothelioma)M,etastatic lntrathoraciTcumors
5. Acute ArthritiScymptoms
Prostate
Acute Lymphatic Leukemia MultipleMyeloma
6. MalignantAcanthosisNigricans
Acinar Cell of Pancreas
lntraabdominalAdenocarcinomas (i.e.S,tomach). Carcinoma of Lung and Thyroid,Lymphosarcoma
36
Comments
Rfersncss
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
Approximately 50 percentof patientsoverage 40 presenting with this disease will have an associated malignancy.
Pulmonary fibrosiasnd reactiveproliferationf terminalbronchiolarand alveolaerpithelium were prominent.
Prompt relieoff symptoms afterresectionof tumor, denervationof lungrootor sectioninogf vagus nerves.Clubbingmay be presentwithout osteoarthropathyb,ut periostitwiisthoutclubbing would be most unusual. Articular signs include erythema, swelling. tenderness of the metacarpophalangeal and/or interphalangeal joints that respond to therapy with estrogens. (In Children)
May be accompanied by amy laiddepositionin synovial tissue Presentation with oecatrupnanl el syndrome Coeonsider also secondary gouty arthritis With subcutaneous fat necrosis.
Characterized by hyperpigmentation, papillomatosis and hyperkeratosis of the axillae. groins, anogenital area, lateral and posterior aspects of the neck. Less frequently, palms, soles, antecubitaalnd popliteaslpacesand mucous membranes areinvolved.
Curtis,AC.; Heckaman, J.H.,and Wheeler,A.H. J.A.M.A. 178: 571-573, 1961. Grace,J,T.,Jr.,andDao,T.L.Cancer 12: 648-650, 1959. Williams, R.C., Jr. Ann. Int. Med. 50: 1174-1181, 1959.
Zatuchni,J.;Campbell,W.N.,and ZarafonetisC,.J.D. Cancer6: 1147.1158,1953. Weaver,AL.; DivertieM,.B.,and Titus,J.L. Mayo Clin. Proc. 42: 754-766, 1967.
Cammarata, R.J.;Rodnan, G.P.,and Jensen,W.N. Arch nt Med. 111: 330-337. 1963. MillerD,.G. Ann lnt Med. 66: 507-521, 1967. Nilsen,LB.; Missal,ME., and Condemi, J.J. Cancer 20: 1930-1933.1967.
Wierman, W.H.;ClagettO..T.,and McDonald, JR. J.A.M.A. 155: 1459-1463,1954. Hammarsten,J.F..and O'Leary,J.A.M.A. Arch.mt. Med. 99: 431-441.1957.
Harrison, J.W., and Scherbel, AL. Postgrad. Med. 28: 274.283. 1960.
Aisner, M., and Hoxie, TB. New England J. Med. 238: 733-737, 1948.
Hamilton,E.B.,and Bywaters,E.G. Ann. Rheumat. Dis.20: 353-362. 1961. Bronsky, D., and Bernstein, A. Ann. nt. Med. 41: 820-823. 1954.
Auger, C. A.M.A. Arch. Path. 43: 400-405. 1947. Osborne, R.R. A.M.A. Arch. mt. Med. 85: 933943, 1950.
Curth, HO.; Hilberg, A.W., and Machacek, G.F. Cancer 15: 364-382. 1962.
37
AssociatedDiseases
B. Neuromuscular Disorders (Not due to metastatidcisease) 1. Parenchymatous CerebellaDregeneration
Tumor Sites
Lung,Ovary,Breastand Uteruspredominating
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
2. Encephalomyelopathy
Lung, Hodgkin'sDisease,Kidney,Breastand Pancreas predominating
3. Multifocal Leukoencephalopathy
Leukemia, Hodgkin's Disease, Lymphosarcoma
4. Polyneuropathy,Motor,Sensoryor Mixed
Lung, MultipleMyeloma, Hodgkin'sDisease, Leukemia,Pancreas,Stomach, Colon and Rectum, Breast and Ovary
5. CarcinomatousMyopathy 6. MyastheniaGravis
Lung (usualloyat cellor smallcellcarcinoma), ProstateB,reast,Rectum and Ovary predominatin
Thymoma
38
Comments
Ref.rences
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
Loss of Purkinje cells throughout cerebellar cortex. Degeneration of dorsal spinocerebellar tracts, superiorcerebellapreduncles,posteriorcolumns and corticospinatlractsaswell.
Brain, WA.; Daniel, P.M., and Greenfield, J. J Neurol Neurosurg & Psychiat. 14: 59.75, 1951. Rowland, L.P., and Schneck, S.A. J Chronic Dis 16: 777-795, 1963. Russell, D.S. Cancer Progress 1960. Pp. 71.74.
Ophthalmoplegia, bulbar palsy, pyramidal tract signs,anteriorhorn celldiseaseand organicmental syndrome.
Brain, A., and Henson, R.A. Lancet2: 971-974 1958. Henson, R.A., Russell, D.S., and Wilkinson, M. Br@n 77: 82-121, 1954 Holt,G.W. Am.J.M.Sc. 250: 86102, 1965.
Demyelinating lesions of the cerebral hemispheres, brainstem,cerebellum
Cavanagh, J.B., et aI. Lancet 2: 524-529, 1959. Richardson, E.P., Jr. New England J Med. 265: 815.823, 1961.
Idiopathidcegenerationof meninges.nerveroots, dorsalrootganglioncellsand peripheranlerves The Lymphomas and Leukemias may be associated with a multifocal leukoencephalopathy characterizebdy progressivdeemyelinatinglesions. There may be a Landry-Guillian@Bararsecending paralytipcolyradiculoneuropathy.
Lennox, B., and Pritchard, D. Quart J Med. 19: 97@109, 1950. Victor, M.; Banker, B.Q., and Adams, RD. J Neurol Neurosurg & Psychiat. 21: 73-88, 1958. Hutchinson, E.C., et al. Brain 81: 75-92, 1958. Klingon, G.H. Cancer 18: 157-163, 1965.
Wilner, E.C., and Brody, J.A. Neurology 18: 1120.1124, 1968.
DennyBrown, D. J Neurol Neurosurg & Psychiat. 11 73-87,1948. Rooke, ED., et al. M Clin North America 44: 977@988, 1960. Grimes,O.F. Ca 16: 167-170, 1966.
15-30percentcoexistenceof thymoma. Aregener. ative anemia, acquired hypogammaglobulinemia and Cushing's syndrome also noted in association with thymic tumors.
Aingertz, N. Acta path et microbiol scandinav. 29: 9-25, 1951. Bernatz, P.E.; Harrison, E.G., and Clagett, O.T. J Thoracic & Cardiovas Surg. 42: 424-444, 1961. Maldonado, J.E.; Bayrd, E.D., and Kiely, J.M. Mayo Clin Proc. 39: 60-71, 1964. Aubin, M.; Straus, B., and Allen, L. Arch Int Med. 114: 389@398. 1964.
39
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
AssociatedDiseases
C. Endocrine Effects and Associated_Metabolic Disorders 1. Hyperadrenocorticism With Or Without The Classic Features Of Cushing's Syndrome
Tumor Sites
Bronchus (Oat Cell), Thymus (Epithelial Type). Bronchial (Carcinoid), Thyroid (Medullary), Pancreas (Acinar and Islet Cell, may be associatec with the ZollingerEllison syndrome and hypoglycemia)
2. InappropriatSeecretionOf Antidiuretic Hormone
Bronchus (OatCell)predominating
3. Hypoglycemia And Extra-pancreatic Tumors
Fibrosarcoma, either intrathoracic or retroperitoneal, Mesothelioma, Other mesoderm@ tumors of large size, Primary hepatoma, Other epithelial tumors of large size.
4. Hypercalcemia And Hypercalciuria Not Due Solely To Osseous Metastases.
Lung, Breast, Kidney, Ovary, Pancreas, Colon.
5. A. Carcinoid Syndrome (Argentaffin and Non-Argentaf'f in Tumors)
B. Atypical Carcinoid Syndrome Increased Secretion Of 5-Hydroxytryptophan And Histamine
With
6. Thyroid Dysfunction
A. Small Intestine. Bronchus (Adenoma), Appendix, Colon and Rectum, Duodenum, Ovary, Gall Bladder, Pancreas (Acinar and IslE Cell), Thyroid, and Bronchus (Oat Cell)
B. Stomach, Pancreas, Bronchus (Oat Cell).
HydatidiformMole and Choriocarcinoma
40
Comments
References
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
The plasma or tumor of a number of these patients contains an increased amount of an ACTH like substance and frequently melanocytestimulating hormone. A significant number of patients demon strated bilateral adrenocortical hyperplasia, severe hypokalemic alkalosis, skin pigmentation, edema and diabetes mellitus
A syndrome characterized by hyponatremia and failure of sodium conservation by the kidneys. Markedly decreased serum osmolality and a persistently hypertonic urine. In the absence of appropriate water restriction the positive water balance may eventually lead to water intoxication: lethargy, confusion, seizures and coma. Isolation of antidiuretic activity from the tumor has suggested intrinsic synthesis
Important mechanisms responsible for hypoglycemia would include (1) the large size of the tumor with increased utilization of glucose (2) secretion of an insulin-like substance dnd (3) deficient glucogenesis
Only presumptive evidence that the tumor is elaborating a hypercalcemic agent or parathyroid hormone-like substance. Clarification awaits a sensitive and specific assay for parathyroid hormone.
Pathophysiologic effects attributed to excess elaboration of serotonin and/or kinin peptides potentiated by hepatic metastases. Carcinoid syndrome is characterized by cutaneous flushing, tachycardia, chest, abdominal or leg pain, hyperperistalsis, broncho-constriction, valvular heart lesions (endocardial fibrosis and plaque formation) resulting in pulmonary stenosis, tricuspid insufficiency or left-sided cardiac involvement, and pellagroid skin lesions with intestinal malabsorption.
Associated with increased plasma concentration of thyroid stimulating hormone and not simply increased protein-binding of thyroid hormone. In several instances extracts of tumor tissue contained thyrotrophin activity. Most patients do not manifest hyperthyroidism.
Allott, EN., and Skelton, MO. Lancet 2:
278-283. 1960.
HiIls,A.G.,andWoeber,
K.A. Ann Int Med. 54
1295-1300, 1961.
Meador, C.K., et al. J CIin Endocrinol. 22:
693-703. 1962.
Azzopardi, J.G., and Williams, E.D. Cancer 22:
274-286, 1968.
Reem, G.H., and Vanamee, P. J Chron Dis. 16: 737-755, 1963. Bower, B.F., et al. New England J Med. 271: 934-938, 1964. Utiger,A.D. M.Clin North America52: 381@391, 1968.
Lowbeer, L. Am J Clin Path. 35. 233-243, 1961. Silverstein, M.N.; Wakim, K.G., and Bahn, R.C. Am J Med. 36: 415-423, 1964. Nissan, S.; Bar-Maor, A.. and Shafrir, E. New England J Med. 278: 177-183, 1968.
Lemon, H.M. Proc Soc Am Assoc Cancer Aes. 3: 338, 1962. Snedecor. P.A., and Baker, H.W. Cancer 17: 14921496, 1964. Myers, W.P.L.. Tashima, C.K., and Rothschild, E.O. M Clin North America 50: 763-778, 1966.
Thorson, A., et al. Am Heart J. 47: 795-817. 1954, Sjoerdsma,A. A M A Arch Int Med. 102: 936-938. 1958. Lipsett, M.B., et al. Ann Int Med. 61. 733-756, 1964. Dollinger, M.A., and Gardner, B. Surg. Gynec & Obst. 122: 1335-1347, 1966.
OdeIl,W.D.. et aI.J.CIin Endocrinol Metabolism 23: 658-664. 1963.
41
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
Associated Diseases 7. Gynecomastia
Tumor Sites
Associated Cancers: Lung, Kidney, Stomach.
@ Vascular and Hematologic Manifestations 1. Polycythemia
2. Migratory Thrombophlebitis
Cerebellar hemangioblastoma'. H ypernephroma Hepatoma, Pheochromocytoma @U,terine fibroma. Benign renal lesions: cyst, adenoma. Virilizing Ovarian Tumors
*May occur in the same patient with angiomatosis retinae of the von Hippel-Lindau syndrome.
Associated cancers: Lung, Pancreas, Prostate, Ovary, Stomach, Colon and Rectum predominate
42
Downloaded from caonline.amcancersoc.org by on October 18, 2010 (American Cancer Society, Inc.)
Comments
Concomitantly, in lung cancer, most of the patients have hypertrophic osteoarthropathy. In some instances gonadotrophic activity has been demonstrated in the tumor tissue accompanied by high levels in the plasma and urine and increased excretion of urinary estrogens. As with clubbing, however, gynecomastia may be a concomitant manifestation of non-neoplastic pulmonary diseases.
Elaboration of erythropoietin-like material by the tumor tissue with stimulated erythropoiesis. Whereas patients with polycythemia vera usually have thrombocytosis, leukocytosis and splenomegaly, in addition to the increase in the total volume of circulating red cells, the tumor associated erythrocytosis group usually do not.
Cancer cells have not been found in the veins at the site of the thrombotic lesions. Nonbacterial thrombotic(marantic)endocarditiwsith arterial embolization, fibrinolytic purpura, consumption coagulopathy and cryofi bri nogenemia are infrequentloyf assistancienearlydiagnosis.
References
Williams, M.J., and Sommers, S.C. Cancer 15: 109-117, 1962. Fusco, F.D., and Rosen, S.W. New England J Med. 275: 507-515, 1966. Camiel, M.R.; Benninghoff, D.L., and Alexander. L.L. Dis Chest 52: 445.450, 1967. Faiman, C., et al. New England J Med. 277: 13951399, 1967.
Jacobson, L.O.; Gurney, C.W., and Goldwasser, E. Advances Int Med. 10: 297-327, 1960. Starr, G.F.; Stroebel, C.F., Jr., and Kearns, T.P. Ann Int Med. 48: 978-986, 1958. Rosenbach,L.M.,and XefterisE,.D. J.A.M.A. 176: 136-1 37, 1961. Escobar, M.A., and Trobaugh, F.E., Jr. A.M.A Arch Int Med. 110: 339-344, 1962. Singmaster. L. J.A.M.A. 163: 36-37, 1957. Valentine, W.N., et al. Ann Int Med. 69: 587606, 1968.
Lieberman, J.S., et al. J.A.M.A. 177: 542-545, 1961. Byrd, A.B.; Divertie, M.B., and Spittell, J.A. J.A.M.A. 202: 1019-1022, 1967.
43