In a series of 78 patients with secondary amyloidosis, associated neoplastic diseases were found in 13 (17%). Included are 5 cases of multiple myeloma, 3 cases of lymphoma, and the rest were carcinomas. Cases are reported of patients with carcinoma of the stomach, gall bladder, urinary bladder, kidney or colon, illustrating the various associated neoplasms. The literature concerning the incidence of the two -conditions in relation to each other is reviewed.S. Afr. Med. J., 48, 1944 (1974)

Lender, M

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1944 S.A. MEDICAL JOURNAL 21 September 1974Amyloidosis Associated with NeoplasticDiseasesM. LENDERSUMMARYIn a series of 78 patients with secondary amyloidosis,associated neoplastic diseases were found in 13 (17%).Included are 5 cases of multiple myeloma, 3 cases oflymphoma, and the rest were carcinomas. Cases are re-ported of patients with carcinoma of the stomach, gallbladder, urinary bladder, kidney or colon, illustrating thevarious associated neoplasms. The literature concerning theincidence of the two -conditions in relation to each otheris reviewed.S. Afr. Med. l., 48, 1944 (1974).Amyloidosis is known to be associated with neoplasticdisease. The association is particularly well documentedfor multiple myeloma,'" and Hodgkin's disease.····· Theassociation of amyloidosis with neoplastic diseases otherthan multiple myeloma and Hodgkin's disease has alsobeen noted, but the incidence and documentation in theliterature appear to be smaller.'···· Medullary carcinomasof the thyroid gland are known to contain varying amountsof amyloid in the stroma: However, the amyloid is con-fined to the tumour,'· while we are dealing with cases ofgeneralised amyloidosis.The present article reports the incidence of amyloidosisassociated with neoplastic diseases, and includes casereports of patients with neoplastic diseases other thanmultiple myeloma or lymphoma.SOURCE OF PATIENTS AND INCIDENCE OFAMYLOIDOSISThe patients in this study form part of a current seriesof patients with amyloidosis diagnosed in the 3 generalhospitals in Jerusalem since 1949, and include 78 caseswith systemic amyloidosis. Thirteen patients (17%) arecases of amyloidosis associated with neoplastic diseases.Of the 13 patients, 5 had multiple myeloma (4 females),3 had lymphomas (2 females), and the remaining 5 patients,having other kinds of neoplastic diseases, are the subjectsof the following reports.Department of Medicine, Shaare Zedek Hospital, Jemsalem,IsraelM. LENDER, M.D.Date received: 27 rv1ay 1974.CASE REPORTSCaseIA female, born in Syria, was first diagnosed at the ageof 75 years as having hypothyroidism and myxoedema,and treatment with thyroid preparations was initiated.Five years later, chronic congestive heart failure graduallydeveloped and was treated, but at the age of 85 years shewas admitted to hospital because of severe congestiveheart failure.On examination her blood pressure was found to be95/50 mmHg, the skin dry and of parchment-like con-sistency, the face swollen and the tongue enlarged, and theneck veins were engorged. The chest was emphysematousand rales were heard at both lung bases. Heart soundswere normal, and a mild systolic murmur was heard overthe base. The liver was enlarged to 15 cm below the rightcostal margin, with many nodules palpable over its sur-face. There was pitting oedema of the legs. Circulationtime (arm-to-tongue) was 21 seconds. The ECG showedan old myocardial infarction. A compressed fracture ofthe ninth dorsal vertebra was noted on X-ray film. Onurinalysis 4+ protein was found. The haemoglobin was10,3 g/l00 ml and blood glucose was 118 mg/lOO ml. Totalserum proteins were 5,1 g/lOO ml (albumin 1,8 g/l00 ml,uric acid 11,3 mg/ I00 ml, cholesterol 190 mg/lOO m\). Thebilirubin, calcium and phosphorus were normal. Protein-bound iodine was 2,2 fLg/1OO ml. In the ward the patientwas oliguric and died after 4 days.At autopsy, the immediate cause of death was dis-covered to be multiple recent and old pulmonary emboli.The autopsy also revealed carcinoma of the gall bladder in-vading the liver. Amyloidosis was found in the kidneys,adrenals, pancreas, a salivary gland, in a small scar inthe myocardium, and in many arteries.Case 2A male, born in Morocco, underwent right nephrolitho-tomy at the age of 25 years. A year later he underwentresection of a Meckel's diverticulum, and at that timetraces of protein were found in the urine. At the age of35 years he underwent right hernioplasty, and 3 years laterwas admitted to hospital because of urinary tract infectionand an elevated blood urea.On . admission he appeared pale, blood pressure was125/70 mmHg, and a blowing systohc murmur was heardover the heart. The liver and spleen were not palpable, norwas there leg oedema. On urinalysis 3 + protein was found,with many red and white blood cells. Culture of the urine21 September 1974 S.-A. MEDIESE TVDSKRIF 1945revealed Pseudomonas aeruginosa. In the blood, haemo-globin was 7,4 g/ 100 ml, haematocrit 2400, leucocyte count15700/mm3 , blood urea 188 mg/100 ml and glucose106 mg/100 ml. Total serum proteins were 4,7 g/IOO ml,(albumin 1,1 g/lOO m\), and cholesterol 140 mg/lOO m!.The bilirubin and alkaline phosphatase were normal. Achest X-ray film was normal. The ECG demonstrated leftheart strain. A cytoscopy was performed and manytumours were observed on the urinary bladder wall. Thepatient died in terminal renal failure.At autopsy anaplastic carcinoma of the urinary bladderwas found, stenosing the ureteral orifices. Bilateral hydro-ureters and hydronephrosis with bilateral chronic pyelone-phritis were also noted. Generalised amyloidosis wasfound, involving kidneys, intestine. spleen. liver andadrenals.Case 3A female, born in Iraq, complained of dyspnoea oneffort and palpitations at the age of 58 years. A year lateratrial fibrillation developed. At the age of 60 years shewas first admitted to hospital and thyrotoxicosis was diag-nosed. Urinalysis was negative, and the haemoglobin was10,2 g/IOO m!. The blood chemistry tests, including urea,glucose, proteins and cholesterol, were normal. Eightmonths later she was readmitted because of increasingdifficulties in swallowing, nausea, and loss of weight.On examination severe cachexia and pallor were found.The blood pressure was 110/80 mmHg and the pulse ir-regular. The haemoglobin was 7,9 g/lOO ml, total serumproteins 5,6 g/IOO ml (albumin 1,6 g/lOO ml), cholesterol114 mg/lOO ml, serum iron 34 flg/lOO ml, and on urinalysis1+ protein was found. Lymphadenopathy was found inthe neck. A 7-cm turnour was palpated in the epigastrium,but the liver and spleen were not palpable nor was legoedema noted. A barium meal revealed a 5-cm fillingdefect in the mid-oesophagus, and the gastric mucosaappeared irregular. On ECG, atrial fibrillation was noted.The patient was treated symptomatically and died after77 days.At autopsy, carcinoma of the stomach of the ulcero-infiltrative type was found, involving the lesser curvature,with metastases to the oesophageal wall, causing stenosisof the oesophagus, and with metastases to the pancreasand lymph nodes. Amyloidosis of the kidneys was found.Colloid hyperplasia was noted in the thyroid gland.Case 4A female born in Yugoslavia was first hospitalised at theage of 43 years because of increasing weakness. A leftrenal cell carcinoma was found, nephrectomy was per-formed, and for the next 2 years the patient was asympto-matic. At that time a metastasis was found, first in the leftparotid gland area and later in the lungs. At the age of46 years the patient was readmitted because of fever.On admission dyspnoea was noted, and a swelling wasseen at the left parotid gland causing partial paralysis of12the facial nerve with regional lymphadenopathy. Bloodpressure was 130/90 mmHg. The liver was palpable 4 cmbelow the right costal margin. The ECG was normal, buttwo metastatic lesions were noted on X-ray film in the rightlung and one round lesion in the left lung. On urinalysistraces of protein were found, with few leucocytes. Thehaemoglobin was 9,5 g/IOO ml, and the sedimentation rateincreased to 110 in the first hour. The blood biochemistrywas normal. The patient's condition gradually deterioratedand she died after 3 months.At autopsy, recurrence of the carcinoma was found inthe site of the nephrectomy, with metastases in the lung,thyroid, liver, pancreas, right kidney, right adrenal. leftovary, uterus, right breast, and right axillary, mediastinal,carinal, peripancreatic and mesenteric lymph nodes.Generalised amyloidosis was also found.CaseSA male, born in Hungary, suffered rectal bleeding at theage of 60 years. A year later acompressed fracture of thethird lumbar vertebra was found. Hepatomegaly was notedwith elevated blood alkaline phosphatase. On bariumenema examination, a constriction was demonstrated 10 cmabove the rectum. A course of radiotherapy was initiatedto the lumbar area. Five months later the patient wasreadmitted. His condition had deteriorated, and he waspale, with blood pressure 130/70 mmHg. The liver waspalpable 5 cm below the right costal margin. In the urine2 + protein was found, but Bence-Jones protein was absent.Blood haemoglobin was 8,7 mg/IOO ml, and blood bio-chemistry was normal except the alkaline phosphatase.which was 15 units (Bessey-Lowry). Serum protein electro-phoresis was normal. In the bone marrow an increasednumber of plasma cells was present, but this was notdiagnostic of multiple myeloma.Biopsy specimens obtained through colonoscopy de-monstrated the presence of malignant polypoid carcinomaof the rectum. On the same biopsy specimen amyloidosisof the colon was demonstrated. The patient underwentlaparotomy and partial colectomy, but died 2 monthslater with septic shock. Autopsy was not performed.DISCUSSIONThe purpose of the present article is to draw attention tothe appearance of secondary amyloidosis in the presenceof carcinomatous neoplastic disease. The present series aswell as a review of the literature demonstrate that manyneoplastic diseases can be complicated by secondaryamyloidosis",s,n,,, and the incidence of such cases, as re-flected in some of the larger series published, is compiledin Table I. The percentage runs from as low as 2,400· tothe highest incidence of 32 o{,.'Attempts to examine the situation from the other pointof view, that is, the incidence of amyloidosis in series ofcases of neoplastic diseases, brought a less fruitful yield.Much attention was given to multiple myeloma. In this1946 S A. MEDICAL JOURNAL 21 September 1974TABLE I. INCrDENCE OF CASES OF AMYLOIDOSIS ASSOCIATED WITH NEOPLASTIC DISEASES IN SERIES OFCASES OF AMYLOIDOSISNo. of cases Total No. of 10 of casescases with Total No. of withMultiple neoplastic cases of neoplasticAuthor r;lyeloma Lymphomas' Carcinomas diseases amyloidosis diseasesHiguchi' 12 506 2,4Dahlin" 3 2 5 10 44 23Calkins and Cohen' 4 0 0 4 21 19Briggs" 0 3 1 4 73 5,5Cardell' 3 4 0 7 22 32Blum and Sohar" 5 0 9 14 200 7Present series 5 3 5 13 78 17... Including Hodgkin's disease.disorder the incidence of amyloidosis varies from 6% to15,%.,,3 Among 234 patients with Hodgkin's disease ex-amined at necropsy, amyloidosis was found in 5 cases{l,1 %).13 Renal cell carcinoma is another example where amethodical trial was carried out in order to find the trueincidence of secondary amyloidosis. In a series of 273cases with renal cell carcinoma, 8 cases (2,9%) were foundto be associated with amyloidosis: Of 93 instances of car-cinoma of the uterus, amyloid involvement of the kidneyswas found in 4 cases.7 A most instructive analysis waspublished by Kimball,' who in a series of 4033 cases ofcancer, found amyloidosis in 16, establishing an in-cidence of 0,4%. Hodgkin's disease and multiple myelomacomprised a significantly higher percentage of the amyloi-dosis group than was expected from their frequency inthe total autopsy series.' In this last series 6 cases out of16 were neoplastic diseases other than multiple myelomaand Hodgkin's disease.The problem exists as to why amyloidosis appears ingreater proportion among patients with multiple myelomaand lymphomas. Work done by Glenner and associates""·indicates that amyloid fibrils may be of immunoglobulinorigin, and formation of amyloid fibrils by intralysosomaldigestion of light polypeptide chains of immunoglobulinswas suggested. Other work done by Ben-Ishay andZlotnick,17.1S demonstrated the presence of amyloid fibrilsin the reticulo-endothelial cells and suggested that thosecells are implicated in amyloid production.All these observations may provide a possible expla-nation of the higher incidence of amyloidosis in neoplasticdisorders related to the reticulo-endothelial system. It stillleaves unexplained the appearance of a variety of carci-nomas in association with amyloidosis. Possibly, thealleged altered immunity in these disorders may be con-nected to appearance of amyloid.I should like to thank Dr B. J. Hurwich, Chief of the RenalUnit, and the Department of Medical Records, Shaare ZedekHospital.The author is supported by a grant from B. De-RothschildFoundation for Advancement of Science in Israel, Inc.REFERENCES1. Calkins. E. and Cohen. A. S. (1%0); Bull. Rheum. Dis .• 10. 215.2. Kimball. K. G. (1961); Ann. Intern. Med .• 55, 958.3. Ossennan, F. E. and Takatsuki, K. (1963); Medicine (Baltimore), 4'357.4. Cardell, B. C. (1961); Brit. Med. J., 1, 1145.5. Falkson, G. and Falkson, H. C. (1973); S. Afr. Med. J .. 47, 62.6. Higuchi, K. (1930); Virchows Arch. Path. AnaL. 239, 538.7. Ask-Upmark, E. (1940); Acta med. scand., 104, 512.8'. Berger, L. and Sinkoff, M. W. (1957); Amer. J. Med., 22, 791.9. Williams, E. D. (1965); J. Clin. Path., 18, 288.10. Hill, C. S., Ibanez, M. L., Samaan, N. A., Ahearn, M. J. andClark. R. L. (1973); Medicine (Baltimore), 52, 141.11. Briggs, G. W. (1961); Ann. Intern. Med., 55, 943.12. Dahlin, D. C. (1949); Ibid., 31, 105.13. Razis, D. V., Diamond, N. and Craver, L. F. (1959); Amer. J. Med.Scl., 238. 327.14. Glenne" G. G., Ein, D. and Terry, W. D. (1972); Amer. J. Med.,52, 141.15. Glenner, G. G. (1972); Hum. Pathol., 3. 157.16. Glenner, G. G., Terry, W. D. and Isersky, C. (1973); Semin. HematOl.,10, 65.17. Ben-Ishay, Z. and Zlotnick, A. (1968); Israel J. Med. Sci., 4. 987.18. Zlotnick. A. and Ben-Ishay, Z. in Bonomo. L.. ed. (1970); Proceedingsof International Symposium on Immune Complex Diseases, p. 48.Milan: Carlo Erba Foundation.!9. Blum, A. and Sohar, E. (1962); Lancet, I, 721.

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Amyloidosis associated with neoplastic diseases

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Amyloidosis associated with neoplastic diseases

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