Chronic glomerular microangiopathy complicating metastatic carcinoma

Chronic Glomerular Microangiopathy Complicating Metastatic Carcinoma ALDEN L. HOSTET[ER,MD, RAYMOND R. TUBBS,DO, THOMAS ZIEGLER, MD, GORDON N. GEPHARDT, MD, JAMES 1. McMAHON, PHD,AND MARTIN J. SCHREIBER,JR., MD Six cases o f metastatic carcinoma associated with chronic glom e r u l a r microangiopathy and renal failure are reported. All had prominent subendothelial lucent zones and double-contoured glomerular basement membranes. There was no immunohistologic or ultrastructural evidence for immune complex entrapment in glomeruli. By immunohistology, material antigenically related to fibrin or fibrinogen was identified in glomerularbasement membranes despite a paucity of typical fibrillar fibrin. Four patients received mitomycin C before the onset o f renal disease, and one patient received chemotherapy other than mitomycin C before developmentof renal failure. One patient had no chemotherapy but was given radiotherapy, which did not include the kidneys in the irradiated field. These six cases emphasize the diverse pathophysiologic mechanisms by which glomerular microangiopathy may arise in metastatic carcinoma. HUM PATHOL

18:342--348, 1987. Six patients with metastatic carcinoma developed microangiopathic hemolytic anemia, thrombocytopenia, and chronic renal failure with histologic glom e r u l a r changes consistent with the h e m o l y t i c uremic syndrome (HUS). T h e etiology of chronic glomerular microangiopathy in patients with metastatic carcinoma remains unclear although several possible explanations have been proposed. Several reports of patients with glomerular microangiopathy associated with metastatic carcinoma suggest intravascular tumor aggregates may stimulate fibrin and platelet deposition, and result in microangiopathic hemolytic anemia. 1-4 O t h e r authors 5-tl attribute these changes to mitomycin C therapy. The subpopulation o f patients with mitomycin-induced HUS has , been well rexiewed by Proia and colleagues. 12 In 1979, A n t m a n et al. 13 characterized 55 patients in her review of cancer-associated microangiopathic hemolytic anemia. It appeared that many of these patients did not receive mitomycin, although this point was not specifically addressed. 13 The four patients r e p o r t e d herein and two patients previously rep o r t e d 14 represent cases with similar pathologic findings but dissimilar clinical presentation and therapy, emphasizing the diverse pathophysiologic mechanisms by which glomerular microangiopathy may arise in the setting o f metastatic adenocarcinoma.

MATERIALSAND METHODS

Percutaneous renal biopsy tissue was examined from cases 2, 4, and 5. Open-renal biopsy tissue was examined from case 6. Necropsy tissue was otfiined f r o m cases 1 t h r o u g h 3 within five h o u r s postmortem. Formalin- and Hollande's-fixed, paraffinembedded tissue was sectioned at a thickness of 4 to 5 p.m and stained with hematoxylin-eosin, periodic a c i d - S c h i f f , Masson trichrome, and Jones' silver strains. Tissue for immunohistologic studies was snapfrozen in isopentane precooled in liquid nitrogen at - 130 ~ C. Frozen sections were prepared at a thickness of 4 p.m, and direct immunofluorescence and direct immunoperoxidase were done as previously described. 15 T h e slides were allowed to reach room temperature for 5 minutes. Optimally diluted, peroxidase conjugated antibodies with specificity for IgG, IgA, IgM, C3, and fibrin/fibrinogen (Cooper Biomedical, Malvern, Pennsylvania; Dako, and Biogenex Laboratories, Dublin, California) were pipetted onto the tissue sections and incubated in a humidified chamber for 30 minutes. Excess antibody was removed by flooding the sections with phosp h a t e - b u f f e r e d saline (PBS). T h e sections were washed rapidly in three consecutive changes of PBS. T h e sections were washed briefly in Tris-HCl buffer. T h e substrate-chromogen color reaction product was developed in three to six consecutive changes o f Hanker-Yates reagent and 0.003 per cent hydrogen peroxide in Tris-HCl buffer. Tissue was processed for electron microscopy by fixing small tissue cubes in glutaraldehyde, postfixing in osmium tetroxide, and embedding in Spurr resin. One-micron-thick sections were prepared and stained with toluidine blue. Thin sections were prepared and stained with uranyl acetate and lead citrate, and e x a m i n e d and p h o t o g r a p h e d with a Phillips 40 or 410 transmission electron microscope. RESULTS

Clinical case presentations are summarized in tables 1 and 2. Received from the Departmentsof Pathologyand Nephrology and Hypertension,The Cleveland Clinic Foundation,Cleveland, Ohio. Revisionaccepted for publicationJuly 31, 1986. Address correspondence and reprint requests to Dr. Tubbs: Department of Pathology,The ClevelandClinicFoundation,9500 Euclid Avenue, Cleveland,OH 44106. 0046-8177/87 $0.00 + .25

342

Pathologic Findings [Table 3] The necropsy studies of cases 1 through 3 revealed metastatic adenocarcinoma, which did not involve the renal parenchyma nor the lower urinary collecting systems. No bone marrow metastases were

GLOMERULARMICROANGIOPATHYCOMPLICATINGMETASTATICCARCINOMA [Hostetteret al.) TABLE t.

Age (yrs) Sex Diagnosis

Urinalysis Casts Creatinine clearance Hypertension BUN/ creatinine clearance PT/PTT Platelet count

Chronic GIomerular Microangiopathy and Metastatic Carcinoma: Clinical Findings of Six Patients Case I

Case 2

Case 3

Case 4

Case 5

Case 6

48 Male Adenocarcinoma of cecum, Dukes' disease, mucinous 4 + protein, hematuria

40 Female Adenocarcinonm of cecum, Dukes' disease, mucinous 3 + protein, hematuria

52 Male Adenocarcinoma of salivary gland and hmg with metastases 3 + protein, hematuria

49 Male Adenocarcinoma of lung and bone with metastases

37 Male Adenocarcinoma-unknown primary site

65 Female Adenocarcinoma of uterus

4 + protein, hematuria

3 + protein, hematuria

RBC, hyaline, granular 11 ml/min

Rare RBC, granular 23 ml/min

I - 3 RBC per HPF Not done

4 + protein, marked hematuria Many RBC

RBC, hyaline

Not done

Not done

1 - 3 RBC per HPF, granular 29 mllmin

Onset with HUS

None

Onset with HUS

141/4.4 mg/dl

7013.1 mgldl

4 months after HUS 71/4.2 mg/dl

Onset with HUS

106/2.2 mg/dl

Mildly increased blood pressure 55/2.9 mg/dl

Normal 27,000/ram s

Normal 17,000/ram s

Normal 16,000/mm 3

Normal 136,000Imm 3

Normal 49,000/mm 3

Normal 124,000/ram 3

7913.2 mg/dl

ABBREVIATIONS: RBC, red blood cells; HPF, high-power field; HUS, hemolytic uremic syndrome; BUN, blood urea nitrogen; PT/ P I T , prothrombin time/partial thromboplastin time.

6 and the postmortem kidney specimen in cases 1 through 3 revealed virtually identical changes. By light microscopy, all glomerular basement membranes were thickened to varying degrees. Periodic acid-Schiff and Jones' sih'er staining revealed reduplication of the basement membranes in many capillary loops (fig. I). Endothelial cells were o f t e n swollen and contained enlarged nuclei. T h e mesangium was typically hypercelhtlar. T h e mesangial matrix was increased in the more severely afflicted glomeruli, and a few were totally hyalinized. Serial sections of the biopsy specimens (cases 2, 4, 5, and 6) revealed material with staining characteristics of fibrin in rare capillary loops (fig. 2). These were frequent and widely distributed in the postmortem material (cases 2 and 3). Phosphotungstic acid hematoxylin stain d e m o n s t r a t e d total o b l i t e r a t i o n o f occasional glomerular capillary loops with focal fi-

identified in any case. In case 1, mucinotts carcinoma permeated blood vessels and tumor emboli, occasionally enmeshed in fibrin, were present in the lungs, liver, and spleen. Many intravascular fibrin thrombi, u n a s s o c i a t e d with n e o p l a s m , were seen in the kidneys, lungs, and heart in cases 1 and 2, and the brain in case 1. Some thrombi were undergoing organization. There were no renal vein thrombi or vegetations on the cardiac valves. In case 2, mucinous carcinoma extensively involved the peritoneum and mesenteric lymph nodes. In case 3, metastatic, poorly differentiated adenocarcinoma was present in all lung lobes, and massive intracerebral hemorrhage with brain stem herniation was the cause of death. Intramyocardial hemorrhage also was noted. No p o s t m o r t e m examination was performed on cases 4 and 6. T h e renal biopsy specimens in cases 2, 4, 5, and

TABLE 2.

Chronic Glomerular Microangiopathy and Metastatic Carcinoma Therapy and Course of Six Patients Case l

Case 2

Chemotherapy

5-FU CCNU

5-FU

Total Dose (Mito-C) Radiation

None None

Mito-C 134 mg None

Course

Died 6 weeks post HUS; diffuse thrombi, metastatic carcinoma

Died l week post HUS; diffuse thromboses, GI hemorrhage

Case 3

Case 4

Case 5

Vinbl, Dox, Bleo, Cis Mito-C 66 mg Neck 75 gy Died 8 weeks post ItUS; cerebral hemorrhage

Vinbl, Cis, MTX Mito-C 89 mg Femur 36 gy Died 10 months post HUS; metastatic carcinoma

5-FU, Dox, Vinc Mito-C 105 mg Femur 30 gy Alive 2 years post HUS

Case 6 None None Pelvis 45 gy Died 26 months post HUS; metastatic carcinoma

ABBREVIATIONS: 5FU, 5 fluorouracil; CCNU, [l-(2-chloroethyl)-3-(4-methylcyclohexyl)-l-nitrosurea]; Vinbl, vinblastine; Dox, doxorubicin; Cis, cisplatin; Bleo, bleomycin; Mix, methotrexate; Vinc, vincristine; Mito-C, mitom)cin C; HUS, hemolytic uremic syndrome; GI, gastrointestinal.

343

HUMAN PATHOLOGY TABLE 3.

Volume 18. No. 4 [April 1987J

Chronic Glomerular Microangiopathy and Metastatic Carcinoma Pathologic Findings of Six Patients Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Hypercellular

Hypercellular; hyalinized

Increased BM material

Normocellular; hyalinized

Hypercellular

Glomerular basement membrane Immunohistology IgG IgA IgM C3

Doublecontoured

Dot,blecontoured; 1 + fibrin

Doublecontoured; 4 + fibrin

Doublecontoured

Increased BM material; hyalinized Doublecontoured; 2 + fibrin

Fibrinogen "Fibrin" Electron Microscopy Subendothelial lucent zones

2+ Not d o n e

2+

Present, with fine granulofibrillar deposits --

Present, with fine granulofibrillar deposits --

Podocyte processes Mesangium

Broadened

Broadened extensively Normal

Vessels, tubules

Normal

Histopathology Mesangium

Fibrin tactoids

. . -~

Normal

.

.

.

. ---

--

Arteriolar deposits, tubular protein casts

. . 3+ 1+ mesangium Not d o n e -Present, with fine granulofibrillar deposits In glomerular lumen Normal Fibrillar deposits Normal

.

Doublecontoured; 2 + fibrin

.

2+

1+ 2+ 1+ mesangium, 2 + vessels 3+ Not done

Present, with fine granulofibrillar deposits --

Marked, with fine granulofibrillar deposits In lucent zone

Broadened extensively BM-like material Normal

Broadened focally BM-like material Arteriolar thickening, tlfick tubular BM

1+ ---

2+ 3 + vessels -4+ Marked, with fine granulofibrillar deposits In lucent zone Broadened focally Normal Normal

ABBREVIATION: BM, basement m e m b r a n e .

brinoid necrosis (only in case 2). An intra-arteriolar thrombus was present in case 2. No glomerular crescents were identified. Congo red and crystal violet stains for amyloid were negative. Proteinaceous cast material was present in some tubular lumens. Tubular loss with focal interstitial lymphocytic infiltration was proportional to glomerular sclerosis. Blood vessels in cases 2 and 6 also showed mild hyaline arteriolar sclerosis. I m m u n o f l u o r e s c e n c e studies of autopsy specimens in cases 1 and 2 revealed no staining for IgG, IgA, IgM, or C3. Immunohistochemistry studies revealed negative staining for IgG in all cases. IgA was present in case 5, where it was weak, quite focal, and segmental. IgM was present in cases 3 through 6, usually within the.mesangium and having a focal and segmental pattern, the significance of which could not be determined. C3 staining was present in three cases; in the walls of larger parenchymal vessels in two cases and in the mesangium of one case. Material immunologically related to fibrinogen or fibrin was identified in five of six cases where tissue was available. Fluorescein-conjugated antifibrinogen (Behring, San Diego, California) outlined most of the capillary loops in cases 1, 2, and 5. Immunoperoxidase for "fibrin" (Biogenex) was markedly positive in cases 4 and 6 where it stained the thickened peripheral capillary loops and material within the urinary space (fig. 3). 344

T h e premortem biopsy tissue submitted from case 2 contained no glomertdi. Electron microscopy in each case showed glomerular capillary basement membranes moderately to greatly expanded by a subendothelial lucent zone containing loose, particulate, finely "granulofibrillar" deposits and scattered cellnlar elements causing narrowing or obliteration of the capillary lumen (fig. 4). T h e granulofibrillary deposits were found principally along the lamina rarefraca interna of tile glomerular basement membrane and in several cases extending into the mesangial regions. This material did not demonstrate tubular substructure. Intraglomerular fibrin tactoids (having the periodicity of fibrin) were quite sparse but identified in three cases (fig. 5). T h e s e tactoids were located within the subendothelial lucent zone in cases 5 and 6, and within the capillary lumen, closely applied to the endothelium in case 3. Reduplication of basement membrane-like material was seen in the more severely thickened loops. Focal to extensive foot process b r o a d e n i n g was present in all but case 3. Electron-dense deposits were not identified within the mesangium or in relation to tim basement membranes in any of the glomeruli. No platelet thrombi were identified. Individual platelets were rarely seen. No amyloid fibrils w e r e seen. B o w m a n ' s c a p s u l a r e p i t h e l i u m was

GLOMERULAR MICROANGIOPATHYCOMPLICATING METASTATICCARCINOMA [Hostetter et al.]

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FIGURE 1 Cleft]. Double-contoured basement membranes were present in all cases. A peripheral capillary loop shows loss of normal structure and striking fibrinoid change observed only in case 2. (Jones methenamine silver stain, x 600.] FIGURE 2 (top right]. Case 5. Focal fibrin thrombi were trapped in thickened peripheral capillary loops. (Periodic acid-Schiff stain. x 375.] FIGURE 3 [bottom right]. Case 6. Material antigenically related to fibrin was present in the thickened peripheral capillary loops and within the urinary space. (Avidin-biotin complex immunoperoxidase technique, x 600.]

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HUMAN PATHOLOGY

Volume 18, No. 4 CApri11987)

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normal. Several electron-dense deposits were seen in arterioles of case 3, as has been described in hyalin arteriolosclerosis. In most cases, the interstitium was focally edematous and contained a sparse population of lymphocytes. T h e tubules were unrenmrkable. DISCUSSION

T h e HUS described by Gasser and coworkers x6 in 1955 consists of renal microangiopathy with clin346

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ical signs of uremia, hemolytic anemia with red-cell fragments, and thrombocytopenia. A h h o u g h the most common in children, it has since been reported in association with or as a complication of acute infections (bacterial and viral), oral contraception, pregnancy, postpartnrition, as well as with immunodeficiency states, immnnization injections, and renal transplant rejection, i7 It also has been described in association with metastatic carcinoma and as a complication o f mitomycin C therapy./-13 T h e renal pathology seen in patients with HUS

GLOMERULARMICROANGIOPATHYCOMPLICATINGMETASTATICCARCINOMA [Hostetter et al.)

are virtually identical to the findings that can be seen in thrombotic t h r o m b o c y t o p e n i c p u r p u r a (TTP), scleroderma, malignant hypertension, and diabetes. Case 1 did demonstrate fibrin thrombi in the heart as well as the brain, which is a feature of TTP; however, neurologic symptoms were not present until h o u r s before death. None of the patients described showed evidence of the systemic fibrosis of scleroderina. Malignant hypertension was not considered likely because the renal failure preceded the hypertension in all cases. None o f the patients reported herein were diabetic. In addition to HUS, neoplasm can cause several other glomerular lesions, which were excluded in this case. Usually a m e m b r a n o u s glomerulonephritis is seen and results from immune complex deposition. Amyloid deposits are the basis of glomerular lesions in other cases, specifically in myeloma and Hodgkin's disease. These lesions are well described elsewhere and were not difficuh to distinguish from the authors' cases. 18 A number o f interesting theories have been proposed regarding the etiology of glomerular microangiopathy associated with HUS. In 1962, Brain et al. 19 reported five cases o f microangiopathic hemolytic anemia in patients with widespread malignancy. Increased fibrinogen byproducts were present in four cases. In two cases of the series reported by Lohrmann, l coagulation studies suggested diffnse intravascular coagulation (DIC) as an etiology, and five of s'even cases d e m o n s t r a t e d renal vascular fibrin thrombi. Lohrmann postulated that a diffuse intravascular coagulative state could lead to decreased fi~inolysis, increased fibrin precipitation, and subseent hemolysis, or {hat intravascular tumor aggregates could cause fibrin and platelet precipitation, leading to erythrocyte fragmentation. He concluded that in adults without uremia or hypertension who present with microangiopathic hemolytic anemia, the most probable cause is metastatic carcinomaJ Carcinoma can have a profound effect on coagulation, which normally is a cybernetic system constantly driven toward the deposition of fibrin. The thrombin drive is in delicate balance with inhibitors of coag~ulation and the fibrinolytic system to ensure that tln~ombosis does not occur. Malignant cells alter this balance and cause a spectrum of coagulopathy ranging from hypercoagulation and thrombosis to hemorrhage. As postulated by Bick, 2~ some patients have a dominant thrombin drive and minimal secondary lysis and present with localized or disseminated thrombosis. In contrast, other patients have minimal thrombin drive and marked secondary tibrinolysis, and present clinically with hemorrhage. Many patients with carcinoma have intermediate findings along this spectrum and develop DIC with both thrombotic and hemorrhagic complications. 2~ Malignant cells can initiate fibrin formation without s u b s e q u e n t activation of the fibrinolytic system. Some investigators have described Thromboplastin-like activity in tumoi-s by that would initiate local or systemicfllrombosis. Rickles and coworkers 2r 9

347

reported elevation of Fibrinopeptide A in 60 per cent of cancer patients, which paralleled the disease progression and suggested that activation of coagulation resulted from a tumor-generated procoagulant. 21 The amount of procoagulant or thromboplastin-like substance released may determine whether thrombosis or hemorrhage occurs. Many patients with malignancy have low antithrombin III levels, which could further destabilize the coagnlative state. Mucinous adenocarcinomas are most commonly associated with intravascular thrombosis. The sialic acid present in secreted mucin can cause the nonenzymatic activation of factor X. Ahhough DIC is relatively common in cancer patients, microangiopathic hemolytic anemia is quite rare. Antman et al. l~ in their review of microangiopathic hemolytic anemia and cancer argue against DIC as an important etiology, and propose both mechanical and chemical p a t h o p h y s i o l o g i c inechanismsJ 3 Many reports o f mitomycin C associated microangiopathic hemolytic anemia and renal failure are presently in the literature. Hanna and colleagues ~ followed 143 patients with gastrointestinal and pancreatic adenocarcinoma, all of which received mitomycin C as a component of their chemotherapy protocol. Fourteen patients developed renal disease either as an acute rapidly fatal m i c r o a n g i o p a t h i c hemolytic anemia with thrombocytopenia, or as a chronic, progressive renal impairment. 9 HUS is now recognized as an important dose-related complication of mitomycin C therapy. Mitomycin is not the only drug with this side effect. Jackson et al. 22 reported H U S in five patients with metastatic carcinoma who received chemotherapy other than mitomycin C. T h e mechanism of action of mitomycin or other exogenous chemicals for the development of HUS is unknown. Both mechanical and chemical factors may be necessary to produce the HUS in cancer patients. The neoplasm may initiate an imbalance in coagulation resulting in a DIC, with thrombosis and damage seen systemically or predominantly in the renal vasculature. Tumor-associated immune complexes have been implicated by others. 23,~4 Mitomycin C and other chemotherapeutic agents may cause HUS by similar or entirely different mechanisms to those suggested. Finally, some other interaction between the tumor and chemotherapeutic agents may result in these histopathologic changes. T h e authors report six patients with metastatic carcinoma who developed microangiopathic hemolytic anemia. Four of the patients received mitomycin C as a c o m p o n e n t of chemotherapy, one received chemotherapeutic agents other than mitomycin C, and one patient received only radiation treatment. HUS developed within f o u r months of the initiation of chemotherapy in the patient who did not receive mit0mycin C. H U S d e v e l o p e d nine months after the conclusion of radiation therapy in the patient who received no chemotherapy. Carcinoma was not clinically a p p a r e n t at that time. H U S d e v e l o p e d an

HUMAN PATHOLOGY

Volume `18, No. 4 [April '1987]

a v e r a g e o f s e v e n m o n t h s a n d t h r e e w e e k s ( r a n g e : six m o n t h s to twelve m o n t h s a n d t w o weeks) a f t e r t h e i n i t i a t i o n o f m i t o m y c i n C t h e r a p y in f o u r cases. T h e s m a l l e s t d o s e o f m i t o m y c i n C was 66 m g (16.5 m g o v e r t h r e e m o n t h s ) in c a s e 3 a n d t h e l a r g e s t was 134 m g (20 a n d 30 m g d o s e s o v e r e i g h t m o n t h s ) in c a s e 2. D e a t h o c c u r r e d w i t h i n e i g h t w e e k s in b o t h cases. T h i s s u p p o r t s t h e f i n d i n g s o f V a l a v a a r a a n d o t h e r s 25 t h a t r e n a l t o x i c i t y to m i t o m y c i n C is s i g n i f i c a n t a b o v e a c u m u l a t i v e d o s e o f 50 m g p e r m m L T h e d o s e d i d not correlate with the eventual outcome of the pat i e n t s in t h e a t t t h o r s ' s e r i e s . I n cases 1 t h r o u g h 3, d e a t h o c c u r r e d w i t h i n six to e i g h t w e e k s o f t h e o n s e t o f H U S , a n d t h e c o u r s e a p p e a r e d n o t to b e a f f e c t e d b y p l a s m a p h e r e s i s , in t w o cases w h e r e it was u s e d . T h r o m b o s e s o r h e m o r r h a g e w e r e m a j o r c o n t r i b u t i n g f a c t o r s in t h e c a u s e o f death. All had widely metastatic carcinoma. Cases 4 through 6 followed a more chronic course, surviving f r o m t e n m o n t h s to g r e a t e r t h a n two y e a r s a f t e r t h e o n s e t o f H U S . T h e s e l a t t e r cases s e e m e d to d e r i v e benefit from plasmapheresis, a finding reported by o t h e r s , 7AI,26 a n d o n e p a t i e n t is p r e s e n t l y ' s t a b l e o n p e r i t o n e a l dialysis. T h e c a u s e o f d e a t h in cases 4 a n d 6 was r e p o r t e d l y , b e c a u s e o f w i d e l y m e t a s t a t i c c a r c i noma, ahhough no postmortem examinations were performed. I n all cases, w h e t h e r a s s o c i a t e d w i t h t u m o r o r m i t o m y c i n C, t h e u r i n a l y s i s s h o w e d 3 to 4 + p r o t e i n u r i a , h e m a t u r i a , a n d v a r i a b l e n u m b e r s o f r e d ceil casts, s u g g e s t i n g m a r k e d g l o m e r u l a r d a m a g e . Y e t in n o case d i d r e n a l f a i l u r e a p p e a r to b e a s i g n i f i c a n t f a c t o r in t h e p a t i e n t ' s d e a t h . T w o p a t i e n t s d i e d o f hemorrhagic complications shortly after the onset of HUS and the remainder died of metastatic disease. This differs from the report of Kressel and cow o r k e r s , 27 in w h i c h u r e m i c s y m p t o m s w e r e u l t i mately considered a significant cause of patient morb i d i t y a n d mortality'. T h e s e six cases as well as a variety, o f r e p o r t s in the literature emphasize the diverse pathophysiologic mechanism by which glomerular microangiopathy m a y a r i s e in m e t a s t a t i c c a r c i n o m a .

REFERENCES 1. Lolarmann HP, Adam W, Heymer B: Microangiopathic hemolytic anemia in metastatic carcinoma: report of eight cases. Ann Intern Med 79:368, 1973 2. Lynch EC, Bakken CL, Case) TH, et al: Microangiopathic hemolytic anemia in carcinoma of the stomach. Gastroenterology 52:88, 1967 3. Milutinovic J, Irby S, Fisher M: Hemolytic uremic syndrome and metastatic malignancy. South Med J 75:1409, 1982 4. Marcos OO, Escnin F, MiguelJL, et al: Hemolytic uremic syndrome in a patient with gastric adenoearcinoma: partial recovery of renal function after gastrectomy. Clin Nephrol 24:265, 1985

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5. Bruntsch U, Groos G, Tigges F, et al: Microangiopathic hemolytic anemia, a frequent complication of mitomycin therapy in cancer patients. EurJ Cancer Clin Oncol 20:905, 1984 6. Crocker J, Jones E: Itaemolytic-uraemic syndrome complicating long-term mitomycin-C and 5-fluoronracil therapy for gastric carcinoma. J Clin Pathol 36:24, 1983 7. Gulati SC, SordiIlo P, Kempin S, et al: Microangiopathic hetool) tic anemia observed after treatment of epidermoid carcinoma with mitomycin-C and 5-fluorouracil. Cancer 45:2252, 1980 8. Hamner RW, Verani R, Weinman EJ: Mitomycin associated renal failure: case report and review. Arch Intern Med 143:803, 1983 9. Hanna WT, Krauss S, Regester RF, et ah Renal disease after mitomycin C therapy. Cancer 48:2583, 1981 10. Pavy hiD, Wiley EL, Abeloff hiD: Hemolytic-uremic syndrome associated with mitomycin therapy. Cancer Treat Rep 66:457, 1982 11. Price TM, Murgo AJ, KeveneyJJ, et al: Renal failure and hemolytic anemia associated with mitomycin C. Cancer 55:5 I, 1985 12. Proia AD, Harden EA, Silberinan HR: Mitomycin-induced hemolytic-urenfic syndrome. Arch Pathol Lab Med 108:959, 1984 13. Antman KH, Skarin AT, Mayer RJ, et al: Microangiopathic hemolytic anemia and cancer: a review. Medicine 58:377, 1979 14. Laftay DL, Tubbs RR, Valenzuela R, et al: Chronic glomerular microangiopathy and metastatic carcinoma. HUM PATIIOL 10:433, 1979 15. Tubbs RR, Gephardt GN: Use and interpretation ofimmunoperoxidase procedures in renal disease. In Rosen S (ed): Pathology of Glomerular Disease. New York, Churchill Livingstone, 1983, p 11 16. Gasser C, Gautier E, Steck A, et al: Hanaolytischuramislae Syndrome: bilaterale Nierenrindennekrosen bei akuten erworbenen Hamolytischen anamien. Schweiz Med Wochenschr 85:905, 1955 17. Goldstein hill, Churg J, Strauss L, et al: Hemolytic-uremic syndrome. Nephron 23:263, 1979 18. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Intern 11:297, 1977 19. Brain MC, Dacie JV, Hourihane DO: Microangiopathic haemolytic anemia: the possible role of vascular lesions in pathogenesis. BrJ Haematol 8:358, 1962 20. Bick RL: Alterations of hemostasis associated with malignancy: etiology, pathophysiology, diagnosis and management. Semin Thromb ttemost 5:1, 1978 21. Rickles FR, Edward RL, Barb C, et al: Abnormalities of blood coagulation in patients with cancer. Fibrino-peptide A generation and tumor growth. Cancer 51:301, 1983 22. Jackson AM, Rose BD, Graft LG, et al: Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 101:41, 1984 23. Couser WG, Wagonfeld JB, Spargo BH, et al: Glomerular deposition of tumor antigen in membranous nephropathy associated with colonic carcinoma. Am J Med 57:962, 1974 24. Helin H, Pasternack A, Hakala T, et al: Glomerular electrondense deposits and circulating immune complexes in patients with malignant tnmours. Clin Nephrol 14:23, 1980 25. Valavaara R, Nordman E: Renal complications of mitomycin C therapy with special reference to the total dose. Cancer 55:47, 1985 26. Lyman NW, Michaelson R, Viscuso RL, et al: Mitomycin-induced haemolytic uremic syndrome. Successful treatment with corticosteroids and intense plasma exchange. Arch Intern Med 143:1617, 1983 27. Kressel BR, Ryan KP, Duong AT, et al: Microangiopatlfic hemolytic anemia, thrombocytopenia, and renal failure in patients treated for adenocarcinoma. Cancer 48:1738, 1981