Year : 2008 | Volume
: 51 | Issue : 2 | Page : 230--233
Membranoproliferative glomerulonephritis in a carcinoma with unknown primary: An autopsy study
Kirti Gupta1, Ritambhra Nada1, Ashim Das1, Mahi Sushil Kumar2,
1 Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
2 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Department of Pathology, PGIMER, Chandigarh - 160 012
Kidney disease frequently complicates malignancy and its treatment. Although many solid and hematologic cancers may involve the renal parenchyma, clinical sequelae are usually not prominent. Published reports cite membranous nephropathy as the most common malignancy-associated glomerulopathy, occurring with many carcinomas and occasionally with leukemia and lymphoma followed by minimal change disease. Rarely membranoproliferative glomerulonephritis (MPGN) has been reported in patients with malignancy. The mechanism by which malignancy induces disease remains unproved, but may involve deposition of tumor antigen in the subepithelial space with in situ immune complex formation and subsequent complement activation. Treatment of the underlying malignancy may lead to resolution of nephrotic syndrome, lending indirect support to this theory. We report a rare autopsy case of a patient with metastatic carcinoma (with unknown primary) associated with MPGN. The association between MPGN and metastatic carcinoma with unknown primary is uncommon and has not been previously reported in the literature.
|How to cite this article:|
Gupta K, Nada R, Das A, Kumar MS. Membranoproliferative glomerulonephritis in a carcinoma with unknown primary: An autopsy study.Indian J Pathol Microbiol 2008;51:230-233
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Gupta K, Nada R, Das A, Kumar MS. Membranoproliferative glomerulonephritis in a carcinoma with unknown primary: An autopsy study. Indian J Pathol Microbiol [serial online] 2008 [cited 2019 Oct 20 ];51:230-233
Available from: http://www.ijpmonline.org/text.asp?2008/51/2/230/41665
Membranous glomerulopathy is cited as the most common malignancy associated nephropathy. Rarely, MPGN has also been reported in patients with carcinomas and hematological malignancy. Herein, we report an autopsy case of a patient with metastatic carcinoma (with unknown primary) associated with MPGN.
A 37-year-old male presented with low-grade fever, cough and expectoration for 3 weeks. Two weeks later, he developed breathlessness, gum bleeding and epistaxis. There was no history of skin rash, joint pain, or altered sensorium. On examination, he was found to have pallor, icterus and pedal edema with raised JVP, lymphadenopathy and hepatosplenomegaly. Bilateral diffuse crepitations in all lung fields were noted. Investigations revealed maintained blood parameters except for thrombocytopenia. In the peripheral blood smear, there were features of intravascular hemolysis with fragmented RBCs, microcytes and schistocytes. Coagulation profile was maintained. Liver enzymes were raised with increased bilirubin level (2.2 mg/dl). Renal function test were deranged with raised blood urea and serum creatinine. Urine microscopic examination could not be carried out. The chest X-ray revealed bilateral patchy acinar opacities in the upper and mid zones suggestive of bronchopneumonia and alveolar hemorrhages. His condition deteriorated and he expired a day after admission to the hospital following a cardiorespiratory arrest.
A complete autopsy was performed following an informed consent. Externally, no obvious abnormality or swelling was noted. The spleen weighed 475 g was enlarged with a firm capsular surface. The cut surface revealed diffuse nodularity with grayish white tiny nodules centered on white pulp, giving a follicular prominence [Figure 1A]. Microscopically, the architecture was diffusely replaced by cords, ribbons and trabeculae of tumor cells around the central arteriole [Figure 1B]. The cords and sinuses of red pulp were also replaced by tumor cells present singly. The cells had an eccentric nucleus, vesicular chromatin and conspicuous nucleoli. Tumor cells with similar morphology in cords and ribbons were present within the hepatic and marrow sinusoids [Figure 1C and D]. The bone marrow also showed fibrosis with complete replacement of the marrow architecture and new bone formation. Peripancreatic lymph nodes were enlarged (2 × 1 cm) with sinusoidal metastasis and foci of extramedullary hematopoiesis.
The morphologic features suggested a moderately differentiated adenocarcinoma. The panel of immunohistochemical markers performed included cytokeratin (CK), vimentin, neuron-specific enolase (NSE), chromogranin, leucocyte common antigen (LCA), CD31, prostate-specific antigen (PSA) and estrogen receptor (ER). The neoplastic cells were positive for CK and PSA [Figure 1E and F], thereby suggesting a likely primary in the prostate or salivary gland. The rest of the markers were negative in the tumor cells. The presence of osteoblastic secondaries prompted the inclusion of PSA in the list. Thyroid, heart, stomach, esophagus, pancreas, adrenals, gastrointestinal tract seminal vesicles, testes and vas deferens and brain were within normal limits. The prostate gland grossed and blocked in its entirety failed to reveal a tumor focus. Externally, no obvious swelling on the face was noted by the prosector.
The lungs weighed 1260 g were heavy with features of fresh and old alveolar hemorrhages on microscopic examination. The kidneys weighed 330 g were normal sized with distinct corticomedullary junction. Microscopic examination revealed an increase in mesangial cellularity and thickening of basement membrane [Figure 2A]. No spikes were noted on methamine-silver staining. The tubules, interstitium and blood vessels were essentially normal. Immunohistochemistry revealed moderate granular positivity with antisera specific for complement factor 3 (C3) along peripheral glomerular capillary basement membrane and mesangium [Figure 2B]. There was no immunostaining with antisera specific for IgG, IgA, IgM and fibrinogen. The immunostaining for PSA showed positivity in few of the mesangial cells and endothelial cells [Figure 2C]. Ultrastructurally, irregular electron dense deposits were present in subendothelial location with mesangial cell interposition and laying down of new basement membrane [Figure 2D-F]. Few intramembranous and mesangial deposits were also seen. Tubules, interstitium and arteries were normal ultrastructurally.
The association between glomerular pathology and extrarenal malignancy was first described by Galloway in 1922.  Lymphomas and leukemias are the most common malignancies, with 6-60% incidence in patients with diffuse lymphoma at autopsy.  Pulmonary, gastric and breast carcinomas are the most common solid tumors to metastasize to kidney.  Although the overall frequency of glomerular disease in malignancy is low, paraneoplastic glomerular disease is well described.  A number of case reports have appeared linking nephrotic syndrome with Hodgkin's disease, leukemia,  and various carcinomas such as carcinoma of stomach, colon and ovary.  It is generally considered that solid tumors are associated with membranous glomerulonephritis.  Other glomerulopathies are seldom reported. Review of literature cites case reports of occurrence of membranoproliferative glomerulonephritis (MPGN) with small cell carcinoma, low-grade lymphoma and mixed germ cell tumor. The pathogenesis of MPGN is incompletely understood and both primary and secondary forms are generally regarded as immune complex-mediated disorders.  Glomerular lesions like MPGN have not been described in any of the previously reported cases of a metastatic carcinoma with unknown primary.
Several studies have shown glomerular deposits containing specific tumor antigens together with their antibodies.  Cryoglobulins are known to result in MPGN lesions in cases with lymphomas. In the present case, the tumor expressed positivity for CK and PSA and PSA immunostain performed on the kidney section showed expression in the mesangial cells and capillary endothelium. There were no cryoglobulins in this case and immunostaining for IgM was negative in the kidney. Electron microscopic evaluation of electron-dense deposits in kidney also did not suggest presence of cryoglobulins. However, the positivity for anti-C3 favors an immune-mediated process as the likely pathogenetic mechanism in the present case. Although a detailed urine microscopic examination could not be carried out, but deranged biochemical levels of blood urea and serum creatinine are indicative of glomerular involvement.
Widespread metastatic malignancy without detectable site of origin after an extensive diagnostic workup is put under the category of carcinoma with unknown primary. This makes up 3-5% of autopsied cases in a referral center.  It is hypothesized that the strong host immune reaction against tumor cell resulted in complete effacement of the primary tumor after it metastasized.  The present case was placed under this category after excluding and sampling all possible primary sites including lungs, thyroid, prostate, pancreas, seminal vesicle and testes. The salivary glands could not be sampled and the possibility of a metastatic carcinoma with primary in salivary glands is extremely rare. The malignancy had resulted in glomerular injury with morphology of MPGN, with complement dependent immune-mediated injury as the likely pathogenetic mechanism.
In conclusion, this rare case illustrates the glomerular injury, resulting in MPGN occurring secondary to a metastatic carcinoma with unknown primary.
|1||Galloway J: Remarks on Hodgkin's disease. Br Med J 1922;2:1201-4.|
|2||Xiao JC, Walz-Mattmuller R, Ruck P, Horny HP, Kaiserling E. Renal involvement in myeloproliferative and lymphoproliferative disorders: A study of autopsy cases. Gen Diagn Pathol 1997;142:147-53.|
|3||Wagle DG, Moore RH, Murphy GP. Secondary carcinomas of the kidney. J Urol 1975;114:30-2.|
|4||Eagen JW. Glomerulopathies of neoplasia. Kidney Int 1977;11:297-303.|
|5||Pascal RR. Renal manifestation of extrarenal neoplasms. Hum Pathol 1980;11:7-17.|
|6||Keur I, Krediet RT, Arisz L. Glomerulopathy as a paraneoplastic phenomenon. Neth J Med 1989;34:270-84.|
|7||Helin H, Pasternack A, Hakala T, Penttinen K, Wager O. Glomerular electron-dense deposits and circulating immune complexes in patients with malignant tumours. Clin Nephrol 1980;14:23-30.|
|8||Donadio JV Jr. Membranoproliferative glomerulonephritis. In : Jacobson HR, Stricker GE, Klahr S, editors. The Principles and Practices of Nephrology, 2 nd ed. New York: Decker; 1995. p. 299-302.|
|9||Nyatrom JS, Weiner JM, Wolf RM, Bateman JR, Viola MV. Identifying the primary site in metastatic cancer of unknown origin. JAMA 1979;241:381-3.|
|10||Altman E, Cadman E. An analysis of 1539 patients with cancer of unknown primary site. Cancer 1986;57:120-4.|