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Nephrotic syndrome of unclear etiology hid two primary malignancies
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Paraneoplastic glomerulopathies are glomerular diseases associated with solid or hematologic malignancies.
This association was first hypothesized in 1922. In 1966, Lee and colleagues studied 101 patients with otherwise unexplained nephrotic syndrome and found an overall prevalence of 11% for malignant tumors, with higher rates in elderly age groups. The diagnosis of nephrotic syndrome preceded the diagnosis of the neoplasia in most cases.
Glomerular damage may manifest more frequently in the setting of epithelial tumors, such as lung and gastrointestinal cancers, and is rarely related to other frequent solid epithelial tumors, such as prostate, breast, ovarian or uterine cancers. It was rarely reported in the setting of low-grade or benign tumors, such as benign ovarian teratoma, pheochromocytoma and spinal cord tumors.
Source: G. Annunziata, MD
This report describes a case of nephrotic syndrome associated with two parallel primary malignancies, adenosquamous carcinoma of the lung and transitional cell carcinoma of the bladder.
Upon literature review, paraneoplastic glomerulopathies were described in both cancers, but this is the first case of two primary malignancies manifesting with symptoms of nephrotic syndrome.
Case report
A 79-year-old Hispanic man presented to the hospital with progressive lower extremity edema. His medical history included benign prostatic hypertrophy and a remote history of gonorrhea, treated at age 18.
He was an active 50 pack-years smoker without any alcohol or recreational drug use.
Physical examination revealed 3+ pitting edema on both lower extremities. His initial laboratory exams were compatible with nephrotic syndrome, renal failure (unknown baseline renal function), hematuria and pyuria (Table 1).
A renal biopsy showed findings of membranous nephropathy (MN; Figures 1a and 1b). In addition, one of the 38 sampled glomeruli showed a necrotizing crescent (Figure 1c).
On immunofluorescence microscopy, diffuse granular glomerular capillary wall staining for IgG, IgM, IgA, C3 and C1 was noted (Figure 1d). Immunostains for IgG heavy chains revealed predominant staining for IgG1, weak staining for Ig2, and no staining for IgG3 or IgG4. Electron microscopy revealed diffuse subepithelial immune-type electron-dense deposits (Figure 1E). No mesangial or extraglomerular deposits or endothelial tubuloreticular inclusions were seen.
Figure 1. Renal biopsy. A light microscopy reveals thickened glomerular basement membranes (a). Glomerular capillaries focally display marginating leukocytes (b). One glomerulus shows a necrotizing crescent (c). Immunofluorescence microscopy reveals granular capillary wall stain for IgC (d). Electron microscopy shows subepithelial immune-type electron-dense deposits (e).
Source: Images courtesy of G. Annunziata, MD reprinted with permission.
A Doppler study ruled out renal vein thrombosis, and a comprehensive workup for possible secondary causes of glomerulopathy was initiated (Table 2). A clear etiology was not found. Therefore, the patient was treated with steroids and cyclophosphamide. He was discharged from the hospital with further workup scheduled as an outpatient.
However, 17 days later, the patient was readmitted with dyspnea and cough productive of yellow sputum. A chest X-ray showed a left lower lobe infiltrate. Multiple blood cultures were negative; however, Legionella antigens were found in the urine and yeast-like organisms were isolated from urine and sputum samples, so antibiotic treatment was started and the immunosuppressive therapy was withheld.
A CT scan of the chest and abdomen showed a 1 cm suspicious spiculated pulmonary nodule in the left lower lobe and multiple enlarged mediastinal lymph nodes, most notably a 3 cm x 1.7 cm aortopulmonary window lymph node. A mass arising from the left bladder wall and extending inward also was found, measuring 4 cm x 2.7 cm.
Figure 2. Lung mass. The spiculated mass found in the CT is seen in image a. The other images show histologic pictures taken from the biopsied mass: tumor cell nest (b); neoplastic epithelial cells showing abundant eosinophilic cytoplasm, nuclear pleomorphism, nuclear hyperchromasia and prominent nucleolar (c); PAS stain is positive for intra- and extracellular mucin (d); positive nuclear staining of TTF, consistent with primary adenocarcinoma of the lung (e); positive nuclear staining of p63, suggestive of squamous differentiation (f).
A CT-guided needle core biopsy of the left lower lobe mass (Figure 2) showed an adenocarcinoma with features of squamous differentiation (positive for mucin stain, TTF-1, CK516 and P63), whereas the tissue obtained from the transurethral resection of bladder tumor (Figure 3) revealed a low-grade papillary urothelial carcinoma without invasion of the lamina propria.
His condition improved, and he was discharged with close follow-up.
His lung cancer was staged as T1N3 stage IIIB, surgically unresectable. Treatment was started with chemotherapy with weekly docetaxel (Taxotere, Sanofi-Aventis) 35 mg/m2 and external beam radiation therapy to the lung primary and the mediastinal lymph nodes. The patient received 4 weeks of docetaxel and a total radiation dose of 5,040 cGy.
His peripheral edema gradually resolved and repeat laboratory tests after 3 months showed a significant decrease in the amount of proteinuria (1,491.5 mg/24 hours with a total volume of 950 mL, down from 10,097.5 mg/24 hours with a total volume of 875 mL). After treatment, the patient traveled overseas and was lost to follow-up.
Discussion
Nephrotic syndrome is usually a clinical manifestation of glomerular damage. It may be classified as primary, or secondary to infections, diabetes, autoimmune disorders, amyloidosis or paraproteinemias, drugs/toxins, preeclampsia or cancer.
In a case review of 344 reported paraneoplastic glomerulopathies, MN was the most common (46.2%), followed by minimal change disease (18.6%), crescentic glomerulonephritis (13.9%), membranoproliferative glomerulonephritis (8.4%), IgA nephropathy (7.2%) and focal segmental glomerulosclerosis (5.5%).
Figure 3. Image a shows the mass as found in the CT. Image b is the low-power field view of the biopsied mass, which shows abundant papillary growth of urothelium (arrows). Image c is the high-power field view that shows dysplastic urothelial cells showing small conspicuous nucleoli, nuclear pleomorphism and nuclear hyperchromasia (arrow on right). There are no dysplastic cell infiltrates into stroma of papillary fronts (arrow on left). Those feature low-grade, noninvasive papillary urothelial carcinoma.
Specific patterns of association also were found: Gastric cancer was more frequently associated with membranous nephropathy and crescentic glomerulonephritis; lung cancers with membranous nephropathy and membranoproliferative glomerulonephritis; thymomas with minimal change disease and focal segmental glomerulosclerosis; and renal cell carcinomas with IgA nephropathy, crescentic glomerulonephritis and focal segmental glomerulosclerosis.
Hodgkin’s lymphoma is strongly associated with minimal change disease, which also was reported in other hematologic malignancies.
The diagnostic criteria for paraneoplastic glomerulopathies are not well established, since the exact physiopathology is still unclear. However, some widely accepted criteria warrant strong suspicion:
The exact pathophysiology of the paraneoplastic glomerular disease remains unclear, besides that immune-mediated processes are involved. The Heymann nephritis model demonstrated how an antigen–antibody reaction can cause glomerular lesions identical to those observed in the idiopathic disease in rats. Beck and colleagues recently identified circulating antibodies reactive against the M-type phospholipase A2 receptor — a protein present in human podocytes — in cases of idiopathic MN, hypothesizing in that way a possible mechanism.
He also theorized a model that involved the formation of circulating immune complexes responsible for the glomerular damage caused by proteins expressed by the neoplasia or products of viral oncogenes.
It is well known that tumor antigens have been isolated in immune complexes on the subepithelial surfaces of the glomerular basement membrane (GBM) of patients with malignancies after the elution of the antibody, but a causal relationship was never demonstrated and no universally accepted data are yet available to distinguish the idiopathic from the paraneoplastic forms.
Some authors speculated about the possibility of distinguishing the paraneoplastic from idiopathic MN when more inflammatory cells infiltrating glomeruli are present, with a cutoff established in more than eight cells per glomeruli. In studies on IgG subclasses deposition in different nephropathies, the deposition of IgG1 and IgG2 was noted more frequently in paraneoplastic MN; in idiopathic forms of MN, IgG4 were predominant.
In our case, the number of inflammatory cells infiltrating the glomerulus was 12 (Figure 1b). There was predominant staining for IgG1, weaker staining for IgG2, and no staining for IgG3 or IgG4 heavy chain, consistent with neoplasia-associated MN.
The combination of crescent formation and MN has been described in some cases of primary disease and autoimmune disease but not, to our knowledge, in association with malignancy. This combination appears to be associated with worse outcomes.
Transitional cell carcinoma of the bladder has been associated in few reports with membranoproliferative glomerulonephritis and MN. In this case, we are unable to prove a causative role for the underlying malignancies, but it is plausible that these contributed to the development of MN.
Conclusions
When faced with patients presenting with new onset nephrotic syndrome, clinicians must consider the known possible secondary causes, especially in patients aged older than 60 years. Age- and gender-appropriate cancer screening tests — such as mammography, PSA tests and colonoscopy — are an important first step.
It could be reasonable to obtain chest images — especially if there is a history of tobacco use — and an upper endoscopy. The clinician also may consider tailoring the workup based on the clinicopathological picture and the awareness of the association of some neoplasias with particular patterns of glomerular damage. The risk of diagnosing a malignancy in such patients persists for up to 5 years from the diagnosis of glomerulopathy, so close follow-up is warranted even if initial tests rule out the malignancy.
Multiple case reports have shown reduced proteinuria with treatment of the primary neoplasia, and that was shown in our case, as well.
There are no validated studies about the efficacy of corticosteroids in most of the paraneoplastic glomerulopathies, and caution should be exercised when using steroids and cytotoxic agents in paraneoplastic glomerulopathies. Immunosuppression may worsen the risk for infection, which already is heightened by the nephrotic syndrome, and may theoretically exacerbate the malignancy. Steroids may be warranted only in paraneoplastic minimal change disease, along with the classic oncologic treatments.
In this patient, the immunosuppressive therapy may have initially worsened his already compromised state, thereby facilitating the ineffective processes that prior studies have shown may be associated with significant side effects, particularly in the elderly. The latter treatment was discontinued after only one dose of cyclophosphamide and 18 days of steroids, when the patient re-presented to the hospital and the infections and the cancers were discovered, and his malignancies immediately became the focus of treatment.
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For more information:
Giuseppe Annunziata, MD, Ilmana Fulger, MD, and Tauseef Sarguroh, MD, are physicians in the department of hematology and oncology at St. Barnabas Hospital in Bronx, N.Y. They can be reached at Department of Hematology and Oncology, 3rd floor, Mills Building, 183rd Street and 3rd Avenue, Bronx, NY 10457; email: jfulger@yahoo.com.
Disclosure: Annunziata, Fulger and Sarguroh report no relevant financial disclosures.Acknowledgement: The authors thank Qi Tao, MD, of the pathology department at St. Barnabas Hospital, and Barry Stokes, MD, of the renal pathology department at Columbia University, for their input and help with the pathology images.