MN remains the most common glomerular pathology reported in patients with solid tumors [2, 3] . The true prevalence of malignancy with MN is unknown. However, in 2006, Lefaucheur et al. reported a prevalence of malignancy of 10 % in their retrospective study of 240 patients with biopsy proven membranous nephropathy [4]. In this study, only half of the patients with malignancy-associated MN were known to have symptoms related to their cancer at the time of kidney biopsy [4]. However, most of these patients were diagnosed with malignancy within a year of MN diagnoses. Several other case series have reported prevalence that ranges as low as 1 % to as high as 22 %. Zech et al. reported a prevalence of cancer as high as 22 % in their case series of MN patients who were older than 60 years [5].

The solid tumor malignancies most commonly associated with MN have been respiratory (lung and bronchus), and gastric carcinomas (Table 3.1). This is followed by renal carcinoma, prostate cancer, and thymoma. Breast cancer and other gastrointestinal cancers such as colorectal, pancreatic, esophageal, and hepatic have been also reported with MN. Tumors that have been rarely associated with MN include sarcoma, testicular seminoma, parotid adenolymphoma, adrenal ganglioneuroma, spinal schwannoma, and carotid body tumor .

Are there any clinical features, lab findings, or kidney biopsy findings that help to differentiate primary MN from secondary MN associated with solid tumors? Clinically, it is difficult to differentiate primary MN from secondary MN associated with solid tumors, especially when both types of MN present as nephrotic syndrome. However, in a known case of cancer, the presence of proteinuria or nephrotic syndrome should raise the possibility of underlying secondary type of glomerular disease. Similarly, the development of proteinuria or nephrotic syndrome within 12 months of the diagnosis of cancer should also increase the suspicion of underlying secondary form of glomerular disease, mainly cancer-associated MN. Lefaucheur et al. reported two risk factors that differentiate paraneoplastic MN from primary MN in their retrospective study of 240 patients with biopsy proven membranous nephropathy [4]. They include age over 65 years and history of smoking for more than 20 pack-years. Hence, one should consider cancer in patients with membranous nephropathy who are either older or have a long standing history of smoking. However, Beck in his article reviews the possibility of coincidental diagnosis of MN and cancer, especially in an older age group in which both diseases tend to occur [6] . In 2009, Beck et al. identified circulating autoantibodies to podocyte transmembrane glycoprotein M-type phospholipase A2 receptor (PLA2R) in a majority of their cases of adult primary MN [7]. These autoantibodies were not found in cases of secondary MN. However, Qin et al. in their study did find elevated levels of anti-PLA2R autoantibodies in three out of ten MN patients with solid tumors [8]. Interestingly, all three MN patients with solid tumors and elevated levels of circulating anti-PLA2R autoantibodies had moderate glomerular immunoglobulin G4 (IgG4) deposition on kidney biopsy: A finding that has been described predominately in patients with primary MN. In comparison, all remaining seven patients with tumor-associated MN had no glomerular IgG4 deposition [8] . Clinically, all three MN patients with elevated levels of circulating anti-PLA2R autoantibodies also had either persistence or relapse of proteinuria, despite tumor resection, suggesting that these were patients likely with primary MN [8]. Recently, Hoxha et al. have also showed enhanced staining of PLA2 R in the glomeruli of patients with primary MN compared with normal staining in patients with tumor-associated MN [9]. As opposed to a predominant IgG4 subclass deposition in primary MN, Ohani et al. showed an increased glomerular deposition of IgG1 and IgG2 subtypes in patients with cancer-associated MN [10]. Hence, on the basis of the above data, the presence of circulating anti-PLA2 R antibodies and/or enhanced glomerular PLA2 R staining with the predominance of IgG4 in the glomeruli of patients with MN are suggestive of primary MN even in the presence of cancer. In addition to the above, the presence of the increased inflammatory cells ( > 8 cells per glomeruli) on kidney biopsies was shown to be more suggestive of cancer-associated MN than primary MN, as reported by Lefachuer et al. [4]. However, more studies will need to confirm this finding .

Table 3.2 summarizes the above differentiating clinicopathologic parameters between primary and solid tumor-associated MN.

Although the above laboratory and kidney pathologic findings may herald cancerassociated MN, a high index of suspicion for underlying malignancy is also required when evaluating a case of MN in whom cancer is not yet diagnosed. The Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group recently concluded that further studies are needed to determine the most cost effective panel of investigations for screening an underlying (covert) malignancy in the older patients with MN [11]. In the meantime, until such information is available, it is reasonable to perform routine age- and sex-appropriate screening for malignancy, once other known causes of secondary MN have been excluded. This may include fecal occult blood testing, colonoscopy, mammography, and prostate-specific antigen testing. In patients at high risk for lung cancer (for example, smokers), low-dose chest computed tomography (CT) should be considered. It is important to note that the risk of finding cancer may persist for at least 5 years from the time of kidney biopsy [12]. This prolonged risk period could be as a result of a slow-growing malignancy, use of cytotoxic therapy for MN, or due to increased surveillance [12]. Hence, close medical follow-up and evaluation are needed even if the cancer is not detected on initial screening done following the kidney biopsy findings .

The possible mechanisms whereby solid tumors may be associated with MN [6] include: