Research ArticleClinical Studies
Open Access

Membranous Nephropathy as a Paraneoplastic Syndrome in Cancer of Unknown Primary

KYOICHI KAIRA, HIROAKI AMANO, HISAO IMAI, HIROKAZU OKADA and HIROSHI KAGAMU
In Vivo May 2024, 38 (3) 1503-1508; DOI: https://doi.org/10.21873/invivo.13598

Abstract

Background/Aim: Membranous nephropathy (MN) is a nephrotic syndrome with both idiopathic and secondary etiologies. The mechanism of cancer-associated MN is presumed to involve the immunological production of antibodies against a tumor antigen, although little is known about the detailed mechanism. Lung cancer is a major neoplasm associated with cancer-associated MN. However, the simultaneous occurrence of secondary MN in patients with cancer of unknown primary (CUP) remains unclear. Case Report: Here, we present a case of secondary MN in a 72-year-old female as a paraneoplastic syndrome in CUP. Thoracic radiotherapy up to a total of 60 Gy was initially performed on the right subclavian and mediastinal lymph nodes. Computed tomography revealed marked shrinking of these lymph nodes, and the secondary MN also improved without any symptoms. Conclusion: The presence of proteinuria in patients with CUP suggests the possibility of secondary MN as a rare differential diagnosis.

Key Words:

Membranous nephropathy (MN) is a significant cause of nephrotic syndrome, characterized by the formation of immune complexes (1). Seventy-five percent of MN patients have an idiopathic etiology, whereas the remaining cases are related to malignancies, infections, autoimmune disorders, and medications (2). Although there have been numerous reports of cancer-associated MN, its estimated prevalence in cancer has been determined to be 10% (3). A recent meta-analysis reported that lung cancer was the main tumor type (26%), followed by prostate cancer (13%), hematologic malignancies (12%), colorectal cancer (11%), breast cancer (7%), stomach and esophageal cancer (6%), bladder cancer (5%), cervical and uterine cancer (4%), and renal cell carcinoma (2%) (4). However, the true prevalence of cancer in patients with MN remains unclear. Several previous studies have reported a prevalence between 5% and 22% (4).

The pathogenic mechanism of cancer-associated MN is presumed to involve immunological production of antibodies against a tumor antigen, leading to immune complex formation (5). The transmembrane glycoprotein M-type phospholipase A2 receptor (PLA2R) has been identified as the major target of podocyte antigen in idiopathic MN patients (6). Therefore, the detection of circulating antibodies against PLA2R is helpful for differential diagnosis of idiopathic versus secondary MN.

Cancer of unknown primary (CUP) accounts for 2%-5% of all diagnosed cancers, and such patients generally have poor outcomes after any type of treatment (7, 8). However, the simultaneous occurrence of secondary MN in patients with CUP remains unclear. Here, we report a case of secondary MN as a paraneoplastic syndrome in CUP. The patient provided informed consent for publication of this case report.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Case Report

A 72-year-old female with a history of smoking was referred to our institution because of proteinuria. The patient presented with progressive bilateral edema in the lower extremities. Urinalysis revealed proteinuria 3+, with a positive urinary occult blood test and normal renal function. On follow-up, proteinuria exceeded 3.5 g/day. The serum level of total protein and albumin decreased to 5.4 g/dl (normal range=6.6-8.1) and 2.4 g/dl (normal range=4.1-5.1), respectively. The levels of antinuclear antibodies, antineutrophil cytoplasmic antibodies, and hepatitis antigens/antibodies were within normal ranges. Subsequent renal biopsy revealed subepithelial deposits and spike formation of the glomerular basement membrane in the PAS-stained sections (Figure 1). Immunofluorescence staining showed deposition of immunoglobulin G (IgG) along the glomerular basement membrane, with IgG1 and IgG3 as the predominant subclasses (Figure 2). Electron microscopy also revealed granular electron-dense deposits, which were fairly irregular in size along the subepithelial side of the glomerular basement membrane (Figure 3). The histological features were compatible with the diagnosis of secondary MN. Therefore, systemic evaluation was started to determine the cause of the secondary MN. Contrast-enhanced chest computed tomography (CT) revealed enlargement of the right subclavian and mediastinal lymph nodes (Figure 4A). Two-deoxy-2-[fluorine-18]-fluoro-D-glucose (18F-FDG) positron emission tomography (PET) revealed increased accumulation in the right subclavian and mediastinal lymph nodes, with maximal standardized uptake values (SUVmax) of 5.5 and 3.8, respectively (Figure 5A), corresponding to the findings of the CT imaging. However, the primary lesion was not identified by whole-body evaluation including gastrointestinal endoscopy. A definite needle biopsy of the right subclavian lymph node revealed squamous cell carcinoma (SCC) histologically. We diagnosed MN resulting from primary unknown cancer with a histology of SCC. Four months after the initial examination by 18F-FDG PET (Figure 5A), repeated CT (Figure 4B) and 18F-FDG PET imaging (Figure 5B) were carried out, indicating abnormalities in the right subclavian (SUVmax of 5.8) and mediastinal (SUVmax of 3.6) lymph nodes without any exacerbation. Although the malignant sites in these lymph nodes did not deteriorate for four months, curative radiotherapy on the right subclavian and mediastinal lymph nodes was started until a total of 60 Gy had been administered over 30 fractions. Four months after the initial radiotherapy, there was no increased accumulation of 18F-FDG on PET in the right subclavian and mediastinal lymph nodes (Figure 5C). A chest CT scan also revealed marked shrinking of the corresponding lesions (Figure 4C). The patient did not suffer from bilateral edema in the lower extremities. Her urinalysis revealed proteinuria 1+, with a negative urinary occult blood test, and the serum level of total protein and albumin improved to 6.3 g/dl and 4.2 g/dl, respectively (Figure 6). Two years after the definite diagnosis of secondary MN, there was no evidence of any recurrence and the patient also did not exhibit any symptoms.

Figure 1.
Figure 1.

Renal biopsy specimens. Periodic acid–Schiff staining (A). Periodic acid silver methenamine (PAM) staining revealed spike formation in the basement membrane (arrow) (B). Objective lens 40×.

Figure 2.
Figure 2.

Immunofluorescence microscopy revealed fine granular IgG staining along the glomerular basement membrane. IgG subclass analysis showed a predominance of IgG1 and IgG3 deposition followed by IgG2 and IgG4 in a peripheral granular pattern. Objective lens 40×.

Figure 3.
Figure 3.

Electron microscopy imaging showing electron-dense deposits on the epithelial side of the glomerular basement membrane. Scale bar=10 μm (A). Scale bar=5 μm (B).

Figure 4.
Figure 4.

Chest computed tomography (CT) scan showing the right subclavian (red arrow, upper column) and mediastinal (white arrow, lower column) lymph nodes (A). After four months, CT imaging revealed the same size of the right subclavian (red arrow, upper column) and mediastinal (white arrow, lower column) lymph nodes (B). Four months after the initial radiotherapy, there was marked reduction of the right subclavian (red arrow, upper column) and mediastinal (white arrow, lower column) lymph nodes (C).

Figure 5.
Figure 5.

18F-FDG PET images. 18F-FDG PET imaging revealed increased uptake in the right subclavian lymph node, with SUVmax of 5.5 (white arrow, upper column), and the mediastinal lymph node, with SUVmax of 3.8 (yellow arrow, lower column) (A). After four months, 18F-FDG PET revealed the same increased accumulation on the right subclavian lymph node, with SUVmax of 5.8 (white arrow, upper column), and the mediastinal lymph node, with SUVmax of 3.6 (yellow arrow, lower column) (B). Four months after the initial radiotherapy, there was no increased accumulation on the right subclavian (white arrow, upper column) and the mediastinal lymph nodes (yellow arrow, lower column) (C).

Figure 6.
Figure 6.

Clinical course of urinary protein levels (UPCR) and serum albumin (s-Alb).

Discussion

This is an extremely rare phenomenon involving the occurrence of secondary MN due to SCC of subclavian and mediastinal lymph nodes in patients with CUP. The most common sites of CUP include lung, hepatobiliary, pancreas, kidney, genitourinary, and stomach (9, 10). Adenocarcinoma is the most common histological type, and SCC accounts for approximately 15% of CUP (11). Although metastatic SCC with unknown primary implies a worse outcome, a recent clinical trial demonstrated that programmed death-1 (PD-1) blockade was effective for patients with CUP (12). The tumor immune environment in CUP appears to be similar to that in other solid tumors, such as lung cancer, and head and neck cancer.

Our case exhibited multiple lymph node involvement in the mediastinum with a primary CUP, but there was no exacerbation of these lymph node involvements over four months. Possibly, the immunological reaction against tumor antigens suppressed the tumor growth. As a paraneoplastic syndrome, immune activity appeared to increase, leading to production of antibodies against tumor antigens, which was considered to contribute to immune complex formation. In the present case, MN as a paraneoplastic syndrome was potentially observed as the initial manifestation. Although little is known about the underlying mechanism of secondary MN, the therapeutic course of our case could explain the close relationship between the presence of CUP and the occurrence of MN, as evidenced by the marked improvement of the MN after an effective treatment of malignant sites. A previous report described the increased risk of cancer-associated MN or nephrotic syndrome after PD-1 blockade treatment for cancers (13). Therefore, although our patient exhibited distant metastatic sites requiring systemic treatment, choosing the immune checkpoint inhibitor (ICI) in addition to chemotherapy can be difficult. Physicians should be aware of the administration of ICI for cancer patients with secondary MN. In cancer-associated MN with local advanced disease, radiotherapy alone or chemoradiotherapy without ICI can be recommended in the context of ICI-related risk, as was the case for our patient. Little is known about the optimal treatment of cancer patients with secondary MN; however, strategies that do not affect the immune reaction can be recommended.

To our knowledge, our case is the first report to present secondary MN in patients with CUP. However, therapeutic strategies should be considered similarly to other types of cancer. In locally advanced disease, radiotherapy alone may be preferable to avoid worsening renal function as an adverse event. When proteinuria is observed in patients with CUP, considering the possibility of secondary MN as a rare differential diagnosis is essential.

Footnotes

  • Authors’ Contributions

    KK conceived the study and drafted and critically revised the article. H.I. OY, AM, and HK acquired, analyzed, and interpreted the data and critically revised the article.

  • Funding

    This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received January 4, 2024.
  • Revision received January 25, 2024.
  • Accepted January 29, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Xu Q,
    2. Zou G,
    3. Zhuo L,
    4. Gao H,
    5. Li W
    : Lung cancer patients with nephropathy as the first manifestation: Literature review and clinical study report. Front Oncol 12: 1002155, 2022. DOI: 10.3389/fonc.2022.1002155
    OpenUrlCrossRef
  2. ↵
    1. Li LS,
    2. Liu ZH
    : Epidemiologic data of renal diseases from a single unit in China: Analysis based on 13,519 renal biopsies. Kidney Int 66(3): 920-923, 2004. DOI: 10.1111/j.1523-1755.2004.00837.x
    OpenUrlCrossRefPubMed
  3. ↵
    1. Ponticelli C,
    2. Glassock RJ
    : Glomerular diseases: membranous nephropathy—a modern view. Clin J Am Soc Nephrol 9(3): 609-616, 2014. DOI: 10.2215/CJN.04160413
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Leeaphorn N,
    2. Kue-A-Pai P,
    3. Thamcharoen N,
    4. Ungprasert P,
    5. Stokes MB,
    6. Knight EL
    : Prevalence of cancer in membranous nephropathy: a systematic review and meta-analysis of observational studies. Am J Nephrol 40(1): 29-35, 2014. DOI: 10.1159/000364782
    OpenUrlCrossRefPubMed
  5. ↵
    1. Beck LH Jr.
    : Membranous nephropathy and malignancy. Semin Nephrol 30(6): 635-644, 2010. DOI: 10.1016/j.semnephrol.2010.09.011
    OpenUrlCrossRefPubMed
  6. ↵
    1. Beck LH Jr.,
    2. Bonegio RG,
    3. Lambeau G,
    4. Beck DM,
    5. Powell DW,
    6. Cummins TD,
    7. Klein JB,
    8. Salant DJ
    : M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361(1): 11-21, 2009. DOI: 10.1056/NEJMoa0810457
    OpenUrlCrossRefPubMed
  7. ↵
    1. Pavlidis N,
    2. Pentheroudakis G
    : Cancer of unknown primary site. Lancet 379(9824): 1428-1435, 2012. DOI: 10.1016/S0140-6736(11)61178-1
    OpenUrlCrossRefPubMed
  8. ↵
    1. Pavlidis N,
    2. Fizazi K
    : Carcinoma of unknown primary (CUP). Crit Rev Oncol Hematol 69(3): 271-278, 2009. DOI: 10.1016/j.critrevonc.2008.09.005
    OpenUrlCrossRefPubMed
  9. ↵
    1. Pentheroudakis G,
    2. Golfinopoulos V,
    3. Pavilidis N
    : Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer 43: 2026-2036, 2007. DOI: 10.1016/j.ejca.2007.06.023
    OpenUrlCrossRefPubMed
  10. ↵
    1. Hemminki K,
    2. Bevier M,
    3. Hemminki A,
    4. Sundquist J
    : Survival in cancer of unknown primary site: population-based analysis by site and histology. Ann Oncol 23(7): 1854-1863, 2012. DOI: 10.1093/annonc/mdr536
    OpenUrlCrossRefPubMed
  11. ↵
    1. Krämer A,
    2. Bochtler T,
    3. Pauli C,
    4. Baciarello G,
    5. Delorme S,
    6. Hemminki K,
    7. Mileshkin L,
    8. Moch H,
    9. Oien K,
    10. Olivier T,
    11. Patrikidou A,
    12. Wasan H,
    13. Zarkavelis G,
    14. Pentheroudakis G,
    15. Fizazi K, ESMO Guidelines Committee
    : Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 34(3): 228-246, 2023. DOI: 10.1016/j.annonc.2022.11.013
    OpenUrlCrossRef
  12. ↵
    1. Tanizaki J,
    2. Yonemori K,
    3. Akiyoshi K,
    4. Minami H,
    5. Ueda H,
    6. Takiguchi Y,
    7. Miura Y,
    8. Segawa Y,
    9. Takahashi S,
    10. Iwamoto Y,
    11. Kidera Y,
    12. Fukuoka K,
    13. Ito A,
    14. Chiba Y,
    15. Sakai K,
    16. Nishio K,
    17. Nakagawa K,
    18. Hayashi H
    : Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol 33(2): 216-226, 2022. DOI: 10.1016/j.annonc.2021.11.009
    OpenUrlCrossRef
  13. ↵
    1. Kim Y
    : Relapse of membranous nephropathy with cancer immunotherapy. Clin Kidney J 14(1): 418-420, 2019. DOI: 10.1093/ckj/sfz074
    OpenUrlCrossRef
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Membranous Nephropathy as a Paraneoplastic Syndrome in Cancer of Unknown Primary
KYOICHI KAIRA, HIROAKI AMANO, HISAO IMAI, HIROKAZU OKADA, HIROSHI KAGAMU
In Vivo May 2024, 38 (3) 1503-1508; DOI: 10.21873/invivo.13598
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords