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NEPHROLOGY 2004; 9, 387–391
Case Report
Glomerulosclerosis: A paraneoplastic phenomenon? SHERENE LOI,1 GREGORY J PERRY,1 HUGO STANDISH1 and JOHN DOWLING2 Departments of 1Renal Medicine and 2Anatomical Pathology, Alfred Hospital, Prahran, Victoria, Australia SUMMARY: Glomerulosclerosis is not classically considered a paraneoplastic glomerular lesion. Focal and segmental glomerulosclerosis (FSGS) has rarely been reported in association with solid tumours. We report three cases of FSGS and an additional case of collapsing glomerulosclerosis in patients presenting with nephrotic syndrome and malignancy. KEY WORDS: collapsing glomerulosclerosis, focal segmental glomerulosclerosis, malignancy, nephrotic syndrome, paraneoplastic.
INTRODUCTION All forms of glomerulonephritis may be associated with malignancy; however, it is usually a rare occurrence. Glomerulonephritis may be observed in a variety of malignancies, both solid organ tumours and haematological malignancies. The most common paraneoplastic glomerular lesion is membranous glomerulonephritis.1 Although it is well known that the diagnosis of nephrotic syndrome in an adult aged over 50 years should prompt consideration of an underlying malignancy,1 focal segmental glomerulosclerosis (FSGS) has not classically been considered a paraneoplastic phenomenon. In this paper we present four cases of patients with malignancy that also developed nephrotic syndrome. In three cases the glomerular lesion was FSGS. In the fourth case the primary glomerular lesion was the collapsing form of global glomerulosclerosis. In three cases the renal manifestations preceded the diagnosis of malignancy. CASE REPORT 1 A 72-year-old Caucasian man was admitted with a 2week history of increasing peripheral oedema. There was no history of recent nephrotoxic agents. Six months previously the patient had had a small melanoma, measuring less than 1 mm in depth, resected from his anterior abdominal wall. Specimen margins had been clear of tumour. Physical examination revealed pigmentation.
Correspondence: Dr Gregory J Perry, Department of Anatomical Pathology, Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia. Email:
[email protected] Accepted for publication 26 July 2004.
The jugular venous pressure (JVP) was elevated with moderate peripheral oedema. There were small cervical and bilateral axillary lymph nodes measuring 1–2 cm in diameter, which were mobile and non-tender. Investigations revealed a serum creatinine of 0.60 mmol/L and heavy proteinuria (13 g/24 h). Serum albumin was 19 g/L. Vasculitis screens including antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins and serum and urine electrophoresis were normal. Doppler examination of the renal veins was also normal. The patient progressed to oliguric renal failure despite adequate volume status and commenced dialysis. Renal biopsy showed FSGS together with acute tubular necrosis (Fig. 1). Biopsy results are summarized in Table 1. On day 24 of admission the patient developed a Broca’s dysphasia. A cerebral computed tomography (CT) scan demonstrated multiple hyperdense lesions suggestive of melanoma. Fine-needle aspiration of an axillary lymph node confirmed metastatic melanoma. The patient continued to deteriorate neurologically and died on day 31 of admission. The patient remained dialysis dependent throughout admission. Post mortem was not carried out. CASE REPORT 2 A 60-year-old Caucasian man was admitted for investigation of nephrotic syndrome. Serum creatinine was 0.17 mmol/L. Serum albumin was 7 g/L. Total protein excretion was 30 g per day. Renal ultrasound showed moderate right hydronephrosis ending at the level of the L4-5 vertebrae. Renal biopsy showed FSGS (Fig. 2). The patient commenced prednisolone 60 mg daily and frusemide. A magnetic resonance imaging (MRI) scan revealed right ureteric obstruction caused by a soft tissue mass at the paravertebral level, possibly lymphadeno-
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Segmental IgM, C3, C1q
Global effacement of pedicels; no segmental lesions Patchy effacement of pedicels. Segmental collapse. Obliteration of capillary loops
Fig. 1 Photomicrograph of the renal biopsy from case 1 demonstrating a developing area of segmental sclerosis with associated epithelial cell reaction and capillary loop obliteration (arrow). Silver Methanamine–Masson trichrome stain (¥250).
ATN, acute tubular necrosis; EM, electron microscopy; IMH, immunohistochemistry; TIS, tubulointerstitial sclerosis.
Mild TIS dilated tubules–ATN 29 4
0/29
2/26: perihilar collapse pattern 17/29: cellular/ collapse pattern 26 3
4/26
2/32: cellular phase 32 2
5/32
Mild
Mild diffuse mesangial proliferation Diffuse mesangial proliferation Moderate
Segmental IgM, C3, C1q
Diffuse mesangial proliferation
Global effacement of pedicels; no segmental lesion.
Weak mesangial IgM; segmenta lC3 + C4 in capillaries Segmental IgM only Mild
Mild TIS scattered dilated tubules– ATN Mild TIS widespread dilated tubules– ATN Mild TIS 2/32: glomerular tip 3/32 32 1
Case
No. glomeruli
Mild
EM IMH Additional features Arteriessclerosis/ hyalinosis Tubulointerstitial changes No. glomeruli with segmental glomerulosclerosis and pattern of sclerosis Global sclerosis/ total no. glomeruli
Table 1 Summary of the renal biopsy findings
Global effacement of pedicels; no segmental lesions.
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Fig. 2 Photomicrograph of the renal biopsy from case 2 demonstrating one totally sclerosed glomerulus and an early segmental area of sclerosis in an adjacent glomerulus highlighted by epithelial cell hypertrophy and cytoplasmic vacuolation (arrow). Silver Methanamine–Masson trichrome stain (¥250).
pathy. The obstruction was relieved by ureteric stenting with improvement in plasma creatinine. The patient proceeded to diagnostic laparotomy after a fine-needle aspirate of the lesion proved inconclusive. At laparotomy, enlarged iliac lymph nodes were resected. Histological examination revealed metastatic sarcoma. The primary lesion remained undetected clinically. Despite an initial improvement in renal function and a decrease in proteinuria the patient’s creatinine began to rise without any recurrence of obstruction. The prednisolone was weaned. The patient’s condition deteriorated as a result of progressive malignancy. The patient was transferred to a palliative care setting and died day 55 postadmission. There was no post mortem carried out.
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Glomerulosclerosis and malignancy
CASE REPORT 3 A 56-year-old Caucasian man was referred for investigation of nephrotic range proteinuria (3.75 g/day) and renal impairment with a serum creatinine of 0.15 mmol/L. He had a past history of psychosis (therapy had not included lithium), reflux oesophagitis, wellcontrolled hypertension and atrial fibrillation. His mother had died from gastric carcinoma. Physical examination and renal imaging were unremarkable. Renal biopsy showed primary FSGS. He was managed conservatively with attention to blood pressure and lipids. On review, gastroscopy 7 months later for dyspepsia and reflux symptoms found an adenocarcinoma at the gastro-oesophageal junction. An Ivor–Lewis oesphagectomy was carried out. Proteinuria decreased following surgery to 0.5 g per 24 h. There has been no evidence of recurrent tumour on follow-up visits and the patient’s blood pressure control has been excellent. Three years later the patient has a stable creatinine of 0.12 mmol/L and 0.2 g/day of proteinuria. He remains in complete remission from cancer.
The non-steroidal anti-inflammatory agent she had been using for analgesia was ceased. Despite this her serum creatinine rose to 0.35 mmol/L and albumin fell to 10 g/L. Physical examination and renal imaging were unremarkable, in particular there was no evidence of volume depletion. Renal biopsy revealed the ‘collapse’ form of glomerulosclerosis involving the majority of glomeruli (Fig. 3). Therefore, this case is best described as a diffuse, rather than focal, collapsing variety of glomerulosclerosis. The patient began treatment with prednisolone 60 mg and anticoagulation. Her renal function stabilized. Imaging revealed a new solitary hepatic metastasis. Her cancer antigen (CA) 15-3, which was previously 24 kU/L, was now 100 kU/L. Shortly after this the patient commenced a fourth line chemotherapy. Her hepatic metastases, however, progressed through treatment and she died 4 months later. Her renal function remained stable at 0.32 mmol/L and 24-h protein excretion was unchanged at 13 g. She continued on 30 mg of prednisolone daily until her death. The clinical details for all four cases are summarized in Table 2 and the renal biopsy findings are summarized in Table 1.
CASE REPORT 4 A 43-year-old Caucasian woman with a history of metastatic breast carcinoma was referred for investigation of rapidly progressive renal failure and nephrotic range proteinuria. Her breast carcinoma was initially diagnosed when she was 37 years old. At that stage she underwent a mastectomy, axillary clearance and subsequent chest wall radiotherapy. She received further adjuvant chemotherapy. The patient underwent bilateral oopherectomy because she was moderately positive for hormone receptors. Six months later bony metastases were detected. She received further chemotherapy at this stage with anthracycline (doxorubicin); however, despite this hormonal manipulation and pamidronate therapy, her bony disease continued to progress. She had completed another course of chemotherapy with a taxane derivative (docetaxol) 6 months prior to presentation. There was no visceral disease evident on imaging prior to her renal events. One month prior to admission her serum creatinine rose from 0.10 to 0.18 mmol/L. She had also noticed peripheral oedema and nausea. Her albumin was 20 g/L.
Fig. 3 Photomicrograph of the renal biopsy from case 4 showing global collapse/sclerosis with associated marked podocytic vacuolation. Silver Methanamine–Masson trichrome stain (¥400).
Table 2 Summary of patient details Age (years)
Sex
Proteinuria (g/day)
Tumour primary
72 60 56
Male Male Male
13 7 3.75
Melanoma Sarcoma Oesophageal
43
Female
14
Breast
Histology Invasive Poorly-differentiated Moderate–poorlydifferentiated Poorly-differentiated
Renal function
Temporal relationship
Outcome
Dialysis Declining Stable
Antedated metastatic disease Antedated diagnosis Antedated diagnosis
Deceased Deceased Alive
Stable
Antedated metastatic disease
Deceased
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DISCUSSION Paraneoplastic glomerulopathies are interesting, distinctly heterogeneous phenomena. Multiple glomerular lesions have been reported in association with a variety of cancers, both haematological and solid. The concept of nephrotic syndrome being linked with malignancy is well documented and the first study was published by Lee et al. in 1966.1 He studied 101 patients with nephrotic syndrome over a 10-year period and found 11 patients with carcinomas. Renal disease manifested itself prior to the diagnosis of cancer in two-thirds of the patients. The majority had membranous glomerulonephritis. Subsequently, Eagen2 demonstrated the association of membranous and minimal change disease with Hodgkin’s disease and non-Hodgkin’s lymphoma, leukaemia and myeloma. Since then physicians have been aware of the association between nephrotic syndrome and malignancy in presenting adults over 50 years of age, although the extent of screening that should be undertaken is unclear. Focal segmental glomerulosclerosis in association with malignancy is rare and reported mainly with haematological malignancies; lymphomas (particularly Hodgkin’s disease), leukaemia, malignant thymoma3 and mycosis fungoides.4 In Hodgkin’s disease it is speculated that both minimal change disease and FSGS are different parts of the same disease spectrum because both have gone into remission following successful treatment of the underlying haematological condition.5 Focal segmental glomerulosclerosis and its association with solid tumours is even rarer. It has been reported in association with poorly differentiated adenocarcinoma of the rectum,6 malignant mesothelioma7 and poorly differentiated gall bladder adenocarcinoma.8 In this paper we provide three case reports of FSGS being associated with, and predating, metastatic melanoma, metastatic sarcoma and adenocarcinoma of the oesophagus. The fourth case documents the onset of renal disease being associated with rapid cancer progression; although a background of metastatic breast carcinoma is extensive there had only previously been bony disease. The defining glomerular lesion in this case was a diffuse collapsing form of glomerulosclerosis rather than FSGS. To our knowledge this is the first reported case of this condition. Hence, we prefer the term ‘glomerulosclerosis’ rather than ‘FSGS’ to better reflect the broad nature of changes within the glomeruli (namely focal as well as diffuse) that may be observed in relation to malignancy. Previous descriptions of metaplasia and adenomatoid changes have involved the parietal epithelium of Bowman’s capsule in association with malignant tumours of varying types.9,10 In the description and illustrations of these changes there is no suggestion of sclerotic and obliterative changes relating to the glomerular capillary loops of the affected glomeruli, nor were adhesions described in relation to the epithelial cell changes. Thus,
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we consider that the changes described in this paper are distinct from those metaplastic and adenomatous changes. The lesions we have described appear to be due completely to visceral epithelial cell reaction. A diagnosis of paraneoplastic renal disease should rely first on evidence that complete remission occurs with removal of the tumour or chemotherapy-induced remission of the tumour. Relatively few papers have reported this because of the fact that most malignancies were incurable at the time of diagnosis. Second, proteinuria should correlate with tumour activity. Our first case of metastatic melanoma was too widespread to be treated and in the second case the primary lesion was never found, therefore, we were unable to document a response to treatment or relapse. However, the third case reports FSGS predating the diagnosis of carcinoma with proteinuria decreasing to 0.5 g following curative surgery. There has been no evidence of recurrent tumour or proteinuria on follow-up visits. The fourth case is interesting in that there is a long history of metastatic carcinoma; however, only with bone involvement. The renal manifestation was the first indication of the onset of visceral disease. The rapidly progressive renal impairment also appeared to correlate with aggressive visceral disease. Of note is the fact that the patient’s renal function had stabilized with the use of steroids, but it had not improved. Although it had not worsened even though the disease has progressed on radiological grounds despite fourthline chemotherapy. Speculation can be made about the pathophysiolgical links between malignancy and renal disease. A theory related to T-lymphocyte dysfunction and production of an agent that increases glomerular permeability has been proposed to explain renal lesions in haematological malignancy.11,12 However, the mechanism in solid tumours remains obscure. Konoshita et al.8 proposed that it is the undifferentiated nature of the carcinoma that may have significance in the possibility of the production of this potential agent, although the exact nature of this circulating peptide has not been defined. Our first two case reports of poorly differentiated and widespread carcinoma may support this hypothesis. Many cancer cells acquire the ability to synthesize growth factors13,14 and it is interesting that some of these, such as fibroblast growth factor15 and transforming growth factor beta,16 have been associated with the development of FSGS in experimental animal models. In summary, these four cases suggest that glomerulosclerosis, either focal and segmental or global and diffuse and collapsing, should also be considered as an uncommon paraneoplastic syndrome. The implications of this are that a primary malignancy should be contemplated in adults over 50 years of age that present with FSGS or the collapsing form of glomerulosclerosis. It may imply a poorer prognosis because of the probability that the tumour may be poorly differentiated and widespread at diagnosis.
Glomerulosclerosis and malignancy
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8. Konoshita T, Itoh M, Hatakeyama S et al. Nephrotic syndrome due to focal glomerulosclerosis and undifferentiated carcinoma. Clin. Nephrol. 2000; 54: 404–8. 9. Eulderink F. Adenomatoid changes in Bowman’s capsule in primary carcinoma of the liver. J. Pathol. Bacteriol. 1964; 87: 251–4. 10. Reidbord HE. Metaplasia of the parietal layer of Bowman’s capsule. Am. J. Clin. Pathol. 1968; 50: 240–2. 11. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; 2: 556–60. 12. Lagrue G, Xheneumont S, Branellec A, Weil B. Letter: lymphokines and nephrotic syndrome. Lancet 1975; 1: 271–2. 13. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 14. Dunn IF, Heese O, Black PM. Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs. J. Neurooncol. 2000; 50: 121– 37. 15. Floege J, Kriz W, Schulze M et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. J. Clin. Invest. 1995; 96: 2809–19. 16. Schiffer M, Bitzer M, Roberts IS et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J. Clin. Invest. 2001; 108: 807–16.
