QJ Med 1996; 89:361-367

Solid tumour and glomerulopathy

P. PAI, J.M. BONE, I. McDICKEN and CM. BELL From the Regional Renal Unit, Royal Liverpool University Hospital, Liverpool, UK

Received 11 October 1995 and in revised form 31 January 1996 Downloaded from https://academic.oup.com/qjmed/article/89/5/361/1578010 by guest on 01 October 2021 Summary

We retrospectively examined the prevalence of solid centic GN and one case of focal segmental GN. tumours in patients with (GN) Bronchogenic (6) and gastrointestinal carcinoma followed in our regional renal unit between 1977 (CA) (5) were the commonest tumours encountered. and 1994. We identified 17 cases of what was Other tumours included breast CA (1), renal cell thought to be solid-tumour-related glomerulo- CA (1), prostatic CA (1), an epithelial thymoma and . Tumours and GN were diagnosed together a leiomyosarcoma of the lung. All MGN and mesang- in six cases, and within a year of each other in ial proliferative GN cases developed nephrotic range another four. In addition, there were seven other proteinuria, whereas all patients with rapidly pro- cases with a weaker temporal relationship (median gressive crescentic GN presented with acute renal duration between GN and cancer diagnosis, two failure. Four cases had received immunosuppressive and a half years) but which nonetheless could be therapy prior to tumour diagnosis. We discuss the tumour-related. In total, there were seven membran- validity of each case as tumour-related glomerulo- ous GN, four mesangial proliferative GN, five cres- nephritis.

Introduction Since the first clinicopathological study to present an University Hospital serves a population of 2 million association between cancer and people in the Mersey region of the Northwest of (NS) was suggested by Lee et a\.? the subject of England. We have described in this paper our tumour-related nephropathy has remained a debatable experience of glomerulopathy associated with neo- issue. The prevalence of solid tumour in NS has been plasia in the period of 1977 to 1994. Haematological- reported to vary between 3% and 13%^~9 and preval- malignancy-associated glomerulonephritis has been ence as high as 20% has been described in patients excluded in this review, as the association is well over 60 year old.10'11 However, other case series have recognized. suggested a much lower incidence.12'13 Solid tumours have been most commonly associ- ated with membranous glomerulopathy (MGN); other Methods forms of paraneoplastic glomerulopathies are less well described. These include minimal change, extra- All cases have been referred to us from the northwest capillary crescentic, membranoproliferative, IgA, and region of England. The diagnoses of glomerulo- focal segmental glomerulonephritis. Gastrointestinal nephritis and carcinoma (between 1977 and 1994) (Gl)1'5'8'1^17 and lung tumours1'5'8'18'19 are most com- were identified through the renal departmental com- monly associated with MGN, but others have puter which stores all clinical data of our patient reported this renal lesion with other forms of solid population. All NS patients were routinely screened tumour such as breast, thyroid, kidney, skin, larynx, for tumours by a full clinical examination, full blood pharynx, pancreas, prostate, cervix, and mesenchy- count, full plasma chemistry including liver function mal as well as lymphoid tumour. test, full immunological test, chest X-ray and an The Regional Renal Unit at the Royal Liverpool abdominal ultrasound scan. Further investigations

Address correspondence to Dr P. Pai, Link 6C, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP © Oxford University Press 1996 362 P. Pai etal. would be determined by any abnormalities in these no linear immunofluorescence was demonstrated. tests. For instance, iron-deficiency anaemia would He was given a short trial of plasma exchange and prompt further investigations of the upper and lower immunosuppressive therapy, but this was soon dis- gastrointestinal tract. continued when it became clear that he required chronic dialysis.

Results Mesangial proliferative GN Between 1977 and 1994, we have seen from an Four patients (6-9) had neoplasia and NS as a result average of 120 renal biopsies performed yearly in of mesangial proliferative GN. The tumours were, our unit, 17 patients with glomerulonephritis (GN) respectively, renal cell CA, rectal CA, bronchogenic and neoplasia. None of the patients were known to CA and prostatic CA. have any secondary cause for their GN. The patient In patient 6, renal cell CA was detected in 1990 Downloaded from https://academic.oup.com/qjmed/article/89/5/361/1578010 by guest on 01 October 2021 characteristics are illustrated in Table 1. during an ultrasound scan as part of the investigations for proteinuria. A partial nephrectomy was carried Crescentic GN out with complete excision of the tumour. The renal tissue not involved by the tumour however also Patients 1-5 developed acute renal failure as a result demonstrated a mesangial proliferative GN. IF dem- of crescentic GN. Cancers were recognized at the onstrated strongly positive C3 granular deposits in same time of renal failure in two (2 and 3). All the glomerular mesangium and basement membrane. patients underwent a renal biopsy which showed Some 25% of the glomeruli were sclerosed. So far crescentic GN (100% crescent, in patients 1, 2, 4, this patient is stable with no clinical recurrence of 5; 25% crescent in patient 3). her cancer, although her proteinuria persists. Patient 1 gave a short history of dysphagia due to Renal biopsy of patient 7 demonstrated only very oesophageal CA. She underwent an oesophagogas- mild mesangial proliferation. IgA and C3 were seen trectomy but developed acute oliguric renal failure on immunofluorescence in the mesangium, and in two months later. Serology, including auto- smaller amount, in the GBM. This patient was known antibodies, ANCAs, anti-GBM antibodies and cryo- to have recurrent colonic adenomatous polyps for globulin, was all negative. Renal biopsy demon- which he required regular colonoscopy. Eight months strated florid crescent formation, with strong staining after his NS, he was found to have an inoperable of IgA and C3 deposits in the mesangium. There was adenocarcinoma of the rectum ('Duke' class B). His no demonstrable vasculitis. She died 1 month later. proteinuria improved 4-6 months after surgical A gastrograffin meal requested shortly before her debulking and radiotherapy to the tumour. death suggested tumour recurrence. Renal histology of patient 8 showed mild mesang- Patient 2 was found to have advanced breast CA ial proliferation. In 30% of the glomeruli, there was when she presented with acute renal failure. Renal mesangial proliferation with capsular adhesion. biopsy showed a florid extracapillary crescentic GN Immunofluorescence was negative. He was sub- with pauci-immune deposits in the GBM. Her sero- sequently found to have an incurable bronchogenic CA with metastases 9 months later. logy was positive for anti-neutrophil cytoplasmic antibody to proteinase 3 or c-ANCA (ELISA). There Patient 9 was diagnosed to have a well- was no renal response following pulse steroid, and differentiated prostatic CA 2 years before his NS. the patient was established on chronic haemodialysis Renal biopsy showed a mesangial proliferative GN. programme. She died 6 months later. IF data was unavailable. Following treatment with Patients 3 and 4 had crescentic GN associated stilboestrol and CS, his NS went into remission 2 months later. He died 2 years later from bronchopne- with a bronchogenic CA. Immunofluorescence (IF) umonia. data were unavailable. Patient 3 was given pulse steroid and cyclophosphamide (CPP) for his cres- centic GN. He died 2 weeks later from renal failure Membranous GN and cancer. Patient 4 received a course of radio- therapy 7 months prior to her renal failure. She died Seven patients (10-16) had MGN/NS and carcinoma. shortly afterwards from an intracerebral bleed. All membranous cases had typical IgG epimembran- In patient 5, the lung neoplasm was only disco- ous granular deposits. The neoplasia were CA of the. vered in a pre-transplant chest X-ray 18 months after bronchus (2), gastric CA (2), oesophageal CA (1), an his renal failure. Immunology, including anti-GBM epithelial thymoma and a leiomyosarcoma of the antibodies, was negative. Renal biopsy demonstrated lung. 100% crescents. Immunofluorescent microscopy Patient 10 presented with NS and bronchogenic showed intramembranous deposits of IgG and C3; CA together. Renal biopsy showed thickened base- Table 1 Summary of clinical data

Tumour diagnosis Tumour therapy Patient Age Renal diagnosis Serum creatinine Proteinuria Renal therapy Renal outcome Follow-up (with date) (years)/Sex (with date) (Hmol/I) (g/24 h)

Crescentic GN and malignancy Resection (incomplete) 1 65/F ARF 8/93 441 - Oesophageal CA(T3) 6/93 HD HD Died 9/93 Breast CA 3/92 Mastectomy (incomplete) 2 69/F ARF 3/92 372 - CS, HD HD Died 9/92 Bronchia! CA (met) 2/82 CPP 3 62/M ARF 2/82 430 - HD Died 2/82 PMP IS) Bronchial CA (met) 4/89 Radiotherapy 4 75/F ARF 11/89 900 - HD HD Died 12/89 2. Bronchial CA 10/84 Palliative 5 54/M ARF 4/83 956 - PE, Aza, PMP HD Died 5/85 51 c Mesangioprol iterative GN and tumours )OLU 4.0 Renal cell CA 10/90 Resection i-. 6 72/F NS 10/90 230 None Less proteinuria Alive -i 7 61/M 76 5.9 Rectal CA 7/94 Alive &j NS 11/93 Resection, radiotherapy None Partial remission Q. Bronchial CA 7/78 8 45/M NS 10/77 99 9.5 Palliative CS No change Died 12/78 133 7.4 Prostate CA 2/90 Died 3/95 O 9 65/M NS 6/92 Stilboestrol CS Remission 3 Membranous GN and tumours Bronchial CA 3/77 10 55/M NS 3/77 99 4.0 Resection 3/77 None Remission Died 83 4.4 Lung mass 6/88 1 11 76/M NS 6/88 92 Resection 6/88 None No change Died 89 Gastric CA 3" 11.6 Epithelial thymoma 11/89 12 62/M NS 11/89 185 Resection 1/90 PMP, CPP HD Died 1/92 10 Oesophageal CA 9/85 13 52/M NS 4/84 92 Palliative Diuretic No change Died 9/86 9.5 Gastric CA 6/94 14 74/F NS 7/90 121 Laser None No change Died 95 18 Bronchial CA (met) 11/86 15 60/M NS 6/83 116 CPP CS, Aza 1984- Partial remission Died 1/88 16 Leiomyosarcoma lung 87 16 48/F NS 80 185 None CS CRF Died 87

Age is given at renal presentation. ARF, acute renal failure; NS, nephrotic syndrome; CA, carcinoma; met, metastases; HD, haemodialysis; CS, corticosteroid; Aza, azathioprine;

CPP, cyclophosphamide; PE, plasma exchange; PMP, pulse methylprednisolone. Downloaded from https://academic.oup.com/qjmed/article/89/5/361/1578010 by guest on 01 October 2021 October 01 on guest by https://academic.oup.com/qjmed/article/89/5/361/1578010 from Downloaded 364 P. Pai etal. merit membrane, and a fine and granular deposit of a leiomyosarcoma of the lung on biopsy. She lapsed IgG and complement on immunoperoxidase staining. into coma and died shortly after the tumour dia- Electron microscopy showed extensive electron- gnosis. A CT head scan before her death revealed dense material along the subepithelial side of the the presence of cerebral metastases. glomerular basement membrane. His NS went into remission 6 months following a pneumonectomy for Focal segmental GN his tumour. He died of an unrelated cause 6 years later. Patient 17 was initially referred with haematuria, In patient 11, a mass in the lung was discovered proteinuria (3.8g/24h) and mild renal impairment. during part of the investigation of his NS. Resection Renal biopsy showed a focal segmental GN with of the pulmonary lesion, an adenocarcinoma was negative IF. No specific therapy was indicated for however, not accompanied by any improvement of the renal lesion. A chest X-ray showed pulmonary

metastases 26 months later. Lung biopsy confirmed Downloaded from https://academic.oup.com/qjmed/article/89/5/361/1578010 by guest on 01 October 2021 his nephrotic state. The presence of an iron- the lesion to be a 'secondary' from an unknown deficiency anaemia and positive faecal occult blood primary adenocarcinoma. A gastroscopy and a led to further investigation and discovery of the barium enema failed to reveal any primary lesion. primary gastric CA; the resected lung lesion was One year later, liver secondaries were apparent and only a secondary. He died 6 months later. he died 7 months later. His renal function and Patient 12, a 62-year-old Caucasian man, pre- proteinuria remained unchanged throughout. sented with a short history of severe NS associated with mild renal impairment. He was a retired engin- eer and a non-smoker. A complete immunology screen was negative, but chest X-ray showed a large Discussion well-defined soft tissue mass in the anterior medias- As in many other reports on this subject, membranous tinum. Biopsy of the mass revealed features of a GN predominates in our series. However, other GN thymoma. Renal biopsy demonstrated an early MGN. were also encountered, including rapidly progressive He underwent a complete resection of his anterior crescentic glomerulonephritis (RPCGN) and acute mediastinal mass, which later proved to be an renal failure, mesangioproliferative GN and NS, and epithelial thymoma. His renal function began to focal segmental GN. These associations have only deteriorate in spite of the surgery, and immuno- rarely been reported in the past.3'11'21 suppressive therapy was instituted 3 months later. Lung and Gl tumours predominate in our Despite the use of PMP, CPP and corticosteroid, his renal function worsened and he required chronic series, in keeping with their general prevalence. 22 23 dialysis after another 3 months. A repeat renal Like others, ' we have observed an under- ultrasound scan then showed bilateral reduction in representation of breast cancer here. We also report kidney size. He died of pulmonary oedema 18 an unusual tumour, an epithelial thymoma associated months later. with MGN. In the few reports that describe an Patient 13 was diagnosed with oesophageal CA association between NS and thymoma, minimal 17 months after his NS/MGN. He died one year change disease has been the predominant renal 24 later. In patient 14, advanced gastric CA was disco- lesion. To our knowledge, there is only one other 25 vered 4 years after the NS/MGN. case report of MGN that was associated with a Patient 15 developed bronchial CA with meta- malignant thymoma. stases 2 years following treatment with Aza for heavy In this series, six patients (2 RPCGN, 3 MGN, proteinuria and declining renal function. His renal 1 mesangioproliferative GN) had simultaneous dia- function improved, and proteinuria fell, with no gnosis of both tumours and GN. Six tumours (2 Gl, change in either when his tumour presented. He 2 lung, 1 leiomyosarcoma, 1 unknown primary) remained in a stable renal state until his death 13 postdated the renal lesions by 1 to 7 years (median months later. 3 years). It is probably justifiable to include these Patient 16 was 50 years old when she presented other cases as tumour-related even though there is a with severe NS secondary to MGN. Immunology longer interval between the two diagnoses. This is screen and a chest X-ray were both normal. She was because some tumours, such as leiomyosarcoma and treated with pulse methyl prednisolone and main- gastrointestinal CA, are known to be slow-growing, tained on oral CS therapy, following which her NS and may take many years before there are any went into remission over the next 18 months. clinical manifestations. However, her renal function deteriorated slowly, and Prolonged use of cytotoxic agents has been associ- 7 years later, she was approaching end-stage renal ated with the subsequent development of malig- failure. A chest X-ray prior to her dialysis revealed nancy. In our series, four patients (5,8,15,16) were two large lesions in the left lung. This proved to be treated with some form of immunosuppressive Solid tumour and glomerulopathy 365 therapy prior to tumour diagnosis. Whether the genic CA, urinary tract tumour, colonic CA, hyper- cytotoxic therapy has facilitated the tumour develop- nephroid CA, atrial myxoma) associated with ment in these cases is debatable. Professor J.S. paraneoplastic vasculitis.33'34 Interestingly, we dis- Cameron (personal communication) has observed covered a case of RPCGN (with pauci-immune that four of his eight adult nephrotic patients who deposit), and breast cancer (patient 2) that was developed neoplasia 2-18 years after the renal associated with positive c-ANCA. diagnosis had received cytotoxic therapy. Two of The association of extracapillary crescentic GN our patients (8 and 16) who subsequently developed and oesophageal cancer has not been reported. neoplasia had received corticosteroid alone for a Immunofluorescence microscopy of the renal biopsy finite period of time (9 and 18 months). Two others of this patient (1) showed strong IgA and C3 staining received Aza (5 and 15) as well but only one had in the mesangium with 100% crescents; but only treatment in excess of two years. It is therefore 2 months before the biopsy, she was noted to have possible, but not likely, that the treatment had a role a normal urine sediment. IgA nephropathy is well Downloaded from https://academic.oup.com/qjmed/article/89/5/361/1578010 by guest on 01 October 2021 in facilitating tumour development in our patients. known for its association with various Gl disorders, Although the pathological mechanism of tumour- but association with neoplastic disorders such as related MGN remains largely unknown, tumour- bronchial CA, nasopharyngeal epithelial papilloma associated antigen/antibody complexes, and immune and squamous CA of the tongue35 has only been deposit nephritogenicity have been largely implicated rarely reported. Interestingly, mesangial IgA deposits in glomerular injury and overt neoplastic renal dis- have been presented at autopsy in some individuals ease.26 Accordingly to this theory, successfully with gastrointestinal neoplasia without prior clinical treated tumours ought to be followed by resolution evidence of renal disease.36 The mechanism by of the GN. However, there are relatively few case which immune complex deposit produce clinical reports of remission of MGN following removal of renal disease is not clear. It has been suggested that solid tumour. This is perhaps because the majority chronic mucosal irritation due to some adenocarcin- of carcinomas associated with MGN are surgically oma may be related to an increase in circulating IgA incurable at presentation. Successfully resected and, possibly, mesangial IgA deposits.35 tumours have included breast CA,22 gastric CA,15'27 All mesangioproliferative GN cases in our series bronchogenic CA,3 carotid body tumour,28 phaeoch- had heavy proteinuria in the nephrotic range. In romocytoma,29 and colonic CA.3 In our series, there patient 7, partial remission of NS occurred 7 months was one case of MGN where remission of NS following radiotherapy and 'debulking' of the rectal occurred 6 months after a pneumonectomy for a CA. It is possible that in some tumour-associated bronchogenic CA (patient 10). However, proteinuria mesangial proliferative GN, the tumour cells are persisted in our thymoma patient (12) despite what responsible for a circulating 'soluble factor' which appeared to be complete resection of his tumour. determines the glomerular injury, permselectivity, Others have also reported persistent proteinuria and proteinuria. In patient 6, proteinuria was only after tumour removal.17 In one case of MGN, pro- marginally reduced following complete removal of teinuria persisted in spite of resolution of electron- a renal cell CA. The substantial number of sclerosed dense deposits in a repeat renal biopsy, 4 months glomeruli in the remaining tissue after tumour resec- after removal of a colonic CA.17 The persistent tion with sustained severe renal impairment, might proteinuria was thought to be due to irreversible well be an important factor in the persistent pro- damage to the basement membrane permeability. It teinuria in this latter case. is thought, but unproven, that a similar situation The majority of patients in our series died within pertains to our thymoma patient. Despite a complete 6 months of tumour diagnosis, the crescentic group thymectomy as well as aggressive immunosuppres- having the worst prognosis. It is interesting that sive treatment, he progressed and developed irrevers- findings of subclinical GN have been reported to be ible renal failure. not uncommon in cancer patients36'37 and those with The pathophysiological events leading to tumour- microhaematuria and proteinuria similarly appeared associated crescentic GN are only partially known. to have a poorer prognosis and shorter survival.37 Some suggestions put forward include excess antigen In conclusion, during the period of 1977 and load30 and monocyte activation in the presence of 1994, our unit observed a total of 17 cases of what malignancy.31 Monocytes have been shown to initi- appeared to be solid-tumour-related glomerulo- ate glomerular injury as well as to act as mediators nephritis, giving an incidence of 0.5 cases per million of crescent formation in experimental work.32 population per year in this region. Approximately a Recently, ANCAs have been implicated in paraneo- further 200 male and 80 female cases of idiopathic plastic vasculitis and rapidly progressive glomerulo- nephrotic syndrome were diagnosed over the same nephritis.33 Serum levels of p- and c-ANCA have period of time. Using the data from the Cancer been rarely observed in solid tumours (e.g. broncho- Statistics Registrations for England and Wales,38 we 366 P. Pa/etal. were able to calculate the standardized ratio for significance of extracapillary proliferation: Clinicopathological review of 60 patients. 1976; relative cancer risk of idiopathic NS patients in this 16: 1-19. series as 6.54 (95% Cl, 2.84-10.24) based on Poisson 12. Kaplan BS, Klassen J, Gault MH. Glomerular injury in distribution. This represents a significant cancer risk patients with neoplasia. Annu Rev Med 1976; 27:117-25. associated with NS. We have demonstrated in this 13. Heneghan W, Rao TKS, Nicastri AD. Low incidence of study that mesangio-proliferative GN/NS and rapidly malignancy associated with nephrotic syndrome in the progressive crescentic CN/acute renal failure are elderly. Am Soc Nephrol 13th Annual Mtg, Washington DC, important too, in solid-tumour-associated glomerulo- 1980: Abstr20A. nephritis. Careful clinical assessment for underlying 14. Heckerling PS. Oseophagela carcinoma with membranous solid tumours in patients with idiopathic NS or nephropathy. Ann Intern Med 1985; 103:474. rapidly progressive crescentic GN is essential to 15. Cantrell EG. Nephrotic syndrome cured by removal of allow early detection and treatment of occult cancer. gastric carcinoma. BMJ 1969; 2:739-42.

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