Multicentric papillary renal carcinoma in renal allograft

Multicentric Papillary Renal Carcinoma in Renal Allograft Michael J. DeLong, MD, Dasan Schmitt, BS, Katherine M. Scott, MD, Sanjay Ramakumar, MD, and Yeong-Hau H. Lien, MD, PhD ● A renal transplant recipient with 13 years of excellent allograft function was found incidentally to have a malignant mass in his transplanted kidney. After resection, pathological analysis showed 29 separate lesions of renal cell carcinoma. All tumors were confined within the renal capsule. The majority of tumors (21 of 29 tumors) were chromophil basophilic carcinoma with papillary architecture, 5 tumors were clear cell, 2 tumors were mixed cell type, and 1 tumor was chromophil eosinophilic papillary carcinoma. These histological findings are similar to those reported in hereditary papillary renal carcinoma. To our knowledge, this is the first case of multicentric papillary renal carcinoma occurring in the renal allograft. We speculate that the allograft in this case is predisposed to malignant changes because of preexisting genetic mutations, as well as prolonged immunosuppression. Am J Kidney Dis 42:381-384. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Renal cell carcinoma (RCC); hereditary papillary renal carcinoma (HPRC); c-met; renal transplantation; renal allograft.

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ITH THE IMPROVEMENT in immunosuppressive therapy, both patient and graft survival have been prolonged in renal transplant recipients. Posttransplantation malignancy has become an important cause of loss of graft and life in these patients. Among cancers occurring after kidney transplantation, renal cell carcinoma (RCC) ranks as the fifth most common malignancy, after posttransplantation lymphoproliferative disorders and skin, gastrointestinal, and lung cancers.1 When nonmelanoma skin cancers and in situ carcinoma of the cervix are excluded from malignancies, RCC accounts for 2% of all cancers in the general population, which increases to 5% in solid-organ recipients.2 The majority of RCCs found in transplant recipients develop in the native kidneys of the recipient, but only 9% of tumors develop in the allograft itself.3 Most de novo allograft RCCs are single tumors. We report a case of RCC with 29 foci in the renal allograft diagnosed 13 years after renal transplantation. CASE REPORT A currently 59-year-old white man developed end-stage renal disease in 1987 because of autosomal dominant polycystic kidney disease. He was on long-term hemodialysis therapy for 2 years and underwent a 5-mismatched cadaveric kidney transplantation at the age of 46 years. The donor was a 21-year-old black man who died of a gunshot wound to the head. He had a history of smoking, as well as alcohol and cocaine abuse. Induction immunosuppressive therapy was antilymphocyte globulin, and the patient was maintained on prednisone, 10 mg every other day, and cyclosporine A, 75 mg/d. No episode of rejection was noted. After transplantation, the patient’s graft function had been excellent, with a

serum creatinine level of 1.3 to 1.7 mg/dL (115 to 150 ␮mol/L). In May 2002, an abdominal ultrasound examination was performed for evaluation of right upper-quadrant pain. There were multiple cysts in the native kidneys and liver, consistent with polycystic kidney disease. However, the transplanted kidney showed a 1.9- ⫻ 1.5-cm echogenic mass in the inferior pole. The patient’s abdominal pain resolved soon after the study. Magnetic resonance imaging of the abdomen showed a 3-cm mass in the same location. The mass was solid, with no signs of cystic components or metastasis to other organs. The patient underwent allograft nephrectomy after an intraoperative biopsy showed RCC. The tumor was entirely intracapsular and showed no involvement of the renal artery, renal vein, ureter, or surrounding lymph nodes. The patient was returned to hemodialysis therapy without complications. Serial sectioning of the allograft kidney in 1.0-cm sections in the axial plane showed 29 golden-yellow to yellowbrown nodules that ranged from 0.2 to 3.2 cm (Fig 1). On microscopic examination, these neoplastic foci were observed to have varying histological appearances. Twentyone lesions were solely papillary chromophil basophilic carcinoma with moderate nuclear pleomorphism and infiltration into a pseudocapsule (Fig 2A). Psammoma bodies and other larger calcifications were observed in several papillary lesions, as well as foamy macrophages and regions of necrosis with cholesterol clefts. Five lesions had a predominant clear-cell component (Fig 2B) in an acinar pattern and a

From the Departments of Medicine; Pathology; and Surgery, University of Arizona Health Sciences Center, Tucson, AZ. Received February 14, 2003; accepted in revised form April 8, 2003. Address reprint requests to Yeong-Hau H. Lien, MD, PhD, Department of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4202-0019$30.00/0 doi:10.1016/S0272-6386(03)00663-2

American Journal of Kidney Diseases, Vol 42, No 2 (August), 2003: pp 381-384

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seven percent were found in the native kidney, and 9%, the allograft, whereas 4% did not report the site.3 The occurrence of RCC in the native kidney may be related to the underlying cause of the end-stage renal disease, such as analgesic

Fig 1. Axial plane cut through the kidney allograft showing 4 gross lesions; the 2 largest show central necrosis and hemorrhage.

secondary papillary chromophil basophilic component. Two lesions had equally mixed clear cells and papillary components. A single nodule showed a papillary chromophil eosinophilic carcinoma with much larger cells with granular eosinophilic cytoplasm, moderately pleomorphic nuclei, and syncytial formation (Fig 2C). The majority of tumors were grade 2 using Furhman criteria4; no tumor was grade 3. Staging evaluation showed invasion into the capsule, but no extension to perinephric fat, and vessel and ureter margins were negative for neoplasm, as were 14 lymph nodes. This case therefore is stage I by the Robson system and T2N0 in the tumor, node, metastasis system.4 Immunohistochemical stains for cytomegalovirus and adenovirus on sections of normal and neoplastic kidney were negative. Because of the possibility of hereditary RCC, we contacted the original transplant program to identify the other recipient from this particular donor. The patient unfortunately rejected his allograft and returned to hemodialysis therapy a year ago. There was no evidence of malignancy in the allograft on the most recent evaluation. The nephrologist who is following up the patient has been notified and is aware of the possibility of synchronous disease in the mate kidney.

DISCUSSION

RCC is the fifth most common posttransplantation malignancy.1 An overview from the Israel Penn International Transplant Tumor Registry recorded 256 patients with de novo carcinomas among kidney transplant recipients. Eighty-

Fig 2. Histopathologic examination showing (A) papillary chromophil basophilic carcinoma, (B) clearcell variant RCC, and (C) papillary eosinophilic carcinoma. (Hematoxylin and eosin stain; original magnification, [A, C] ⴛ10; [B], ⴛ40.)

PAPILLARY RCC IN RENAL ALLOGRAFT Table 1.

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Reported Multicentric RCC in Renal Allograft

Recipient Donor Type of Duration of ImmunoGrowth Age (y)* Age (y) Transplant Transplant (y) suppression Function Hormone ACKD

24

27

CAD

13

CsA/Pred

1.7†

No

26

27

CAD

8

2.1†

No

4.5

33

LRD

9

CsA/Pred/ AZA CsA/Pred

Fair

Yes

3.8

28

LRD

11

Fair

Yes

46

21

CAD

13

CsA/Pred/ AZA CsA/Pred

1.7†

No

No

Renal Tumors

2 RCCs, clear cell No Multiple RCCs, granular cell Yes Multiple adenoma, single RCC, papillary Yes Multiple RCCs, clear cell No 29 RCCs, predominantly papillary

Tumors in Mate Kidney

No

Reference

No

Feldman and Jacobs6 Ghasemian et al7 Tyden et al8

NA

Tyden et al8

No

Present Case

No

Abbreviations: CAD, cadaveric donor; LRD, living related donor; CsA, cyclosporine A; Pred, prednisone; AZA, azathioprine; NA, not available. *Age at transplantation. †Values are for serum creatinine level in mg/dL (to convert to ␮mol/L, multiply by 88.4).

nephropathy and Chinese herb nephropathy. In addition, many renal transplant recipients have spent a significant amount of time on hemodialysis therapy before transplantation. This places them at increased risk for acquired cystic kidney disease (ACKD), a condition associated with RCC development after kidney transplantation.5 De novo malignancy in the renal allograft is very rare. Most de novo carcinomas occur in the allograft from 2 to 213.5 months (average, 56 months). Two thirds of carcinomas are RCC, and one fifth are transitional cell carcinoma.3 Reviewing the current literature, we identified 4 cases of multicentric RCC.6-8 Table 1 lists clinical information for those cases, as well as the present case for comparison. There are 2 pediatric patients who received living related donor transplants and 3 adults who received cadaveric kidney transplants. Donor age ranged from 21 to 33 years. Tumors were removed 8 to 13 years after transplantation. Immunosuppressive therapy included cyclosporine A and prednisone. Two patients also were administered azathioprine. Both pediatric patients were administered growth hormone and developed ACKD in the graft. One had multiple adenoma and a single papillary RCC, and the other had multiple RCC of clear-cell type.8 For the 3 adults, none was administered growth hormone or developed ACKD. One of the patients had 2 clear-cell RCCs, 1 patient had multiple granular cell (a clear-cell variant) RCC,

and our patient had multiple papillary RCC. It appears that the pathogenesis of those RCCs in pediatric patients may be different from that in adults. It is possible that growth hormone promotes both cystic formation and malignant changes in pediatric recipients. No tumors were found in the mate kidney in 4 cases. Our case is the first reported multicentric papillary RCC in a renal allograft and had the highest number of neoplastic foci. Pathological findings suggest that our patient had a slow growing and less aggressive course, given its mild presentation. Multiple lesions of well-developed carcinoma were found, with no signs of metastasis outside the allograft. It is interesting that histopathologic findings of the RCC from our patient are quite heterogeneous. These findings are similar to histopathologic patterns of hereditary papillary renal carcinoma (HPRC). HPRC is associated with mutations in the tyrosine kinase domain of the c-met protooncogene.9 The c-met encodes hepatocyte growth factor receptor, which mediates cellular proliferation and growth, as well as branching of developing renal tubules. A mutation in the tyrosine kinase domain typically is a missense mutation and is likely to cause constitutive activation of hepatocyte growth factor receptor and promote tumor formation in the kidney. Lubensky et al10 reported histological findings of 109 HPRCs from 34 patients with c-met

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mutations. All tumors showed a predominance of chromophil basophilic histological subtype with papillary/tubulopapillary architecture. Focal areas of cells with eosinophilic cytoplasm were present in tumors from 9 patients. Areas of clear cells were common in HPRC with c-met mutations. Clear cells ranged from 1% to 70%. Our case has predominant chromophil basophilic papillary cells, a single area of eosinophilic cells, and 17% clear cells, all consistent with HPRC morphological characteristics. It is possible that the c-met proto-oncogene may have a role in the pathogenesis of RCC in our patient. Papillary renal carcinomas are characterized by trisomy of chromosome 7, shown to be duplication of the mutant c-met allele in HPRC.11 Reports in the literature describe the association of loss of chromosome 7 with posttransplantation T-cell lymphoma12 and acute myeloid leukemia.13 It is conceivable that loss of the wild-type chromosome 7 as a result of immunosuppressive therapy combined with a germline c-met mutation may result in the multiple tumor nodules that developed in this patient’s renal allograft. Additional studies are needed to confirm this possibility. The mate kidney apparently did not contain clinically detectable tumors. Obviously, the patient who received the mate kidney needs to be followed up annually with imaging studies to rule out RCC. In this case, we describe a successful renal transplantation requiring total allograft nephrectomy 13 years after transplantation because of multicentric papillary RCC. It is an unusual case because of the high number of tumor foci with predominantly papillary type similar to HPRC. It is possible that the allograft is predisposed to malignant changes because of preexisting ge-

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netic mutations, as well as prolonged immunosuppression. REFERENCES 1. Winklehorst JT, Brokelman WJ, Tiggler RG, Wobbes T: Incidence and clinical course of de-novo malignancies in renal allograft recipients. Eur J Surg Oncol 27:409-413, 2001 2. Penn I: Posttransplant malignancies. Transplant Proc 31:1260-1262, 1999 3. Penn I: Primary kidney tumors before and after renal transplantation. Transplantation 59:480-485, 1995 4. Eble JN: Neoplasms of the kidney, in Bostwick DG, Eble JN (eds): Urologic Surgical Pathology. Philadelphia, PA, Mosby, 1997, pp 82-97 5. Lien YH, Karn I, Shanley PF, Schroter GP: Metastatic renal cell carcinoma associated with acquired cystic kidney disease 15 years after successful renal transplantation. Am J Kidney Dis 18:711-715, 1991 6. Feldman JD, Jacobs SC: Late development of renal carcinoma in allograft kidney. J Urol 148:395-397, 1992 7. Ghasemian SR, Guleria AS, Light JL, Sasaki TM: Multicentric renal cell carcinoma in a transplanted kidney. Transplantation 64:1205-1207, 1997 8. Tyden G, Wernersson A, Sandberg J, Berg U: Development of renal cell carcinoma in living donor kidney grafts. Transplantation 70:1650-1652, 2000 9. Schmidt L, Duh FM, Chen F, et al: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68-73, 1997 10. Lubensky IA, Schmidt L, Zhuang Z, et al: Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 155:517-526, 1999 11. Zhuang Z, Park WS, Pack S, et al: Trisomy 7-harboring nonrandom duplication of the mutant c-met protooncogene allele in hereditary papillary renal carciomas. Nat Genet 20:66-69, 1998 12. Francois A, Lesesve JF, Stamatoullas A, et al: Hepatosplenic gamma/delta T-cell lymphoma: A report of two cases in immunocompromised patients, associated with isochromosome 7q. Am J Surg Pathol 21:781-790, 1997 13. Thalhammer-Scherrer R, Wieselthaler G, Knoebl P, et al: Post-transplant acute myeloid leukemia (PT-AML). Leukemia 13:321-326, 1999