FINAL DIAGNOSIS: RENAL CELL CARCINOMA
The differential diagnosis of malignant suprarenal or adrenal masses includes adrenal cortical carcinoma, pheochromocytoma, renal cell carcinoma, hepatocellular carcinoma, as well as metastatic adenocarcinoma. The radiographic and operative findings can be misleading in some cases since lesions may be interpreted as suprarenal or adrenal masses based on location and relative preservation of underlying kidney parenchyma. Even at the time of surgery, a clear determination of the primary location for a particular tumor cannot be made, especially for large lesions. Based on morphology and immunohistochemical findings, the diagnosis can be made in the majority of cases from this differential diagnosis. However, cases may arise where the morphology and immunohistochemical findings are equivocal and other ancillary procedures such as electron microscopy and even molecular studies may be helpful to distinguish between similar entities. This is particularly true in the distinction between adrenal cortical carcinoma and renal cell carcinoma where the location may be a misleading clue and the pathologic findings are equivocal. We present an interesting case of a suprarenal mass in an elderly man with an intriguing past oncologic history. We will discuss the diagnostic approach to this case and the role of molecular studies in differentiating between diagnostic entities. We will also discuss the implications of the molecular findings in this case as it relates to the past oncologic history.
Several features of this case made the distinction between renal cell carcinoma and adrenal cortical carcinoma difficult. First, on radiographic interpretation, this mass was determined to be a large adrenal mass with central necrosis and hemorrhage worrisome for adrenal cortical carcinoma. Radiographically, the distinction between various lesions in this area including hepatocellular, renal cell, or adrenal cortical carcinoma may be difficult if not impossible 17. Angiography may be help in some cases to distinguish renal cell from adrenal cortical carcinoma 6. The majority of renal cell carcinomas will show a coarse neovascularity while adrenal cortical carcinomas show a more finely dispersed vascularity. Angiography was not performed in this case. Second, the operative findings confirmed a large suprarenal mass that did not appear to involve the superior pole of the underlying kidney. However, the lesion also extended down to encompass the right renal vein and involve the renal hilum. Third, biopsy of this lesion prior to the resection was interpreted as benign adrenal tissue and the lesion was therefore clinically considered to be an adrenal cortical carcinoma especially in conjunction with the radiographic findings. Fourth, several gross and histopathologic features made entertaining a diagnosis of adrenal cortical carcinoma very plausible. Grossly, the tumor was a large, lobulated, tan-yellow lesion with central hemorrhage and necrosis characteristic of gross descriptions of adrenal cortical carcinomas. Most adrenal cortical carcinomas are large lesions in excess of 100 grams with many being over 750 grams 10, 11, 12, 34. Histologically, the tumor was composed of almost exclusively clear cells arranged in nests, trabeculae and solid sheets. Mitoses and pleomorphism were not appreciated in this large mass. The tumor is adjacent to normal appearing adrenal tissue and appeared to push the adrenal tissue as well as invade the adrenal gland. Additionally, adrenal medulla is seen within compressed adrenal tissue. Cytologic features in this case included a clear cell morphology with mainly centrally placed nuclei with mild pleomorphism and small to medium sized nucleoli. Cytomorphologic features favoring adrenocortical carcinoma include endocrine architecture, focal and dramatic anisonucleosis, eccentric nuclei and absence of cytoplasmic vacuolization 30. These cytologic features were not seen in this neoplasm. The immunohistochemical findings on the original section of tumor examined showed rare positive cells for adrenal tissue markers, synaptophysin and inhibin, while other stains lended support to the diagnosis of renal cell carcinoma. CD10, EMA, and cytokeratin AE1/AE3 are positive in 80 to 90 percent of conventional renal cell carcinomas and essentially absent in cases of adrenal cortical carcinomas analyzed 1, 4, 7, 25. Surprisingly, RCC is positive in 76 percent of cases of renal cell carcinoma and as expected negative in all cases of adrenal cortical carcinoma tested 22. Conversely, inhibin, synaptophysin, and Melan A are positive in the majority of cases of adrenal cortical carcinomas and virtually negative in renal cell carcinomas 2, 3, 14, 15, 19, 24, 27, 31. Amidst this contrasting clinical and pathologic evidence is the fact that this mass was entirely surrounded by presumably perinephric adipose and no normal renal parenchyma was identified.
Electron microscopic studies were somewhat difficult to interpret due to fixation artifact. The tumor cells contained mitochondria with lamellar cristae and relatively abundant rough endoplasmic reticulum both features that are more likely to be seen in cells from a conventional renal cell carcinoma 9, 18, 33.
In a further attempt to definitively categorize the tumor, microdissection mutational profiling was performed on the tumor. The tumor demonstrated allelic loss at the 3p21 locus. Loss of 3p has been described in primary renal cell carcinomas by comparative genomic hybridization studies as well as loss of heterozygosity at 3p25, 3p21.1, and 3p14.2 in metastatic clones 8.
Approximately 43% of all renal cell carcinomas demonstrate LOH in at least one loci on the short arm of chromosome 3 ((3p14.1-14.3, 3p21.2-21.3, and 3p25) 20. The deletions and LOH of 3p are features of clear cell (conventional) RCC and are rare in other subtypes of RCC. Although LOH for clear cell RCC is seen at various tumor suppressor genes (3p21, 3p14.2, and 3p12), both in VHL negative and VHL positive tumors, the major clear cell RCC LOH region mapped to 3p21.3 close to the lung cancer tumor suppressor gene region 1 (LCTSGR1) 21.
The most common cause of inherited RCC is Von Hippel Lindau (VHL) disease. This is a multisystem disorder characterized phenotypically by retinal and cerebellar hemangioblastomas, pheochromocytomas, pancreatic and kidney cysts, endolymphatic-sac tumors, islet-cell tumors of the pancreas, and RCC. Approximately 70% of patients with the VHL disease will develop RCC by the sixth decade. The VHL tumor suppressor gene was isolated to 3p25-p26. This gene is associated with a large portion (>70%) of sporadic as well as hereditary forms of RCC. The corresponding protein encoded by this locus (VHL protein) downregulates transcriptional elongation and suppresses the expression of proto-oncogenes and growth factors 13, 28.
The other interesting aspect of this case aside from the diagnostic features is the patient's previous oncologic history. He has in conjunction with the diagnosis of the RCC, a hematologic malignancy, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). No cytogenetic analysis is currently available on the hematologic specimen. A case report exists of translocations of chromosomes 3 and 5 (3;5)(p26;q13) in a patient with chronic T-cell lymphoproliferative disorder 29 and Hodgkin lymphoma occurring in a patient with VHL disease 5. No strong associations between VHL mutations and hematologic disorders have been documented. However, a recent report links mutations in the VHL gene with elevated erythropoietin (Epo) levels in sporadic congenital polycythemia in children. The VHL protein is involved in the degradation of the hydroxylated form of the hypoxia-inducible factor 1 (HIF-1 ). The subsequent loss of the VHL function can result in accumulation of HIF-1 and overproduction of HIF-1 downstream target genes that include Epo 23.
This patient also demonstrated a history of a partial colectomy for "severe polyposis". The exact nature of the polyposis is not clear from the history. Von Hippel Lindau disease and familial polyposis coli have been seen in the same family 16. However, mutations for VHL and adenomatous polyposis coli genes (APC) have not been identified in clear cell RCC tumors 32.
The link between other predominant neoplastic conditions in this patient are even less strong. Osteochondromas nor prostatic adenocarcinoma to date have not been linked to either 3p21 allelic loss or VHL mutation 26. To date no loss of 3p tumor suppressor genes have been associated with primary adrenal cortical carcinoma.
In summary, we present an interesting and diagnostically challenging case of renal cell carcinoma with allelic loss of 3p21 in a patient with multiple and varied neoplasias. In the future, molecular genetic information will provide the missing links between multiple neoplastic and non-neoplastic conditions seen in the same person and/or families.
Contributed by John A Ozolek, MD, Eizaburo Sasatomi, MD, PhD, Patricia A Swalsky, B.S., Sydney D. Finkelstein, MD, Rajiv Dhir, MD