A 74-year-old woman presented with hematuria and was found to have a complex cystic mass in left kidney on imaging. She had a remote history of hysterectomy for ovarian cysts elsewhere. The patient underwent left nephrectomy and grossly a 639.6 g, 16.1 x 12.1 x 5.6 cm kidney with a cystic tan multilobulated papillary mass was present in upper pole, measuring 5.3 x 4.7 x 3.8 cm. Microscopic images (figures 1 and 2) and immunohistochemical staining are as shown (figures 3, 4, 5 and 6). Microscopic sections showed a tumor with tubulo-papillary architecture lined by clear cells, focally exhibiting a linear arrangement of nuclei away from the basement membrane. This tumor was positive for cytokeratin 7, PAX8, carbonic anhydrase IX (CA-IX) (basolateral/”cup like” membranous localization pattern), GATA3, 34BE12, and negative for AMACR, cytokeratin 20, p63, and TTF-1.
The correct answer is ...
Clear cell papillary renal cell carcinoma.
Clear cell papillary renal cell carcinoma (CCPRCC) is a subtype of renal cell carcinoma (RCC) included in 2016 WHO classification. The tumor was first described in kidneys with end-stage renal disease, however, the majority of cases reported subsequently have been sporadic. It is important to recognize this subtype as it follows an indolent course.
Clear cell papillary renal cell carcinoma accounts for 1%–4% of all resected renal tumors. The mean age at presentation is 60 years (range: 18 to 88 years) and there is no sex predilection. They are usually diagnosed as low-stage tumors. They present as well-circumscribed nodules with a mean size <3.0 cm and are usually low grade (WHO/ISUP grade 1 or 2). Tumor necrosis, perineural invasion, and lymphovascular invasion have not been observed. A single metastatic case has been reported.1,2 These tumors have much better prognosis than (conventional) papillary and clear cell renal cell carcinomas (RCCs).
Tumors show a variable mixture of tubular (commonly predominant), papillary, acinar, cystic, cords, and solid growth patterns. Cuboidal or columnar cells with clear cytoplasm and nuclei uniformly arranged away from the basement membrane are the typical cytological features of these tumors. They may have overlapping features with conventional clear cell renal cell carcinoma, and immunohistochemical stains can help in this differential diagnosis.3
Clear cell papillary RCC are diffusely and strongly positive for cytokeratin 7 and show membranous CA-IX staining with absence of luminal staining (basolateral/ “cup-like” membranous localization). The hypothesized cell of origin is the distal nephron, as these tumors are frequently positive for GATA3 and high molecular weight cytokeratin. Specifically, GATA3 is considered a sensitive (76%) and specific (100%) marker for CCPRCC and can be used for accurate distinction from histologic mimics. The positive and negative predictive values are 100% and 74%, respectively. Coexpression of GATA3 and high molecular weight cytokeratin in most CCPRCC supports their origin from distal nephron.4 They are negative for AMACR, CD10, and RCC.5
Primary renal cell carcinomas with both papillary architecture and cells with clear cytoplasm can be diagnostically challenging, and the differential diagnosis includes clear cell RCC, papillary RCC, clear cell papillary RCC, and MiT family translocation RCC. Accurate diagnosis has prognostic implications and immunohistochemical stains can help establish the diagnosis.5
These tumors are mutationally silent and genomically stable. No specific molecular alterations have been identified other than accumulation of sugar alcohol sorbitol on metabolomic profiling, and this contrasts with clear cell renal cell carcinoma that have loss of function VHL alterations (mutation/deletions/epigenetic silencing).6
These are indolent tumors with a benign course and favorable prognosis. They usually present as low stage and low-grade tumors. In a follow-up study of 362 cases, no tumor recurrence, metastasis, or disease-related deaths were reported. Only a single case of metastatic behavior has been reported in the current English language literature.1,2
Ayesha Farooq, M.B.B.S.
Fellow, Surgical Pathology
Sounak Gupta, M.B.B.S., Ph.D.
Senior Associate Consultant, Anatomic Pathology
Assistant Professor of Pathology
Mayo Clinic College of Medicine and Science