Case of the Month: Right Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 29, and is papillary renal cell carcinoma, type 1.

The microscopic morphology is characteristic of papillary renal cell carcinoma (PRCC), type 1. The slides show papillary architecture, consisting of fibrovascular cores lined by a single layer of neoplastic epithelial cells. Some slides show partial trabecular growth pattern, which is common in PRCC. The type 1 designation is manifested by the single layer of small, neoplastic cells with moderate, eosinophilic cytoplasm, uniform, small, round nuclei and variable presence of small nucleoli. The fibrovascular cores are expanded by foamy macrophages and some slides have prominent hemosiderin deposition in both epithelial and neoplastic cells.

As in the presented case, PRCC can be found as an incidental finding (approximately 50%) or rarely, it presents as metastases. PRCC is the 2nd most common renal cell carcinoma, comprising 10-20% of cases and usually occurs in adults, predominating in men 2-4:1. It usually presents as a unilateral mass, however multifocal tumors within the kidney are not uncommon. The prognosis of PRCC is better than that of clear cell renal cell carcinoma.

Grossly, papillary renal cell carcinoma shows a fibrous pseudocapsule with pale tan-brown parenchyma. A granular-friable texture is a manifestation of papillae seen microscopically and tan-yellow parenchyma indicates abundant foamy macrophages within papillae. Frequently, hemorrhage and necrosis are present.

The vast majority of papillary renal cell carcinomas consist of papillary or tubulopapillary microscopic architecture with true papillary formation containing fibrovascular cores covered by neoplastic epithelial cells. Elongated papillations in a linear arrangement may impart a papillary-trabecular pattern and closely packed papillations may impart a solid appearance. The architecture may be varied within a single tumor and may also contain areas of true solid, tubular, glomeruloid or rarely sarcomatoid appearances, and presence of the latter indicates aggressive tumor behavior. The majority of neoplastic cells comprising the tumor have amphophilic or eosinophilic cytoplasm. If clear cells are found, they are usually seen in solid-growth areas or adjacent to areas of necrosis. Nuclear features of PRCC are not distinct and can range from small, round without nucleoli to large and irregular with coarse chromatin and prominent nucleoli. Within the mass, geographic necrosis may be present, the fibrovascular cores may be expanded by foamy macrophages or edema, or less commonly, psammoma bodies may be present. Hemosiderin deposition in neoplastic cells or in the foamy macrophages may be prominent.

Although most cases of PRCC can be diagnosed by histopathology, it has characteristic genetic and molecular findings that are different from other renal neoplasms. These include chromosomal gains of chromosomes 7 and 17 and loss of Y chromosome in tumors in males.

Several grading systems have been proposed to predict outcomes of PRCC, however the utility of the various systems is controversial. Grading systems have used cytoplasmic appearance, Fuhrman nuclear grade, nucleolar prominence, or combination of these features to predict outcome. One of the most commonly used systems divides PRCC into 2 types, type 1 and type 2, based on cytologic and architectural features. The current case shows features of PRCC type 1, specifically papillae lined by a single layer of neoplastic cells that are small with moderate, eosinophilic cytoplasm, uniform, round nuclei and small to absent nucleoli. Psammoma bodies, intra-papillae foamy macrophages and edema are common in type 1 tumors. Type 2 tumors contain papillae lined by pseudostratified cells that are larger with abundant eosinophilic cytoplasm and large, round nuclei with prominent nucleoli. MUC1 immunohistochemistry has been suggested to help differentiate type 1 from type 2 tumors, with 72% of type 1 tumors showing diffuse staining of apical portion of cells and only focal staining of type 2 tumors. Type 1 is more frequent with a better prognosis than type 2 tumors and type 2 tumors generally have higher Fuhrman grade, are higher stage and occur more commonly in younger patients (less than 40 years) than type 1 tumors.

Clear cell renal cell carcinoma can rarely have true papillary architecture. More commonly, it has a pseudopapillary appearance due to cells dropping away from the "feeder" vessels. In addition, PRCC can have areas of clear cells, usually seen in solid-growth areas or adjacent to areas of necrosis. The presence of psammoma bodies and papillae containing foamy macrophages are typical of PRCC. Distinguishing between clear cell renal cell carcinoma and PRCC can usually be accomplished through adequate sampling.

Clear cell papillary renal cell carcinoma and Xp11 translocation renal cell carcinoma are two rare types of renal cell carcinoma. Both have characteristic papillary architecture, like PRCC and they characteristically contain cells with clear cytoplasm. Clear cell papillary renal cell carcinoma is more likely to be small (less than 5.0 cm), and is usually indolent. The clear cells have nuclei that are polarized away from the papillae basement membrane and they lack foamy macrophages, psammoma bodies and hemosiderin. Xp11 translocation renal cell carcinoma may be difficult to separate from other renal neoplasms and should be suspected if the patient is young and/or the stroma contains psammoma bodies. They contain a characteristic translocation of the TFE3 gene on Xp11 to one of multiple partners, most commonly t(X;17) (p11.2;q25), all resulting in overexpression of TFE3 protein. This overexpression can be detected by immunohistochemistry, making nuclear staining for TFE3 a distinctive feature of Xp11 translocation renal cell carcinoma that is absent in other renal cell carcinomas. Xp11 translocation renal cell carcinoma is the most common renal cell carcinoma in children, comprising approximately one third of pediatric renal cell carcinomas. A history of chemotherapy is the only known risk factor for Xp11 translocation RCC in adults (15% of cases).

Immunohistochemistry can be a valuable ancillary tool in distinguishing among renal cell neoplasms when the diagnosis cannot be established by histology alone.

* Type 1 PRCC only; Type 2 PRCC has a variable immunoprofile.
** Carbonic anhydrase

1. Which renal cell carcinoma has characteristic immunohistochemical staining with TFE3?
   
   1. Clear cell papillary renal cell carcinoma
   2. Clear cell renal cell carcinoma
   3. Papillary renal cell carcinoma, type 1
   4. Renal medullary carcinoma
   5. Xp11 translocation renal cell carcinoma
2. Which renal cell carcinoma is characterized by chromosomal gains of chromosomes 7 and 17 and loss of Y chromosome?
   
   1. Clear cell papillary renal cell carcinoma
   2. Clear cell renal cell carcinoma
   3. Papillary renal cell carcinoma, type 1
   4. Renal medullary carcinoma
   5. Xp11 translocation renal cell carcinoma
3. Microscopic examination of a renal mass from an adult patient shows papillary architecture and clear cells. Which of the following immunohistochemical panels will help to best differentiate conventional clear cell carcinoma from papillary renal cell carcinoma?
   
   1. TFE3, CD10
   2. CD10, CK7
   3. CK7, CAIX and AMACR
   4. CK7, CD10 and TFE3
   5. Vimentin, CD10

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2013
Nichole Steidler, MD
Surgical Pathology Committee
University of New Mexico
Albuquerque, NM

1. Xp11 translocation renal cell carcinoma (e). 
2. Papillary renal cell carcinoma, type 1 (c). 
3. CK7, CAIX and AMACR (c).