College of American Pathologists

2010—November Case of the Month

Posted January 3, 2011


CAP Foundation November 2010 Online Case of the Month

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A 60-year-old man presented with abdominal pain, constipation and melena. The patient underwent nephrectomy for clear cell carcinoma of the kidney 7 years ago. Colonoscopy revealed an ill-defined mass in the sigmoid colon with normal overlying mucosa. Abdominal CT showed a 4.0 cm hypervascular mass on the serosal aspect of the sigmoid colon. Segmental resection of the colon was performed. Received was an 18 cm segment of colon with a 4.0 cm serosal-based mass. Sectioning revealed infiltration of the tumor into the muscularis propria, without involvement of the mucosa. The cut surface revealed areas of hemorrhage and necrosis. The tumor cells were cytokeratin(+), PAX-2(nuclear+), CD10(+), RCC marker(+), vimentin(+), CK7(-), CK20(-), CDX2(-), S-100(-), HMB-45(-), chromogranin(-), and synaptophysin(-).

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 22 and is a metastatic renal cell carcinoma.

Criteria for Diagnosis and Comments: The slides show a neoplastic proliferation of large polygonal cells arranged in nests, separated by a rich vascular stroma endowed with prominent sinusoid-like vessels. The tumor cells have sharply defined cell borders with irregularly contoured nuclei and variably prominent nucleoli. There is abundant clear cytoplasm with occasional cytoplasmic granularity. The tumor extends into the muscularis propria, but does not involve the mucosa or submucosa. The morphology and immunophenotype (see Clinical Summary) establish the diagnosis of metastatic renal cell carcinoma.

The most common sites of metastasis of renal cell carcinoma are regional lymph nodes, lung, bone, liver, and adrenal gland. However, the tumor is notorious for metastasizing to unusual locations with metastasis reported in almost every organ including the nasal cavity, larynx, parotid, pituitary gland, pancreas, testis and skeletal muscle. Metastasis to the colon is rare, but can occur many years after nephrectomy and may or may not be accompanied by metastases to other sites.

Immunohistochemical markers that are most useful for the diagnosis of metastatic renal cell carcinoma are - PAX-2 and RCC marker. Other markers like CD10, EMA, kidney-specific cadherin and vimentin have been used, but have low sensitivity and specificity. PAX-2, a renal-restricted nuclear transcription factor, is expressed in 70-80% of metastatic clear cell renal cell carcinomas, and less commonly in other subtypes of renal cell carcinoma. Higher grades of clear cell carcinoma can have decreased expression. RCC marker is a glycoprotein found in the brush border of the proximal tubules of the kidney. RCC marker is positive in 47-85% of clear cell renal cell carcinomas and 60-90% of papillary renal cell carcinomas. Chromophobe renal cell carcinomas are generally negative for both RCC marker and CD10. Coexpression of vimentin and cytokeratin is often seen in clear cell (60-70%) and papillary (~100%) renal cell carcinomas. Chromophobe renal cell carcinoma is typically negative for vimentin. However, this coexpression is not limited to renal cell carcinoma. Clear cell adenocarcinomas of other sites like salivary gland, endometrium, bile ducts and stomach may also express vimentin. Spindle cell carcinomas from other sites also commonly co-express these two antigens. CK7 and CK20 are typically negative in clear cell renal cell carcinoma. CK7 expression is often observed in papillary and chromophobe renal cell carcinomas, and CK20 expression has been noted in type II papillary renal cell carcinoma.

Colonic adenocarcinomas with clear cells are rare. The characteristic cytokeratin phenotype of colon cancer, CK7-/CK20+, is seen in >90% of cases, while most renal cell carcinomas are negative for both CK7 and CK20. CDX-2 is a transcription factor that is expressed in the majority of colorectal adenocarcinomas (>85%), but is negative in nearly half of the poorly differentiated tumors. CDX-2 expression also occurs in tumors arising from the small intestine and less commonly from the stomach, esophagus and ovary. Most other adenocarcinomas including cholangiocarcinoma and pancreatic adenocarcinoma are generally negative. Renal cell carcinomas do not express CDX-2, while colonic adenocarcinomas are negative for RCC.

Melanoma can show clear cell change due to dilatation of premelanosomes or accumulation of lipid. The presence of melanin pigment, plasmacytoid morphology and prominent nucleoli can suggest the diagnosis. Demonstration of melanocytic differentiation with S-100, HMB-45 and/or melan A distinguishes it from other clear cell tumors.

Perivascular epithelioid cell tumors (PEComas) are a group of related mesenchymal tumors that include angiomyolipoma, lymphangioleiomyomatosis, clear cell (sugar) tumor of the lung, and other morphologically and immunophenotypically similar neoplasms that can arise in soft tissue or visceral sites. There is a marked female preponderance and the most common visceral sites are uterus and gastrointestinal tract. These tumors are composed of sheets and nests of epithelioid and less commonly spindle cells with clear or granular eosinophilic cytoplasm. These tumors can be morphologically indistinguishable from other clear cell neoplasms, but the characteristic immunohistochemical features establish the diagnosis. Nearly all PEComas express HMB-45 and/or melan A. Most tumors co-express smooth muscle actin, and some are also positive for desmin, but most are negative for S-100 protein and keratin Coexpression of melanocytic and smooth muscle markers and absence of keratin easily separates PEComas from carcinomas. The expression of smooth muscle actin and absence of S-100 protein help in the distinction from melanoma.

Neuroendocrine tumors like carcinoids, adrenocortical carcinoma and paraganglioma can show clear cytoplasm. Expression of chromogranin and synaptophysin separates carcinoids from metastatic renal cell carcinoma. CD10 can be expressed in both tumors and is not helpful in this distinction. The expression of inhibin, melan A and calretinin in adrenocortical carcinoma distinguishes it from renal cell carcinoma. Adrenocortical carcinomas express synaptophysin, but are negative for chromogranin. As opposed to renal cell carcinoma, most adrenocortical carcinomas are negative for pancytokeratin, although vimentin is often positive. Paragangliomas with clear cells retain their typical ‘zellballen’ pattern, express chromogranin and synaptophysin, and variably exhibit an S-100 protein positive population of sustentacular cells. All of these neoplasms are negative for RCC antigen.

Other entities in the differential diagnosis would include sarcomas and clear cell carcinomas from other sites. Some sarcomas can have epithelioid morphology with clear cytoplasm, mimicking a clear cell carcinoma. Epithelioid leiomyosarcoma and epithelioid gastrointestinal stromal tumor are the most likely tumors in this category and can be distinguished from carcinoma by immunoreactivity for smooth muscle markers and c-kit respectively. Carcinomas from a wide variety of sites can exhibit clear cell features, including those originating in the prostate, endometrium, vagina, cervix, ovary, thyroid and liver. The clinical presentation, and pattern of immunoreactivity with cytokeratins (like CK7/CK20) and lineage specific markers such as TTF-1, PSA, Hep Par 1 etc. can help confirm the diagnosis.

Supplementary Questions:

Question Diagnostic Set
1. Which of the following is true of the immunophenotype of renal cell carcinoma? A. Both CK7 and CK20 are usually positive in clear cell renal cell carcinoma
B. RCC antigen is expressed in nearly 100% of clear cell renal cell carcinoma
C. Vimentin is negative in most cases of chromophobe renal cell carcinoma
D. CD10 is negative in most cases of papillary renal cell carcinoma
2. Which of the following tumors typically lacks expression of the transcription factor CDX-2 by immunohistochemistry? A. Periampullary adenocarcinoma
B. Colorectal adenocarcinoma
C. Cholangiocarcinoma
D. Gastric adenocarcinoma
3. Which of the following is true about immunohistochemical distinction of clear cell renal cell carcinoma and adrenocortical carcinoma? A. Expression of vimentin favors clear cell renal cell carcinoma
B. Chromogranin and synaptophysin are generally positive in adrenocortical carcinoma
C. Cytokeratin is expressed in clear cell renal cell carcinoma but is usually not expressed in adrenocortical carcinoma
D. Expression of melan A and inhibin is often seen in both tumors


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Sanjay Kakar, MD, FCAP
Surgical Pathology Committee
UCSF and VA Medical Center-San Francisco
San Francisco, CA