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Kidney tumor - adult malignancies

Adult renal cell carcinoma

Renal cell carcinoma-general


Reviewers: Sean Williamson, M.D. (see Reviewers page)
Revised: 10 December 2014, last major update June 2012
Copyright: (c) 2003-2014, PathologyOutlines.com, Inc.

General
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● Formerly called hypernephroma due to perceived origin from adrenal gland

Epidemiology
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● In US in 2010, were 58,240 new renal cancers and 13,040 deaths; 92% were renal cell carcinoma, 7% renal pelvis carcinoma, 1% Wilms tumor (American Cancer Society Statistics)
● Usually > 50 years old, 2/3 male, only 1% bilateral

Clinical features
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Risk factors:
● Renal transplantation, acquired renal cystic disease due to end stage renal disease, cigarette smoking (particularly for renal pelvis tumors), obesity, high blood pressure, treated neuroblastoma

Metastases:
● 25% present with metastases (lung, bones, lymph nodes, adrenals, liver, brain), sometimes at unusual locations (as seen with melanoma and choriocarcinoma) such as contralateral adrenal gland, anus (Arch Pathol Lab Med 2002;126:856), gallbladder, pancreas (Urol Oncol 2011 Jan 28 [Epub ahead of print])
● Metastases often solitary and detected years or decades after removal of primary
● Rarely metastases to bladder (Mod Pathol 1999;12:351) or phalanges (Mod Pathol 1991;4:66)
● Most common recipient of metastases from another tumor (usually lung)

Familial renal cell carcinoma syndromes
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von Hippel-Lindau disease (see clear cell type):
● Due to germline mutation of VHL gene at chromosome 3p25
● Renal lesions: renal cysts and clear cell renal cell carcinoma
● Other organs: Retinal/CNS hemangioblastoma, pheochromocytoma, pancreatic cyst/neuroendocrine tumors

Hereditary papillary renal carcinoma:
● Due to activating mutation of MET oncogene at chromosome 7q31
● Autosomal dominant, late onset bilateral papillary renal tumors

Hereditary leiomyomatosis and renal cell carcinoma:
● Autosomal dominant, familial
● Due to germline fumarate hydratase mutations
● Cutaneous or uterine leiomyomas
● Renal tumors are often papillary with characteristic large nucleus with a very prominent inclusion-like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo
● Poor prognosis (Am J Surg Pathol 2007;31:1578)

Birt-Hogg-Dubé syndrome:
● Autosomal dominant with incomplete penetrance
● Due to germline mutations in BHD gene at chromosome 17p11.2, which codes for folliculin
● Skin lesions: fibrofolliculomas, trichodiscomas, acrochordons
● Lung: cysts, spontaneous pneumothorax
● Renal tumors variable – oncocytoma, clear cell carcinoma, and hybrid oncocytic-chromophobe tumors with areas of clear cells (Am J Surg Pathol 2002;26:1542)

Tuberous sclerosis:
● Mutations in TSC1 and TSC2 genes via an alternate pathway not involving VHL mutations (Mod Pathol 2002;15:205)
● Multiple, bilateral angiomyolipomas (or epithelioid angiomyolipoma)

Clinical description
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● Image-guided biopsy of solitary small renal masses increasingly utilized for treatment planning, since pathology cannot be predicted by clinical features (Am J Clin Pathol 2008;130:560, Hum Pathol 2005;36:1309)
● "Great mimic" due to associated paraneoplastic syndromes of Cushing’s syndrome, gynecomastia, hypercalcemia, hypertension, leukemoid reaction, polycythemia, Stauffer syndrome (hepatomegaly with hepatic dysfunction), systemic amyloidosis, polyneuromyopathy
● Most tumors are detected incidentally due to increased use of imaging; historically were large (10 cm) at diagnosis
● "Classic" clinical features of costovertebral pain, palpable mass and hematuria are now present in only 10%

Radiology images
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MRI shows massive extension into inferior vena cava (arrows)

Prognostic factors
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● Stage and nuclear grade most important (Am J Surg Pathol 2002;26:281)
● Histologic classification may be significant, although less so after TNM classification (Am J Surg Pathol 2003;27:612)
● Lymphatic invasion associated with nodal metastases (Am J Clin Pathol 2007;128:198)

Treatment
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● Radical nephrectomy, partial nephrectomy for small peripheral tumors (5-25% of patients may have multifocal tumors)
● Cure possible even with extension into renal vein, inferior vena cava and right atrium
● Chemotherapy and radiation traditionally considered ineffective; however, increasing interest in interferon and anti-angiogenic agents (sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab, pazopanib)
● Excision of solitary metastases is often effective
● Occasionally regresses without treatment (as seen with germ cell tumors, melanoma, neuroblastoma)
● 5 year survival: 68% (all histologic types and stages), varies from 60-80% in stage I vs. 5% in stage IV, lower for renal pelvis carcinoma (51%) compared to renal cell carcinoma (70%)

Gross description
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● Well-circumscribed, centered on cortex, may bulge/distort kidney contour
● Often extends into renal vein or vena cava, renal sinus invasion common in large tumors
● May have satellite nodules, often hemorrhage, necrosis, calcification and cystic change causing variegated appearance

Gross images
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Tumor less than 3 cm


Arising in adult-type polycystic renal disease


Diffusely infiltrative


Massive tumor extension into renal vein and inferior vena cava


Retrograde extension of tumor down the left internal spermatic vein into the spermatic cord


Metastases to small intestine


Nodal metastases

Micro description
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● Subtypes are described separately; commonly nuclear grooves (96%) and inclusions (65%, Arch Pathol Lab Med 2008;132:940)
● Precursor lesion is intratubular epithelial dysplasia (seen in 1/3) with crowded tubular epithelium, large, vesicular nuclei, eosinophilic macronuclei, resembles carcinoma in situ (Mod Pathol 1996;9:690, Am J Surg Pathol 1994;18:1117)

Micro images
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Cutaneous metastases: H&E and CD10


Neuroendocrine carcinoma is less well differentiated than carcinoid

Virtual slides
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Various images

Cytology description
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● 25% sensitive for bladder washings/urine, higher for retrograde brushing
● FNA helpful to differentiate cyst from carcinoma or to confirm recurrence
● High false positive rate for FNAs in one study (Arch Pathol Lab Med 2002;126:670)
● Benign renal tubular epithelial cells may be sampled, mimicking carcinoma
● Tumor cells have abundant cytoplasm that is vacuolated, fluffy or granular, usually with indistinct cell borders (but chromophobe renal cell carcinoma has distinct borders)
● Tumor nuclei have variable atypia, irregular contours, haphazard orientation with abnormal chromatin, variably prominent nucleoli
● Renal tubular cells have well defined cell borders, homogenous cytoplasm, round, regular and orderly nuclei
● Important features to distinguish from other neoplasms include heterogeneous cell population, small cytoplasmic vacuoles and hemosiderin deposits (Arch Pathol Lab Med 2005;129:1017)

Cytology images
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Normal kidney glomerulus and renal tubular cells


Cells in alveolar arrangement demonstrate vacuolated cytoplasm, vesicular nuclei, prominent nucleoli

Positive stains (vary by histologic subtype)
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Most commonly used:
● AE1-AE3, EMA, RCC-Ma (80% sensitive, 67% in metastases, most sensitive for papillary, 0% sensitive in collecting duct, Am J Surg Pathol 2001;25:1485)
● CD10 (81%), PAX2 (Am J Clin Pathol 2009;131:393), PAX8 (Appl Immunohistochem Mol Morphol 2011;19:293)

Other positive stains:
● Kidney-specific cadherin, N-cadherin, CD15
● Occasionally vimentin (25%), S100 (5%), PSA in tumor associated vasculature only (Mod Pathol 2008;21:727)

Negative stains
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● CK7, CK20, inhibin (Mod Pathol 1998;11:1160), MelanA/Mart1, calretinin, TTF1, CEA

Differential diagnosis
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Epithelioid angiomyolipoma: has classic angiomyolipoma-like areas present in some cases; HMB45+, MelanA/Mart1+, variable smooth muscle marker+
● Renal cell carcinoma metastases to brain (inhibin-, AE1/3 +, CD10+, EMA+) resemble hemangioblastoma (inhibin+, AE1/3-, CD10-, EMA-, Am J Surg Pathol 2003;27:1152, Brain Pathol 2010;20:511)
● Metastases to skin (CD10+) may resemble cutaneous adnexal tumors, but eccrine and apocrine tumors are CD10- (Arch Pathol Lab Med 2006;130:1315)

Additional references
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eMedicine, US National Cancer Institute

End of Kidney tumor - adult malignancies > Adult renal cell carcinoma > Renal cell carcinoma-general


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