Kidney tumor - adult malignancies - Clear cell renal cell carcinoma

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Kidney tumor - adult malignancies

Adult renal cell carcinoma

Clear cell renal cell carcinoma

Reviewers: Sean Williamson, M.D. (see Reviewers page)
Revised: 27 June 2012, last major update June 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
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● Also called conventional / classic type
● Historical names: hypernephroma due to belief that it derives from adrenal gland; also Grawitz tumor

Epidemiology
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● 70% of adult renal epithelial tumors

Etiology
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● Origin: tumor cells are derived from proximal convoluted tubule
● 3p- (considered the initial mutation) in 98% (3p25 is von Hippel Lindau [VHL] gene)
● VHL is tumor suppressor gene that encodes elongin, which inhibits the generation of a transcriptional elongation complex of vascular endothelial growth factor
● Loss of VHL causes an increase in VEGF, which may cause the increased vascularity of these tumors

Clinical features
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● Risk factors: adult polycystic disease, smoking (RR = 2.0), obesity in women, hypertension, von Hippel Lindau (VHL) disease, hereditary renal cell carcinoma without VHL, tuberous sclerosis (but not via VHL mutations, Mod Pathol 2002;15:205)

von Hippel Lindau disease
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● Autosomal dominant syndrome with hemangioblastomas of retina and cerebellum, cysts of pancreas, liver and kidney, clear cell tumors of other sites, papillary cystadenoma of epididymis, pheochromocytoma
● Associated with bilateral or multiple renal cell carcinomas in 50% (eMedicine)

Poor prognostic factors
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● High stage, renal sinus invasion (Am J Surg Pathol 2000;24:451)
● Possibly high survivin expression (Hum Pathol 2008;39:1176)
● Metastases: occur in 27-37%; in declining order of frequency - lung, lymph nodes, liver, bone, adrenal glands, kidney, brain, heart, spleen, intestine, skin – metastases to other unusual sites also occur, such as soft tissue, gallbladder, salivary gland
● Survival: poorer prognosis than papillary and chromophobe carcinoma; overall 38% die of disease

Case reports
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Metastases:
● Anus (Arch Pathol Lab Med 2002;126:856)
● Larynx (Arch Pathol Lab Med 2000;124:1833)
● Parotid gland (Hum Pathol 1989;20:195)
● Thyroid (Thyroid Res 2008 Oct 24;1(1):6, Arch Pathol Lab Med 1999;123:703)

Other:
● Neuromelanin pigmentation (Am J Surg Pathol 1995;19:350, Hum Pathol 2001;32:233)
● Gamna-Gandy nodules (Arch Pathol Lab Med 2003;127:372)
● With syncytial giant cells (Arch Pathol Lab Med 2004;128:1435)
● With intravascular diffuse large B cell lymphoma (Arch Pathol Lab Med 2001;125:1239)

Gross description
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● Orange/yellow (from lipid), usually upper pole, well circumscribed (“pushing” borders), hemorrhage, necrosis and calcification are common (resulting in heterogeneous or variegated cut surface)
● Frequent involvement of renal vein and renal sinus (particularly for large tumors)
● Soft fleshy areas may indicate sarcomatous component
● May undergo cystic degeneration, may be multifocal; bilateral in 1% (usually with von Hippel Lindau or tuberous sclerosis)

Gross images
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Well-circumscribed yellow nodular mass

Variegated surface

Hemorrhage and necrosis

Tumor penetrating the capsule

Other features:

Focal myxoid change and hemorrhage and tumor plug in renal vein

Sarcomatoid component

von Hippel Lindau syndrome with multiple renal tumors and cysts

Metastasis presenting as anal hemorrhoid

With other tumors:

With angiomyolipoma

With leiomyosarcoma of renal vein

Micro description
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● Compact, tubulocystic, alveolar or rarely papillary architecture of cells with clear cytoplasm (from glycogen/lipid), distinct but delicate cell boundaries; cell size is 2x normal epithelial tubule cell
● Often glassy hyaline globules (multiple/small or single/large) and myospherulosis; usually nuclear grade 2 or higher; chicken wire / delicate vasculature is common (sinusoids near each packet of cells)
● Occasionally is irregular central area of edematous stroma
● May have angioleiomyomatous features (Am J Surg Pathol 2006;30:1372), smooth muscle stroma (Hum Pathol 2009;40:425), myospherulosis (Arch Pathol Lab Med 2000;124:1476), overlapping morphologic features of papillary carcinoma (Arch Pathol Lab Med 2003;127:1176)
● Some tumors may have pseudo-papillary architecture due to high-grade changes and loss of cell cohesion (Am J Surg Pathol 2008;32:1780)

Micro images
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Patterns:

Alveolar growth of large polygonal cells with clear cytoplasm, uniform round nuclei and inconspicuous nucleoli


Nests of clear cells with prominent vasculature

Alveolar and acinar architecture are mixed


Acinar

Pseudopapillary architecture due to loss of cohesion

Nuclear features:

Grade 1 nuclei are regular with indistinct nucleoli

Grade 2 nuclei have irregular contours and nucleoli present at 40x

Grade 3 nuclei have more irregular contours and nucleoli present at 10x

Nuclear grooves and inclusions (fig 3)

Other microscopic features:

Gamna Gandy nodules (figure 3: von Kossa stain)


Intracytoplasmic hyaline globules (image on right contributed by Dr. Sean Williamson)

Syncytial giant cells

Sharp tumor border

Dense stroma with calcifications and siderophages

Multiple tumor nodules

Necrosis

Lymphatic invasion (podoplanin stain):

Various images

Metastases:

Anus

Larynx

Ovary

Pancreas

Thyroid

Stains:

Sudan red+ lipid droplets

CD10

EMA+ (MUC1+)

Fig. A: EMA+; B: LeuM1+; C: pan-keratin+

RCC-Ma

Vimentin+

With intravascular B cell lymphoma:

Fig B: arrows at clear cell carcinoma, arrowhead at vessels with large atypical lymphoid cells; fig C: lymphoma cells with prominent nucleoli (arrows); fig D: CD20+ lymphoid cells

Comparisons:

Clear cell hidradenoma


Clear cell hepatocellular carcinoma

Virtual slides
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Image

Grade 3 tumor

VHL associated tumor

Cytology images
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Myospherules

Atypical cells #1; #2; #3

Positive stains
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Most important:
● PAS without diastase, oil red O (frozen tissue only), low molecular weight cytokeratin (CK 8/18, CK19, CK7), EMA/MUC1 (membranous), vimentin (note: coexpression of keratin and vimentin is somewhat specific), CD10 (94%), RCC-Ma (85%)
● Carbonic anhydrase IV (Am J Surg Pathol 2008;32:377)
● PAX2 (Am J Surg Pathol 2008;32:1462)
● PAX8 (Am J Surg Pathol 2011;35:816, Appl Immunohistochem Mol Morphol 2011;19:293)

Other positive stains:
● Alpha-1-antitrypsin, alpha-1-antichymotrypsin, CD13, CD15
● GST-alpha (Am J Clin Pathol 2005;123:421)
● LeuM1, S100, VHL (Am J Clin Pathol 2008;129:592), villin, variable N-cadherin

Negative stains
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Most important:
● Hale’s colloidal iron, mucin, cytokeratin 34betaE12 (Int J Gynecol Pathol 2005;24:239), CK20, AMACR (Am J Surg Pathol 2008;32:1780)

Other negative stains:
● c-kit (CD117), CA125, CEA (Hum Pathol 2004;35:697), E-cadherin, HepPar1, inhibin, MelanA, parvalbumin, thyroglobulin, TTF1

Suggested panels
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(1) vimentin+, CK 8/18+
(2) vimentin+, GSTalpha+ (Arch Pathol Lab Med 2007;131:1290)

Electron microscopy description
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● Abundant glycogen, well defined long microvilli similar to brush border of normal proximal tubules, numerous cell junctions
● Variable fat, scant organelles, may have scant microvesicles

Molecular description
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● 3p- (considered the initial mutation) in 98% (3p25 is von Hippel Lindau gene)
● Also 5q21+ (70%), 14q- (41%)
● Sporadic cases usually demonstrate VHL inactivation and reduced frequency of ciliated tumor cells (Mod Pathol 2009;22:31)
● Nondeleted allele of the VHL gene shows somatic mutations or hypermethylated induced inactivation in 80% of cases

Molecular drawings
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3p region

Differential diagnosis
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● Clear cell hidradenoma: no nuclear atypia; less prominent vasculature; CK5+, CK7+, 34betaE12+, variable CEA, vimentin-, CD10- (Arch Pathol Lab Med 2005;129:e113)
● Clear cell hepatocellular carcinoma: HepA+, polyclonal CEA+, ubiquitin+ for Mallory bodies, EMA-, LeuM1-, pancytokeratin- (Mod Pathol 2000;13:874)
● Pancreatic endocrine tumors: in von Hippel Lindau patients, they resemble clear cell carcinomas, but also have cords, festoons and gyriform architecture; also chromogranin+, synaptophysin+ (Am J Surg Pathol 2001;25:602)
● Metastases are usually RCCma+ or PAX2+ although this is not specific (Am J Surg Pathol 2008;32:1462)
● Eosinophilic cells: clear cell RCC may have areas with abundant eosinophilic cytoplasm rather than clear, particularly high-grade tumors
● Admixed areas with typical features of clear cell RCC generally support classification of the entire lesion as clear cell carcinoma

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

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