Clear Cell Carcinoma

 

Epidemiology:

    •  50s and 60s
    • M:F 2-3:1
    • Smoking is most significant risk factor

 

Common sites:

    •  

 

Gross features:

    • solitary
    • yellow/gold
    • variegated
      • foci of ischemic, gray-white necrosis
      • foci of hemorrhage
      • areas of softening
    • spherical mass
    • tendency to invade renal vein

 

Histologic features:

    • solid/acinar/trabecular/tubular growth pattern (not papillary)
      • compartmentalized into solid acinar structures by delicate, richly vascularized fibrous septa
      • may have cystic areas
      • may have pseudopapillary or sarcomatoid patterns
    • well-demarcated from adjacent kidney with pushing margin
      • usually no true capsule
    • rich capillary vascular network
    • cells with rounded or polygonal shape
    • abundant clear or pink granular cytoplasm
      • granular cytoplasm contains glycogen and lipids
    • delicate branching vasculature
      • often forms acinar structures
    • Grading:
      • ISUP grade (2013):
        • 1 – nucleoli inconspicuous or absent at 40x
        • 2 – nucleoli clearly visible at 40x but inconspicuous or invisible at 10x
        • 3 – nucleoli prominent and easily visualized at 10x
        • 4 – tumour giant cells and/or marked nuclear pleomorphism with clumping of chromatin, or sarcomatoid differentiation, or rhabdoid differentiation
      • Furhman grade:
        • 1 – nuclei like lymphocytes – small (10 microns), round, uniform, inconspicuous nucleoli
        • 2 – nuclei 15 microns, slightly irregular nuclei, nucleoli only seen at 40x, open chromatin
        • 3 – nuclei 20 microns, very irregular, nucleoli at 10x, open chromatin
        • 4 – bizarre, multilobated, pleomorphic nuclei, macronucleoli, mitoses easily seen
      • Solid (non-acinar), pseudopapillary, and sarcomatoid patterns are more likely to be high grade
        • Spindle cells should be considered evidence of high grade
    • Rhabdoid areas:
      • Presence in any amount bumps grade to 4/4
      • Abundant eosinophilic cytoplasm
      • Large, triangular nucleus pushed to the periphery

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

CAIX

very

 

Brush-border antigens 

 

 

LMWK (CK8, 18, 19, CAM5.2)

 

 

Vimentin

“many”

 

CD10

Most (90%)

 

AMACR

(focal or diffuse cytoplasmic)

70%

 

 

EMA

Majority

 

CD68

most

 

MUC1

Most

 

MUC3

Most

 

PAS + / PASD – (abundant glycogen)

 

 

Hale’s colloidal iron (absent or clumped/droplet-like)

 

 

RCC marker

most

 

PLAP

frequently

 

CEA (neg)

rarely

 

Inhibin (neg)

 

 

CK7 (neg)

Focal cytoplasmic in 25%

 

CK20 (neg)

 

 

HMWK (neg)

Rarely expressed

 

S100 (neg)

rarely

 

AFP (neg)

rarely

 

CD117 (neg

Focal cytoplasmic in 7%

 

 

Molecular features:

    • 98% show loss of sequences on the short arm of chromosome 3 (3p13)
      • Simple interstitial or terminal deletions
      • Unbalanced translocations
        • Der(3)t(3;5)(p11-22;q13-31) is most frequent
        • Loss of 3pter-3q12 or 3pter-3q21 with a concurrent translocation of the remaining 3q segment to other chromosomes
      • 3 target areas particularly frequently lost:
        • 3p14
          • FHIT
        • 3p21
          • RASSF1A
            • Silenced by hypermethylation in 90% of primary clear cell RCC
          • DRR1 (3p21.1)
        • 3p25
          • VHL (Von Hippel-Lindau) gene inactivation (tumour suppressor gene RAF-1)
          • Resulting high levels of HIF-1 (hypoxia-inducible factor-1)
          • Resulting high levels of VEGF, TGF-Beta-1, and IGF-1
    • Gain of 5q31-qter show better prognosis
      • Der(3)t(3;5) as above usually
    • OGG1 mutations (3p26.2)
    • Other non-random abnormalities:
      • Monosomy 8, 9 (distant mets and poor outcome), 13, 14
      • Trisomy 12, 20
      • Structural abnormalities of 5q, 6q, 8p, 9p (distant mets and poor outcome with loss), 10q, 14q (poor outcome, higher grade and stage)
        • May be related to tumour progression
    • Familial:
      • Von-Hippel-Lindau (VHL) syndrome
      • Hereditary clear cell carcinoma (same gene as VHL)

 

Other features:

    •  Paraneoplastic syndromes:
      • polycythemia
      • hypercalcemia
      • hypertension
      • Cushing’s syndrome
      • Sex hormonal imbalance (feminization, gynecomastia, masculinization)

 

References:

    • Robbins 2005
    • Sternberg 2004
    • Essentials of AP 2006
    • Zhou M, Magi-Galluzzi C.  Genitourinary Pathology: a volume in the series Foundations in Diagnostic Pathology.  2007
    • Am J Surg Pathol Volume 35, Number 7, July 2011
    • Delahunt B et al.  The International Society of Urological Pathology (ISUP) Grading System for Renal Cell Carcinoma and other prognostic parameters.  Am J Surg Pathol 2013;37:1490-1504.