Adrenocortical Carcinoma

 

Epidemiology and Etiology:

    • Any age
    • Rare
    • F:M = 2.5:1
    • 40-50y mean age

 

Common sites:

    •  

 

Gross features:

    • large (many >20cm)
    • variegated with areas of necrosis, hemorrhage, and cystic change
      • calcifications (30%)
    • poorly-demarcated
    • invasion of adrenal vein and inferior vena cava is common
    • metastases:
      • liver
      • lymph nodes (retroperitoneal)
      • lung
      • bone
    • majority present as stage IV

 

Histologic features:

    • variable atypia – may be similar appearance to adenoma
    • some composed predominantly of spindle cells
    • lymphatic and venous invasion is common
    • Weiss criteria for malignancy (need 3 or more):
      • Weight >100g
      • Broad fibrous bands
      • Diffuse growth pattern
      • Diffuse tumour necrosis
      • Angioinvasion/perineural invasion
      • Capsular/venous/sinusoidal invasion
      • <25% clear cells
      • 6 mits/50hpf
      • nuclear pleomorphism
    • Modified Weiss criteria for malignancy (need 3 or more):
      • High nuclear grade (Fuhrman
      • Mitoses > 5 / 50HPF
      • Atypical mitotic figures
      • < 25% of tumour cells are clear cells
      • diffuse architecture (>33% of tumour)
      • necrosis
      • venous invasion (smooth muscle in wall)
      • sinusoidal invasion (no smooth muscle in wall)
      • capsular invasion
    • other reported criteria for malignancy
      • MIB-1 index
      • Topoisomerase II alpha index
    • oncocytic variant:
    • myxoid variant:
      • extracellular mucin
      • may have pseudoacinar formations
    • adrenal carcinosarcoma (very rare):
      • mixed features of sarcomas, for example:
        • rhabdomyosarcoma
        • osteogenic differentiation
        • chondroid differentiation
    •  

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 Alpha-Inhibin

 

 Not specific

MART-1 (melan-A)

 

Not specific, also seen in benign adrenal

Steroidogenic factor 1 (SF-1)

 

 More specific?

Chromogranin (neg)

 

Most reliable for distinguishing from adrenal medullary tumours 

synaptophysin

 

 

CK (weak or neg)

Vimentin

Not specific

EMA (neg)

CEA (neg)

MIB-1 (5-20%)

Beta-catenin

~30%, correlates strongly with CTTNB1 mutation

Not specific

CTTNB1 mutation also present in adenomas (but ?more focal staining in adenoma)

 

Molecular features:

    • almost all are sporadic
    • CTTNB1 mutations (~30%)
      • Found in adenomas as well
      • Correlates strongly with strong diffuse Beta-catenin IHC staining (nuclear almost always)
    • hereditary syndromes:
      • Li-Fraumeni syndrome
      • Beckwith-Wiedemann syndrome
    • Ploidy is unhelpful in differentiating from adenoma
    • Common chromosomal imbalances on CGH
      • More alterations than in adenoma in general

 

Other features:

    • EM:
      • Typical steroid-producing cells:
        • Abundant RER and SER
        • Numerous mitochondria
          • Well-developed tubular or lamellar cristae
        • lipid
    • more likely to be functional (80%) than adenomas are
      • glucocorticoids (45%)
      • glucocorticoids and androgens (45%)
      • androgens alone (10%)
      • aldosterone (<1%)
      • oncocytic variant usually non-functioning
    • in pediatric population, large tumour size and age > 3.5cm is poor prognostic
    • poor prognosis (50-70% 5y survival)
      • most important prognostic factors:
        • age
        • stage
      • most important pathological prognostic factors:
        • mitotic rate
          • MIB-1 index
        • tumour size
    • familial associations:
      • Li-Fraumeni syndrome
      • Beckwith-Wiedemann syndrome

 

References:

    • Robbins 2005
    • WHO Tumours of Endocrine Organs (2004)
    • … (adrenocortical genetics papers)