What s New in Adrenal Gland Pathology. Marina Scarpelli

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1 What s New in Adrenal Gland Pathology Marina Scarpelli

2 Background Histological criteria for adrenocortical proliferative lesions Immunohistochemical markers Molecular markers

3 Histological Criteria for Adrenocortical Proliferative Lesions Established The Weiss system (1984) The Weiss system revisited (Aubert et al. 2002) New Diagnostic algorithms: - Blanes et al, Volante et al, 2010

4 The Weiss System 1. High nuclear grade 2. Mitotic rate >5 per 50 HPF 3. Atypical mitotic figures 4. Eosinophilic tumor cell cytoplasm 5. Diffuse architecture 6. Necrosis 7. Venous invasion 8. Sinusoidal invasion 9. Capsular invasion

5 The Weiss System Most specifc criteria for diagnosis Most important predictors of survival Mitotic rate >5 per 50 HPF Atypical mitotic figures Venous invasion Mitotic rate Atypical mitotic figures

6 Modified Weiss Scoring System Mitotic rate (>5 per 50 HPF) [2] Cytoplasm (clear cells 25% or less of the tumor) [2] Abnormal mitoses [1] Necrosis [1] Capsular invasion [1] A score of 3 or greater correlates with subsequent malignant behavior Aubert et al 2002

7 New diagnostic algorithms MF counting was the most important malignancy criterion especially the evaluation of variability.

8 New diagnostic algorithms Lack of a well-preserved reticulin framework 100% sensitive and 96% specific in the identification of malignant lesions

9 Immunohistochemistry Differential Diagnosis Hepatocellular carcinoma Renal cell carcinoma Pheochromocytoma

10 Immunohistochemistry Inhibin A: % Melan-A clone A103: %

11 Sensitivities and specificities of different antibody panels Pan et al. 2005

12 Potential pitfalls Positive CD10 staining either membranous or cytoplasmic or mixed in ACC and ACA (Mete et al, 2010) The use of different antibody clones, antigen retrieval methods, incubation time and concentration and limited tissue samples may cause possible discrepancies

13 Adrenal cortical lesions vs. Pheocromocytoma Routinely used markers Calretinin Chromogranin Inhibin A Melan A Synaptophysin New markers Microtubuleassociated protein 2 (MAP-2) SF-1

14 Adrenal Cortical Lesions vs Pheocromocytoma (Sangoi and McKenney, 2010) Adrenal cortical markers Pheochromocytoma markers

15 Adrenal cortical lesions vs Pheocromocytoma Chromogranin proved to be the most sensitive and specific marker for pheochromocytoma regardless of staining intensity An antibody panel comprised of Chromogranin plus SF-1 and either Calretinin or Inhibin is most effective Sangoi and McKenney, 2010

16 GENETIC OF ACC TP53 mutations Rearrangements, LOH and abnormal imprinting of the 11p15.5 locus (elevated IGF2 mrna expression levels) ACTH-adenylate cyclase pathway WnT pathway (abnormal accumulation of β-catenin)

17 P53 immunohistochemistry The rate of positivity among carcinomas has been highly variable ranging from 5% to 52% Abnormal expression does not appear to have significant prognostic effect Lack of reproducibility makes this marker unuseful for practical use

18 IGF-II Immunohistochemistry 92.5% ACC and 54.7% of adenomas immunoreactive (Erickson et al. 2001) 13 ACC out of 17 immunoreactive and 21 out of 22 adenomas negative (Schmitt et al, 2006) 18 out of 23 ACC positive and 41 ACAs and 15 normal adrenal negative (Soon et al,2009)

19 IGF-II immunohistochemistry Strongly expressed in normal adrenal medulla Not expressed in the cortex

20 IGF-II immunohistochemistry Positive carcinomas exhibit a perinuclear dotlike immunoreactivity Diffuse cytoplasmic staining can occour in adenomas Helpful for the differentiation of benign from malignant adrenocortical tumors

21 Mib1 Immunohistochemistry Levels of Mib1 expression are consistently higher in carcinomas Increased Mib1 immunoreactivity has been significantly associated with shortened disease-free interval and survival

22 Mib1 immunohistochemistry There is no standard accepted threshold value for establishing malignancy A cut-off level of 5% is generally accepted

23

24 Conclusions Criteria proposed by Weiss 25 years ago remains the mainstay for the diagnosis of adrenal cortical carcinoma in the adult population Data generated by molecular genetic techniques have contributed to better characterize adrenal tumors The diagnostic use of these biomarkers awaits further validation

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