XXXII International Academcy of Pathology Congress King Hussein Bin Talal Convention Centre Amman, Jordan Day 3: Wednesday, October 17 th , 2018 18-SS-4: Contribution of Immunohistochemistry in Diagnostic Pathology Case 4: Brain Tumors Eyas M Hattab, MD, MBA AJ Miller Professor and Chair Department of Pathology and Laboratory Medicine eyas.hattab@louisville.edu
Clinical History 51‐year‐old man with a history of recurrent strokes and a slowly growing suprasellar mass identified on imaging. The patient had the stigmata of Cushing syndrome and required treatment with RU‐486 prior to surgery. The patient underwent endoscopic nasal resection. E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Reticulin E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
IHC E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
IH IHC • + Synaptophysin • + Chromogranin • Anterior pituitary hormones • LMW‐CK/Cam5.2 • MIB1 • ?p53 • ?Pituitary Transcription factors E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
ACTH E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
CAM5.2 E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
p53 E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
MIB1 E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
SF1 TPIT E M H AT TA B , M D , M B A PIT1 L O U I S V I L L E . E D U
Diagnosis? E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Coricotroph adenoma, sparsely granulated E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Role of Transcription Factors in Classification of Pituitary Adenomas What about atypia, mitoses, high proliferation, p53? E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2004 WHO Adenomas: IHC/EM‐based T erminology /Classification PRL‐secreting ACTH‐secreting Densely granulated PRL cell adenoma Densely granulated ACTH cell adenoma Sparsely granulated PRL cell adenoma Sparsely granulated ACTH cell adenoma GH‐secreting TSH‐secreting Densely‐granulated GH cell adenoma TSH cell adenoma Sparsely‐granulated GH cell adenoma Silent GH/PRL‐secreting Silent corticotroph adenoma subtypes 1 Acidophil stem cell adenoma and 2 Mammosomatotroph cell adenoma Silent adenoma subtype 3 Mixed GH/PRL cell adenoma Null cell Gonadotropin‐secretin g Null cell adenoma Gonadotroph cell adenoma Oncocytoma E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2017 WHO Classification of Endocrine Tumors: Paradigm Shift Adenoma classification/terminology largely based on adenohypophyseal cell lineage ( ± pituitary hormones) E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Pituitary Cytogenesis Asa SL and Ezzat S. Annu Rev Pathol Mech Dis. 2009;4:97-126 E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Cell Lineage Adenoma Classification • Follows main adenohypophyseal transcription factors (PIT1, SF1, TPIT) • Refined by pituitary hormones and ultrastructure characteristics • New terminology E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
New Adenoma Terminology • Combines cell lineage AND hormone secretion – Lactotroph adenoma (PRL‐secreting adenoma) • Derived from PIT1 lineage • Secretes prolactin – Gonadotroph adenoma • Derived from SF1 lineage • +/‐ FSH/LH • “Null cell adenomas” staining for SF1 = gonadotroph adenoma E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Adenoma Diagnostic Workup • Most achieved using pituitary hormone IHC • Can be refined by supporting IHCs (CAM5.2) SG somatotroph adenoma Fibrous bodies Acidophil stem cell adenoma LMWCK (CAM5.2) Crooke hyaline change Corticotroph cell differentiation • Transcription factors if necessary – Null cell adenoma – PIT1‐positive pleurihormonal adenoma • EM rarely required E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Adenoma Diagnostic Workup (IHC) Positive Name accordingly Adenoma PIT1‐positive Multiple hormones + PIT1 Anterior Pit hormones, plurihormonal adenoma +/‐ cam5.2 Positive Name accordingly Negative Transcription Factors Negative Null cell adenoma E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Adenoma Diagnostic Workup (IHC) Lactotroph +PRL adenoma Corticotroph +ACTH adenoma Gonadotroph Adenoma +FSH or LH adenoma PRL, GH, ACTH, Somatotroph +GH FSH, LH, TSH adenoma Thyrotroph +TSH adenoma + multiple PIT1, SF1, TPIT hormones Negative PIT1, SF1, TPIT E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2017 WHO: Corticotroph Lineage(TPIT‐positive) Adenomas Adenoma type Immunophenotype Transcription factor and other cofactors Corticotroph adenomas ACTH, CK TPIT Densely granulated adenoma Sparsely granulated adenoma Crooke cell adenoma Silent corticotroph adenomas Lloyd et al (eds). WHO Classifications of Tumours of Endocrine Organs. 2017 E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2017 WHO: “Grading” Changes • 2004 WHO: – Adenoma (typical) – Atypical adenoma – Carcinoma • Diagnostic criteria for atypical adenoma: – Poorly defined – Poorly reproducible – Not predictive of long term behavior E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2004 WHO: Atypical Adenoma • Diagnostic criteria: – Atypical features suggestive of aggressive behavior such as invasive growth – Elevated mitotic index – Ki‐67 labeling index ≥3% – Extensive nuclear p53 immunoreactivity E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Aggressive Adenomas • Clinically defined (deviates from the benign clinical behavior of a typical adenoma) • Definition varies: – A large, invasive, rapidly growing tumor – A tumor with early recurrence despite gross total resection – A tumor resistant to treatment (radiation and/or medical therapy) • “Aggressive” and “invasive” are often used interchangeably E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2017 WHO Recommendations: • “Atypical adenoma” terminology is ABANDONED. • No new classification by tumor grading • Clinically aggressive tumors, evaluate for – Tumor proliferation (mitotic count and Ki‐67 index)‐no specific cutoff – Tumor invasion • No utility for p53 immunostaining on a regular basis • No specific recommendation on how to report • Does not require inclusion of invasion in pathologic reporting – “emphasizes that adenoma invasion should be noted as an important prognostic feature in identifying clinically aggressive adenoma” – ?By MRI studies and/or intra‐operative impression E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
2017 WHO Recommendations: • Recognition of adenomas that have more aggressive behavior regardless of their histological “grading”: – “Special” subtypes – Elevated proliferative activity E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Likelihood of recurrence of pituitary neuroendocrine tumors Low probability High probability for Malignant tumor For recurrence Recurrence Adenoma (typical) Adenoma with elevated Pituitary carcinoma Proliferative activity Special subtypes of Adenomas: • Sparsely granulated Somatotroph adenoma • Acidophilic stem cell Adenoma • Crooke cell adenoma • Silent corticotroph • PIT1‐positive plurihormonal adenoma Lopes MBS. Acta Neuropathol 2017;134:521‐535 E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Coricotroph adenoma, sparsely granulated, with elevated proliferative activity (See Comment) E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
Adenohypophyseal Cell Lineage Classification Transcription factor Lineage Adenoma type PIT1 Acidophilic Lactotroph adenomas Sparsely granulated adenomas Densely granulated adenomas Acidophilic stem cell adenomas Somatotroph adenomas Densely granulated adenomas Sparsely granulated adenomas Mammosomatotroph adenoma Mixed somatolactotroph adenoma Thyrotroph adenomas PIT1‐positive plurihormonal adenoma SF1 Gonadotroph Gonadotroph adenomas TPIT Corticotroph Corticotroph adenomas Crooke cell adenomas Silent corticotroph adenomas Undetermined Null cell adenomas E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
ACTH E M H AT TA B , M D , M B A L O U I S V I L L E . E D U
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U SF1
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U SF1
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U PIT1
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U PIT1
E M H AT TA B , M D , M B A L O U I S V I L L E . E D U PIT1
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