Practical Procedures for Problematic Parathyroids …/99th/pdf/companion03h05.pdf · Dr. S.L. Asa Pituitary and Parathyroid Pathology 1 Practical Procedures for Problematic Parathyroids

Dr. S.L. Asa Pituitary and Parathyroid Pathology

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Practical Procedures Practical Procedures for Problematic for Problematic

Parathyroids and Pituitaries Parathyroids and Pituitaries Sylvia L. Asa, M.D., Ph.D.

Pathologist-in-Chief and Medical Director, Laboratory Medicine ProgramUniversity Health Network

Senior Scientist, Ontario Cancer Institute

Professor, Department of Laboratory Medicine and Pathobiology University of Toronto

Pituitary ProblemsPituitary Problems

The autopsy pituitary: Grossing and handling

The surgical specimen: Pituitary or not?If pituitary, hyperplasia or adenoma?If adenoma, what kind?What is this inflammation all about?

S

T

TPL

ALACTH

GH

PRL

PL

AL

The Autopsy PituitaryThe Autopsy Pituitary


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Pitfalls in Autopsy PituitariesPitfalls in Autopsy Pituitaries

Infarcts and fibrosisBasophil invasion of the posterior lobeCrooke’s hyaline changeHypophysitisTumorsTumorsTumors

The Surgical Biopsy:The Surgical Biopsy:Is This PituitaryIs This Pituitary??

Pituitary adenomas (or very rare carcinoma)Craniopharyngiomas, cystsOther CNS lesions» neuronal tumors, paraganglioma, pituicytoma, glioma,

meningioma, schwannomaVascular and mesenchymal tumors» spindle cell oncocytoma, granular cell tumors, chordomas

Lymphomas, leukemias, histiocytoses, germ cell tumorsMetastatic

What Is This CystWhat Is This Cyst??

Rathke cleft cyst vs CraniopharyngiomaArachnoid Cyst Dermoid vs Epidermoid


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This is Pituitary; Now WhatThis is Pituitary; Now What??

Make sure you don’t miss hyperplasia:

Do a Retic stain!

Pituitary Hyperplasia: ReticulinPituitary Hyperplasia: Reticulin

Hyperplasia Adenoma

It Is Adenoma It Is Adenoma –– Is That EnoughIs That Enough??

NO!But what now?


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Prognostic Markers in Prognostic Markers in Pituitary TumorsPituitary Tumors

Best is still tumor typeBest is still tumor typeClinicopathologic features – size, invasionOthers suggested:» MIB-1 (<5%, 5-15%, >15%)» PTTG (same idea as MIB-1)» p27 (lost in corticotroph adenomas)» p53 (no proven value)

Pituitary Tumor ClassificationPituitary Tumor Classification

Silent subtype 3Null cell, oncocytoma

PlurihormonalUnclassified

Silent gonadotrophGonadotropin Excess

Gonadotroph

Silent thyrotrophTSH excess

Thyrotroph

Silent lactotrophPRL excess

LactotrophAcidophil stem cell

Silent somatotroph

GH excessDG/SG somatotrophMammosomatotroph

Silent corticotrophACTH excess

Corticotroph adenoma

SilentFunctioning

Immunohistochemical ClassificationImmunohistochemical Classificationof Pituitary Adenomasof Pituitary Adenomas

Major ComponentGH-PRL-TSH» GH

» SG, DG

» GH/PRL» PRL» TSH

ACTHGonadotropinUnclassified

Other ReactivityPit-1» α-subunit

» Keratins

» α-subunit, ER» ER» α-subunit

TpitSF-1???


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Pitfalls in CushingPitfalls in Cushing’’s Diseases Disease

Usual finding: basophil microadenomaProblem 1: Large chromophobe adenomaProblem 2: No adenomaProblem 3: Crooke’s cell adenoma

Sparsely Granulated Corticotroph AdenomaSparsely Granulated Corticotroph AdenomaPAS

ACTH

CushingCushing’’s Diseases Disease::The Case of the Missing AdenomaThe Case of the Missing Adenoma

Cushing’s vs Pseudo-Cushing’s» Crooke’s hyaline change


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Cytology of Cytology of ““NormalNormal”” GlandGlandPAS

ACTH and Cam 5.2ACTH and Cam 5.2ACTH

Cam 5.2

CrookesCrookes’’ Cell AdenomaCell Adenoma

Keratin accumulation in cytoplasm


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AcromegalyAcromegaly--Gigantism (Gigantism (↑↑ GH):GH):Differential DiagnosisDifferential Diagnosis

Adenoma vs hyperplasiaSomatotroph vs Mammosomatotroph adenomaDensely vs Sparsely granulated adenomaGangliocytoma

Somatotroph HyperplasiaSomatotroph Hyperplasia

H&E Reticulin GH

Ectopic GRH in Endocrine TumorsEctopic GRH in Endocrine Tumors

H&E GRH


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AcromegalyAcromegaly--Gigantism (Gigantism (↑↑ GH);GH);Pituitary AdenomasPituitary Adenomas

Somatotroph vs MammosomatotrophDensely vs Sparsely granulated (keratin)

H&E Cam 5.2 H&E Cam 5.2

Sellar Gangliocytoma with Sellar Gangliocytoma with Pituitary AdenomaPituitary Adenoma

H&E GHRH GH

Prognostic and Therapeutic Prognostic and Therapeutic Considerations in AcromegalyConsiderations in Acromegaly

Hyperplasia» look for source of GHRH excess

Densely granulated somatotroph adenoma» likely responsive to somatostatin analogue therapy

Sparsely granulated somatotroph adenoma» may be due to altered GH autoregulation» may be candidates for GH antagonist therpay

Mammosomatotroph adenoma» possible response to dopaminergic agents


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Pitfalls in HyperprolactinemiaPitfalls in Hyperprolactinemia

Adenoma vs Other TumorAdenoma vs HyperplasiaAdenoma vs Lymphocytic HypophysitisSparsely Granulated vs Densely GranulatedAcidophil Stem Cell Adenoma

Inflammatory Lesions of the Inflammatory Lesions of the Pituitary: HypophysitisPituitary: Hypophysitis

Lymphocytic hypophysitisGranulomatous hypophysitisXanthomatous hypophysitisInfundibulo-neurohypophysitisSecondary hypophysitis

Lymphocytic Hypophysitis: HistologyLymphocytic Hypophysitis: Histology


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Granulomatous HypophysitisGranulomatous Hypophysitis

Xanthomatous HypophysitisXanthomatous HypophysitisThe least common form of primary hypophysitisResembles xanthomatous inflammatory processes elsewhere, such as xanthomatous cholecystitis, endometritis or pyelonephritisCystic on radiologic or surgical evaluationMay be a response to ruptured cyst???

InfundibuloInfundibulo--NeurohypophysitisNeurohypophysitis

RarePresent with isolated diabetes insipidusLocalized enlargement of posterior lobe/stalkLymphoplasmacytic infiltrate resembling LH? Autoimmune disorder


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Pitfalls in TSH HypersecretionPitfalls in TSH Hypersecretion

Thyrotroph hyperplasia

Pituitary TSH ExcessPituitary TSH Excess

HyperplasiaH&E» large chromophobic

“thyroidectomy cells”» interspersed acidophils

and basophilsPAS» positive globules

Reticulin stain» acini intact, enlarged

AdenomaH&E » monotonous population of

elongated chromophobes» marked nuclear atypia» nil else

PAS» positive globules

Reticulin stain» acini disrupted

Histology: Thyrotroph HyperplasiaHistology: Thyrotroph Hyperplasia

H&E PAS Reticulin


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The Role of the PathologistThe Role of the Pathologistin the Management of Patients in the Management of Patients with Pituitary Pathologywith Pituitary Pathology

To ensure correct diagnosisTo guide correct managementTo be responsible for ongoing investigations to determine pathogenesis and future therapies

ReferencesReferencesAsa SL: Tumors of the Pituitary Gland. Fascicle 22, Third Series, in The Atlas of Tumor Pathology, Armed Forces Institute of Pathology, Washington DC, 1998.(Fourth series in press)ASA SL: Practical Pituitary Pathology: What Does the Pathologist Need to Know? Arch Pathol Lab Med 2008;132:1231-1240 ASA SL, EZZAT S: The pathogenesis of pituitary adenomas. Nature Reviews Cancer 2002; 2:836-49.ASA SL, EZZAT S: The pathogenesis of pituitary tumors. Annu Rev Pathol 2009;4:97-126..


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Parathyroid ProblemsParathyroid Problems

Parathyroid or not?If parathyroid, hyperplasia or adenoma?What about carcinoma?

The The ““OldOld”” Approach to Approach to Parathyroid SurgeryParathyroid Surgery

Identify all parathyroid glandsRemove dominant pathologyBiopsy all other glands

→Put the onus on the Pathologist to make the diagnosis of hyperplasia vs adenoma» often wrong or impossible!

The The ““NewNew”” Approach to Approach to Parathyroid SurgeryParathyroid Surgery

Radioguided surgery identifies the dominant glandLimited approach traumatizes only that glandIntraoperative PTH measurement confirms resection of culprit lesion

→ Pathologist only needs to confirm that abnormal (cellular) parathyroid tissue was resected


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Parathyroid Parathyroid vsvs Thyroid on FNAThyroid on FNA

Parathyroid has delicate vascular patterns, small cell size and numerous, disperse, stripped nucleiParathyroid CAN have intranuclear inclusionsIHC can be applied to FNA samplesCyst fluid can be tested for PTH to distinguish a parathyroid cyst from a cystic thyroid lesion

Parathyroid Identification at Parathyroid Identification at Intraoperative ConsultationIntraoperative Consultation

PTH vs Thyroid vs Lymph node or ThymusSmaller follicles than thyroidClear cells usually PTH» Fat stains can help

» NB intracytoplasmic fat

Hassal corpuscles

Sometimes impossible

IHC: Thyroid vs Parathyroid TumorIHC: Thyroid vs Parathyroid Tumor

Chromogranin +Parathyroid hormone +

TTF-1 negative


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Hyperplasia Hyperplasia vsvs AdenomaAdenomaHyperplasia» multiple (>1) glands» poorly encapsulated» diffuse or nodular» comparable areas in

adjacent glands» all 3 cell types» mitoses but little

pleomorphism

Neoplasia» solitary» encapsulated» nodule » adjacent normal gland

no hypercellularity» chief cells predominate» nuclear pleomorphism

WrongDoesn’t matter

Primary Hyperparathyroidism:Primary Hyperparathyroidism:AdenomaAdenoma

Primary Hyperparathyroidism:Primary Hyperparathyroidism:AdenomaAdenoma


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Criteria of MalignancyCriteria of Malignancyin Parathyroid Tumorsin Parathyroid Tumors

Large lesion (> 1g)Infiltrative (but so is hyperplasia!)Atypia, mitoses, calcification, necrosis and fibrous bands (none definitive)Vascular invasionMetastases

Worrisome Histologic Alterations Worrisome Histologic Alterations Following FNA of Parathyroid *Following FNA of Parathyroid *

InfiltrativeAtypia, mitoses, calcification, necrosis and fibrous bands Following FNA for cytologic diagnosis of mass, aspiration for PTH measurement, or ethanol ablation of known PTH tumor

* Based on WHAFFT, credit to Dr. V. A. LiVolsi

Atypia and Mitoses in Atypia and Mitoses in Parathyroid LesionsParathyroid Lesions

Carcinoma

Hyperplasia


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Necrosis and CalcificationNecrosis and Calcification

WorrisomeMore common in carcinoma

Not diagnostic alone

Fibrosis:Fibrosis:HyperplasiaHyperplasiavs Carcinomavs Carcinomavsvs PostPost--FNAFNA

Criteria of Malignancy:Criteria of Malignancy:InfiltrationInfiltration

Infiltration through capsule in a proven neoplasmAlso seen in hyperplasia →


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Local Invasion vs Local Invasion vs Intrathyroidal ParathyroidIntrathyroidal Parathyroid

Intrathyroidal parathyroids are common

Can mimic thyroid invasion by carcinoma

Vascular Invasion: Unequivocal Vascular Invasion: Unequivocal Evidence of MalignancyEvidence of Malignancy

Parathyroid Carcinoma:Parathyroid Carcinoma:Metastases Metastases

Lymph nodesBoneLungsAdrenals


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Ancillary Tests for Borderline CasesAncillary Tests for Borderline Cases

Parafibromin loss

ImmunostainsImmunostains

Negative Rb ↓

High MIB-1 ↑p53 positivity

ReferencesReferences

DeLellis RA: Tumors of the Parathyroid Gland. Fascicle 6, Third Series, in The Atlas of Tumor Pathology, Armed Forces Institute of Pathology, Washington DC, 1993 Apel RL and Asa SL: The parathyroid glands. In Endocrine Pathology, LiVolsi VA and Asa SL (eds), Philadelphia, Churchill Livingstone, 2002, pp. 103-147DeLellis RA, Lloyd RV, Heitz PU, and Eng C: Pathology and Genetics of Tumours of Endocrine Organs. Lyons, France IARC Press, 2004

Documents

Practical Procedures for Problematic Parathyroids …/99th/pdf/companion03h05.pdf · Dr. S.L. Asa Pituitary and Parathyroid Pathology 1 Practical Procedures for Problematic Parathyroids