immunohistochemistry for carcinoma of … for carcinoma of unknown primary jason l hornick, md, ......

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IMMUNOHISTOCHEMISTRY FOR CARCINOMA OF UNKNOWN

PRIMARY

Jason L Hornick, MD, PhD

Director of Surgical Pathology Director of Immunohistochemistry

Brigham and Women’s Hospital

Associate Professor of Pathology Harvard Medical School

Boston, MA, USA

Carcinoma of unknown primary

Definition: histologically confirmed metastatic carcinoma for which primary site cannot be identified after standard diagnostic approach:

• Detailed history and physical examination

• Blood counts and biochemical analysis

• Urinalysis and stool occult blood test

• CT of thorax, abdomen, and pelvis

• Histologic review including IHC

Carcinoma of unknown primary

• Account for 2-5% of malignancies diagnosed in the US

• 7th or 8th most frequent cancer

• 4th or 5th most common cause of cancer death in both sexes

• 31,000 new cases in the US in 2012 – down from 45,000 new cases in 1995

• Improved radiologic imaging

• Increasingly specific IHC markers

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Origin of primary tumors (autopsy)

Organ Incidence

Pancreas 20-25%

Lung 15-20%

Colon/rectum 5-10%

Liver/biliary 5-10%

Stomach 5%

Kidney 5%

Ovary <5%

Prostate <5%

Breast 2%

Other 1%

Histologic groups of carcinoma of unknown primary

Histology Frequency

Well or moderately differentiated

adenocarcinoma 60%

Poorly differentiated adenocarcinoma

or undifferentiated carcinoma 30%

Squamous cell carcinoma 5%

Undifferentiated malignant neoplasm 5%

Overview

• Distribution of keratin family members in carcinomas

• Lineage-restricted markers and primary site determination

• Primary tumors of the liver and mimics

• Squamous cell carcinomas

• Primary site determination for metastatic neuroendocrine tumors

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Keratin family members in carcinomas

• Low-molecular-weight keratins (CK8, CK18, CAM5.2) – Glandular epithelium, hepatocytes

• High-molecular-weight keratins (CK5, CK14, 34βE12) – Squamous epithelium, urothelium,

basal cells

Keratin family members in carcinomas: CK7 and CK20

• CK7 wide distribution in epithelial cells

• CK20 restricted to lower GI tract epithelium, umbrella cells of the urinary bladder, Merkel cells

CK7 and CK20 – are they (still) useful?

Phenotype Primary sites

CK7– / CK20+ Colon/rectum

CK7+ / CK20+ Bladder, upper GI, pancreas

CK7– / CK20– Uncommon (prostate, HCC)

CK7+ / CK20– Nearly everything else

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CK20

Metastatic colonic adenocarcinoma

CK7


CK20


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Primary site Marker

Bladder Uroplakin

Breast GCDFP-15

(prolactin-inducible protein)

Breast Mammaglobin

(SCGB2A1/A2)

Colon/rectum Villin

Lung Napsin A

Prostate Prostate-specific antigen

Prostate Prostatic acid phosphatase

Thyroid Thyroglobulin

IHC for lineage/site specification: cytoplasmic/membranous markers

IHC for lineage/site specification: cytoplasmic/membranous markers

• In general, expression is decreased (or entirely absent) with poor differentiation – significant impact on sensitivity

GCDFP

Breast carcinoma

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Breast carcinoma

GCDFP

mammaglobin

Breast carcinoma

Expression of mammaglobin in other tumor types

Tumor type Frequency

Endometrial endometrioid

adenocarcinoma 20-40%

Skin adnexal carcinomas 20-40%

Salivary gland neoplasms 20-50%

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PSA

Prostatic adenocarcinoma

Napsin A

Lung adenocarcinoma

Napsin A

• Warning: napsin A is also positive in most papillary renal cell carcinomas

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IHC for lineage/site specification: nuclear transcription factors

• Insights gained from developmental and cell biology research

• Transcription factors involved in patterning of organ systems, lineage commitment

• Some are highly specific for particular cell type or visceral organ

• Others show expression limited to several tissue types

• Very helpful in determining primary site for CUP

• 10 years ago, very few were used in surgical pathology practice

–TTF1, CDX2, MYOG

• In 2016, over 50 markers with potential diagnostic applications are available

–Carcinomas, lymphomas, melanoma, germ cell tumors, sarcomas



Transcription factor Primary site

CDX2 Colon/rectum, upper GI

GATA3 Breast, bladder

NKX3-1 Prostate

OCT4 Seminoma, embryonal carcinoma

PAX8 Thyroid, kidney, Müllerian

SALL4 Germ cell tumors

SATB2 Colon/rectum

SF1 Adrenal cortex

TTF1 (NKX2-1) Lung, thyroid

WT1 Müllerian, mesothelioma

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• In general, even poorly differentiated carcinomas maintain (relatively) diffuse expression in most cases – high sensitivity

• With increasing study, specificity decreases

• Beware of relying on a single diagnostic marker

TTF1 (NKX2-1)

• Lineage-specific transcription factor long history of use in diagnostic IHC

• Originally named for role in activating transcription from thyroglobulin promoter

• Expressed in normal and neoplastic thyroid follicular cells

• Most widely used application: ascribing lung origin to primary and metastatic adenocarcinomas (and supporting adenocarcinoma over squamous cell carcinoma in poorly differentiated NSCLCA)

TTF1

Lung adenocarcinoma

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Metastatic poorly differentiated lung adenocarcinoma

TTF1

Poorly differentiated (insular) thyroid carcinoma

TTF1

TTF1

• Warning: TTF1 is also positive in a subset of endometrial adenocarcinomas (most common in grade 3 endometrioid and serous)

• Some variation in sensitivity and specificity based on particular clone

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Primary site Positive cases

Pulmonary (adenocarcinoma) 70-90%

Pulmonary (squamous cell carcinoma) <10%

Thyroid (all types) 80-100%

Cholangiocarcinoma (extrahepatic) 5-25%*

Endometrial 5-20%*

Ovarian 5-30%*

Expression of TTF1 in carcinomas I

*These cases usually show expression in only a small fraction of

tumor cells.


Gastric/esophageal <10%

Cervical <5%

Pancreatic <5%

Breast <5%

Urothelial <5%

Colorectal <5%

Hepatocellular <5%

Salivary gland (adenoid cystic) 30-50%

Salivary gland (other) <5%

Adrenal cortical <5%

Expression of TTF1 in carcinomas II

TTF1: potential diagnostic pitfall

• Cytoplasmic staining relatively common

• Diffuse staining in normal hepatocytes and many hepatocellular carcinomas

• Likely represents cross-reactivity with CPS1 (antigen recognized by HepPar-1 antibody)

• Subset of adenocarcinomas from various sites (especially foregut) also show cytoplasmic staining

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Hepatocellular carcinoma

TTF1

WT1

• Wilms tumor 1

• Transcription factor plays diverse roles in cancer depending upon tumor type and biological context

• Expressed in malignant mesothelioma, serous carcinoma

• Positive in nearly all serous carcinomas of the ovary; uncommon in serous carcinomas of the endometrium (variable results in different studies)

WT1

Malignant mesothelioma

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Metastatic mesothelioma

WT1

Metastatic serous carcinoma

WT1

WT1

• Among carcinomas, nuclear WT1 relatively specific for ovarian serous tumors

• Positive in <5% of breast, lung, gastric, colorectal, urothelial carcinomas

• Cytoplasmic staining detected in subset of other carcinomas and various other tumor types – only nuclear staining should be considered positive for ascribing site of origin

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CDX2

• Caudal-type homeobox transcription factor involved in intestinal differentiation

• Nuclear expression in >90% colorectal adenocarcinomas

• Somewhat lower sensitivity in high grade and MSI-H carcinomas

• Widely used to support colorectal origin

• No significant loss of sensitivity in the metastatic setting

CDX2

Colonic adenocarcinoma


CDX2

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CDX2

• Also expressed in carcinomas from other gastrointestinal primary sites associated with intestinal differentiation – Esophagus and stomach

– Pancreas and biliary tree

• Often more heterogeneous staining in tumors from these other sites

• Particularly helpful in differential diagnosis between primary (poorly cohesive) gastric carcinoma and metastatic breast carcinoma

Gastric adenocarcinoma

CDX2

CDX2

• Warning: CDX2 can also be positive in mucinous adenocarcinomas from diverse anatomic sites

–Ovary

–Lung

–Pancreas

–Bladder

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Colorectal and appendiceal 80-100%

Gastroesophageal 40-60%

Pancreatic/biliary 30-50%

Ovarian (mucinous and endometrioid) 40-60%

Ovarian (serous) <10%

Endometrial 5-10%

Pulmonary (mucinous) 70-80%

Pulmonary (non-mucinous) <5%

Bladder (adenocarcinoma) 30-50%

Bladder (urothelial) <5%

Prostatic <5%

Breast <5%

Renal <5%

Expression of CDX2 in carcinomas

GATA3

• Transcription factor originally recognized for role in T-cell function

• Clinically useful as marker for breast or urothelial origin

• Positive in >80% of breast and urothelial carcinomas

• No significant loss of sensitivity in the metastatic setting

• More recent large surveys revealed expression in wide range of tumor types

GATA3

Bladder urothelial carcinoma

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Bladder urothelial carcinoma

GATA3

Breast carcinoma

GATA3

Breast carcinoma

GATA3

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Expression of GATA3 in other tumors

Tumor type Frequency

Squamous cell carcinoma (skin) 80%

Squamous cell carcinoma (cervix) 33%

Squamous cell carcinoma (lung) 10%

Lung adenocarcinoma 5-10%

Skin adnexal carcinomas 80-100%

Mesothelioma 25-60%

Salivary gland tumors 20-50%

Pancreatic ductal adenocarcinoma 40%

Paraganglioma 80%

Choriocarcinoma 100%

Chromophobe renal cell carcinoma 50%

Potential value of GATA3 in differential diagnosis

Positive Negative

Metastatic lobular breast carcinoma Gastric signet-ring-cell carcinoma

Metastatic ductal breast carcinoma Lung/GI/ovarian adenocarcinoma

Urothelial carcinoma Prostatic adenocarcinoma

Squamous cell carcinoma of skin Squamous cell carcinoma of lung

Malignant mesothelioma Lung adenocarcinoma

Paraganglioma Other neuroendocrine tumors

Choriocarcinoma, yolk sac tumor Embryonal carcinoma, seminoma

Am J Surg Pathol. 38:13-22, 2014

NKX3-1

• Homeobox transcription factor, androgen-dependent

• Expression limited to prostate

• Usually more diffusely positive than conventional cytoplasmic markers

• Helpful to distinguish high grade prostatic adenocarcinoma from urothelial carcinoma

• Helpful to suggest prostatic origin in metastatic carcinoma

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NKX3-1

Prostatic adenocarcinoma

Expression of NKX3-1 in carcinomas


Prostatic 90-100%

Breast (lobular) 15-30%

Breast (ductal) <10%

Bladder (urothelial and adenocarcinoma) <5%

Pancreatic/biliary <5%

Hepatocellular <5%

Renal <5%

Colorectal <5%

Gastroesophageal <5%

Pulmonary <5%

Thyroid <5%

SATB2

• More recently described transcription factor expressed in colorectal/appendiceal epithelium

• Similarly high sensitivity and likely higher specificity than CDX2

• Positive in 80-90% of primary and metastatic colorectal adenocarcinomas

• Higher sensitivity than CDX2 for medullary carcinomas

• Unlike CDX2, SATB2 rarely expressed in gastroesophageal and pancreaticobiliary adenocarcinomas

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SATB2

Colonic adenocarcinoma

Poorly differentiated colonic adenocarcinoma

SATB2


Colorectal and appendiceal 80-100%

Renal 25-35%

Gastroesophageal 10-20%*

Pancreatic/biliary 10-20%*

Mullerian 10-20%*

Pulmonary 10-20%*

Bladder (urothelial) 10-20%*

Prostatic 5-15%*

Breast 5-15%*

Thyroid <5%*

Expression of SATB2 in carcinomas

*These cases show expression in only a small fraction of tumor cells.

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PAX8

• One of the most widely used lineage-specific transcription factors in IHC approach to CUP

• Highly sensitive for carcinomas originating in ovary, kidney, thyroid

• >90% serous, endometrioid, and clear cell ovarian carcinomas positive for PAX8

• Much lower rate of expression in ovarian mucinous adenocarcinomas

• PAX2 largely supplanted by PAX8


Renal 85-95%

Thyroid (papillary, follicular, poorly diff) 90-100%

Thyroid (anaplastic, medullary) 60-80%

Ovarian (non-mucinous) 90-100%

Ovarian (mucinous) 10-40%

Endometrial 90-100%

Cervical 90-100%

Expression of PAX8 in carcinomas I

Renal cell carcinoma

PAX8

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Ovarian clear cell carcinoma

PAX8


PAX8

PAX8


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TTF1


Papillary thyroid carcinoma

PAX8

TTF1

Poorly differentiated thyroid carcinoma

PAX8

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Metastatic lung adenocarcinoma

TTF1

PAX8

Pan-PAX?

• Widely used polyclonal anti-PAX8 antibody not specific for PAX8

• Cross-reacts with other PAX family members (PAX5, PAX6, PAX3)

• Responsible for staining in B lymphocytes (PAX5)

• Responsible for staining in pancreatic well-differentiated neuroendocrine tumors (PAX6)

• PAX8-specific monoclonal antibodies available

PAX6

PAX5

PAX8

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Thymic (polyclonal antibody) 80-90%

Pancreatic/biliary 5-10%

Bladder (urothelial) 10-20%

Gastric/esophageal 5-10%

Colorectal/appendiceal <5%

Hepatocellular <5%

Breast <5%

Pulmonary (adenocarcinoma) <5%

Pulmonary (squamous cell carcinoma) 0-30%

Head and neck (squamous cell

carcinoma) <5%

Adrenal cortical <5%

Skin (squamous cell carcinoma) <5%

Expression of PAX8 in carcinomas II

SF1

• Steroidogenic factor 1 (NR5A1)

• Recently investigated transcription factor

• Highly sensitive marker for sex cord-stromal tumor

• Highly sensitive marker for adrenal cortical carcinoma

• Particularly useful in distinguishing primary adrenal cortical carcinoma from metastatic renal cell carcinoma

SF1

Adrenal cortical carcinoma

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ER and PR

• In addition to role as predictive biomarkers in breast cancer, can be useful to ascribe primary site in certain contexts

• Hormone receptor-positive breast carcinomas retain expression in metastatic foci in >90% of cases

• Most useful in patients with known history of hormone receptor-positive breast cancer and other known or suspected malignancies

ER and PR

• Also commonly expressed in primary carcinomas of gynecologic tract

• Most ovarian serous carcinomas express ER

• Can be helpful to distinguish serous from clear cell carcinoma

ER and PR

• ER consistently negative in colorectal, gastroesophageal, hepatocellular, pancreatic/biliary carcinomas

• ER positive (generally weak/focal) in small subset of lung adenocarcinomas

• PR less specific: positive in 30% of cholangiocarcinomas; positive in small subset of gastroesophageal, pancreatic, hepatocellular carcinomas

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Embryonic stem cell transcription factors

• Transcription factors involved in maintenance of pluripotency

• Large body of literature on role in embryonic stem cell biology

• Some of these transcription factors useful in diagnostic IHC

• OCT4 (also known as OCT3/4) widely used in clinical practice

• Other markers less often used

Subtype SALL4 OCT4 NANOG SOX2

Seminoma ++++ ++++ ++++ –

Embryonal carcinoma ++++ ++++ ++++ ++++

Yolk sac tumor ++++ – – –

Teratoma – – – ++

Choriocarcinoma variable – – –

Expression of embryonic stem cell transcription factors in germ cell tumors

OCT4

Seminoma

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Don’t forget to consider a primary liver tumor!

Hepatocellular carcinoma • Alpha fetoprotein (AFP)

– Low sensitivity

• Polyclonal carcinoembryonic antigen (CEA)

– Bile canalicular pattern

• Carbamoyl-phosphate synthase 1 (CPS1) = Hep-Par 1 antibody – Urea cycle enzyme

– Also expressed in 5-10% of adenocarcinomas of diverse sites

• Arginase 1 (ARG1) – Urea cycle enzyme

– Appears to be most sensitive and specific

pCEA


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CPS1/Hep-Par1


ARG1


Potential mimics of HCC

• Adrenal cortical carcinoma – Inhibin

– Melan-A/MART1 (MLANA) – A103 >> M2-7C10

– SF1 (steroidogenic factor 1; NR5A1)

• Renal cell carcinoma – RCC (renal cell carcinoma marker) – low

sensitivity in the metastatic setting

– PAX2 – less sensitive than PAX8

– PAX8 – highly sensitive marker, also positive in thyroid and Müllerian carcinomas

• Poorly differentiated cholangiocarcinoma

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RCC

Metastatic renal cell carcinoma

Metastatic renal cell carcinoma

PAX8

Intrahepatic cholangiocarcinoma

• Radiologic features: – Large solitary mass +/- satellite lesions – Biliary dilatation – Hepatic capsular retraction – Delayed enhancement – Lobar/segmental atrophy

• Histology/immunophenotype essentially indistinguishable from pancreatic ductal adenocarcinoma – CK7/CK19 positive – Loss of SMAD4 (~50%)

• When you encounter a CK7+ AdCA in the liver, consider cholangiocarcinoma

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Biliary dilatation Capsular retraction

Satellite


Capsular retraction Satellite


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Pancreatic ductal carcinoma

SMAD4

Metastatic cholangiocarcinoma

SMAD4

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Squamous cell carcinoma: P63 and P40

• Confirmation relatively straightforward – P63 (also positive in urothelial and subset of

adenocarcinomas; ~20% lung AdCA)

– P40 (much more specific for squamous cell and urothelial carcinomas)

• In general, IHC not helpful to determine primary site (other than P16: HPV-associated SCC of oropharynx, cervix, anal canal)

• In situ hybridization can be helpful (head and neck): – EBER – nasopharyngeal carcinoma

– High-risk HPV – oropharyngeal carcinomas (tonsil, base of tongue)

Lung squamous cell carcinoma

P40

Metastatic HPV-associated squamous cell carcinoma

P16

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Well-differentiated neuroendocrine tumors

• 10-20% of NET present as metastasis of unknown primary

• Midgut (ileum) >> pancreas >> other

• Determination of primary site increasingly important for well-differentiated NET

• Recent introduction of effective systemic therapies

• Different efficacies for midgut vs pancreatic origin

Systemic therapy for metastatic well-differentiated neuroendocrine tumors

Agent Mechanism Efficacy

Midgut Pancreas

Octreotide Somatostatin analogue + +

Interferon-α Immune activation + +

Streptozocin Alkylating agent ̶ +

Temozolomide Alkylating agent ̶ +

Everolimus mTOR inhibitor +/ ̶ +

Sunitinib Tyrosine kinase inhibitor ̶ +

Bellizzi Adv Anat Pathol 2013

Transcription factor expression in well-differentiated neuroendocrine tumors

Transcription factor Primary sites

CDX2 Midgut (ileum), appendix >> pancreas

ISL1 Pancreas

PAX6 (pPAX8) Pancreas, duodenum, rectum

PDX1 Pancreas, duodenum

TTF1 Lung

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Transcription factor expression in well-differentiated neuroendocrine tumors

Transcription factor Primary sites

CDX2 Midgut (ileum), appendix >> pancreas

ISL1 Pancreas

PAX6 (pPAX8) Pancreas, duodenum, rectum

PDX1 Pancreas, duodenum

TTF1 Lung

CDX2 expression in well-differentiated neuroendocrine tumors

Primary site Positive

Lung <5%

Stomach 15-30%

Duodenum 30-45%

Pancreas 15-20%

Jejunum/ileum 90%

Appendix 90%

Rectum 0-30%

CDX2 expression in well-differentiated neuroendocrine tumors


Lung <5%

Stomach 15-30%

Duodenum 30-45%

Pancreas 15-20%

Jejunum/ileum 90%

Appendix 90%

Rectum 0-30%

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Metastatic well-differentiated neuroendocrine tumor from ileum

CDX2


CDX2

Metastatic well-differentiated neuroendocrine tumor from pancreas

CDX2

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TTF1 expression in well-differentiated neuroendocrine tumors


Lung 30-70%

Stomach <5%

Duodenum <5%

Pancreas <5%

Jejunum/ileum <5%

Appendix <5%

Rectum <5%

Lung carcinoid tumor

TTF1

PAX6 expression in well-differentiated neuroendocrine tumors


Lung 0-10%

Stomach 15%

Duodenum 80%

Pancreas 55-70%

Jejunum/ileum 0%

Appendix 15%

Rectum 60%

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PAX6 expression in well-differentiated neuroendocrine tumors


Lung 0-10%

Stomach 15%

Duodenum 80%

Pancreas 55-70%

Jejunum/ileum 0%

Appendix 15%

Rectum 60%

PAX6

PAX5

PAX8

Polyclonal PAX8 antibody

Pancreatic well-differentiated neuroendocrine tumor

pPAX8

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pPAX8


PAX6

Papillary thyroid carcinoma

PAX6

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Lymph node

PAX6

PDX1

• Pancreatic and duodenal homeobox transcription factor

• Also known as insulin promoter factor 1

• Necessary for pancreatic development

• Plays role in maturation of islet cells that secrete insulin (β-cells) and somatostatin (δ-cells)

• In adult pancreas, strong nuclear expression in islet cells, weak staining in centroacinar cells

PDX1 expression in well-differentiated neuroendocrine tumors


Lung 0-5%

Stomach 60%

Duodenum 60%

Pancreas 55-80%

Jejunum/ileum 0%

Appendix 40%

Rectum 15%

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PDX1 expression in well-differentiated neuroendocrine tumors


Lung 0-5%

Stomach 60%

Duodenum 60%

Pancreas 55-80%

Jejunum/ileum 0%

Appendix 40%

Rectum 15%

PDX1

Metastatic pancreatic well-differentiated neuroendocrine tumor

PDX1

Metastatic pancreatic well-differentiated neuroendocrine tumor

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ISL1

• ISLET1

• Transcription factor with N-terminal LIM domains and C-terminal homeodomain

• Plays critical role in develop of pancreatic islets of Langerhans

• In adults, strong nuclear expression in islets

• Clinically used antibodies show cytoplasmic staining in perivascular smooth muscle

ISL1 expression in well-differentiated neuroendocrine tumors


Lung 10-15%

Stomach 0%

Duodenum 90%

Pancreas 70-85%

Jejunum/ileum <5%

Appendix 15-20%

Rectum 90%

ISL1 expression in well-differentiated neuroendocrine tumors


Lung 10-15%

Stomach 0%

Duodenum 90%

Pancreas 70-85%

Jejunum/ileum <5%

Appendix 15-20%

Rectum 90%

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Pancreas

ISL1


ISL1

ISL1


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Small cell carcinoma

• Determination of primary site not important – All patients treated with cisplatin/carboplatin +

etoposide

• Localized Merkel cell carcinoma treated surgically

• TTF1 is not specific for lung in this setting – TTF1 positive in >90% of small cell carcinoma

of lung

– TTF1 positive in 30-50% of extrapulmonary small cell carcinoma

– TTF1 rarely positive in Merkel cell carcinoma

Metastatic small cell carcinoma

TTF1

Other transcription factors in small cell carcinoma

• Small cell carcinomas show marked transcription factor lineage ‘infidelity’!

• Common to detect expression of 5-10 (or more) different transcription factors in both pulmonary and extrapulmonary small cell carcinomas

• Important to be aware of this phenomenon to avoid misinterpretation

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Transcription factor expression in

small cell and Merkel cell carcinomas

Courtesy of Dr. Andrew Bellizzi

IHC for evaluation of

metastatic WDNET of

unknown primary

Bellizzi Adv Anat Pathol 2013

Practice points

• Review radiologic findings (could the biopsy be from a primary liver tumor?)

• Pay close attention to histologic features – Guide judicious panel of IHC markers

• Increasing range of antibodies directed against transcription factors becoming available – for carcinomas and well-differentiated neuroendocrine tumors

• Be aware of reported cross-reactivity (i.e., specificity) to avoid misdiagnosis

immunohistochemistry for carcinoma of … for carcinoma of unknown primary jason l hornick, md, ......

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