04/04/2016 1 Page 1 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 • 7 th or 8 th most frequent cancer • 4 th or 5 th 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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IMMUNOHISTOCHEMISTRY FOR CARCINOMA OF … FOR CARCINOMA OF UNKNOWN PRIMARY Jason L Hornick, MD, ... •Urinalysis and stool occult blood test ... recognized for role in T-cell function
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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
IHC for lineage/site specification: nuclear transcription factors
IHC for lineage/site specification: nuclear transcription factors
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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IHC for lineage/site specification: nuclear transcription factors
• 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)
• 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.
Primary site Positive cases
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
Metastatic 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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Primary site Positive cases
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
• 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