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14 Cytologic Sub-Classification of Lung Cancer: A New Challenge for Practicing Pathologists
Parvin Ganjei-Azar MD Merce Jorda MD, PhD
2011 Annual Meeting – Las Vegas, NV
AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600
Chicago, IL 60603
14 Cytologic Sub-Classification of Lung Cancer: A New Challenge for Practicing Pathologists This session will present aspects of cytologic sub-classification of lung cancer, focusing on the introduction of target therapy and its associated significant therapeutic implications for patients with advanced stage lung cancer. Included in the presentation will be subclassification of non-small cell carcinomas into adenocarcinomas and squamous cell carcinomas, cytologic samples including fine needle aspiration (FNA), bronchoscopic brushing (BB) and washings (BW), and bronchoalveolar lavages (BAL) to establish the diagnosis of lung cancer and subclassification of these tumors.Molecular testing for lung cancer will also be discussed. Formulate a differential diagnosis based on routinely prepared cytologic slides, based on clinical, imaging and cytologic findings.
• Learn how to identify and mark diagnostic cells properly for further application of immunocytochemistry, select a limited panel of antibodies based on available clinical and cytomorphologic imformation and to interpret immunostain results, and become fam
• Differentiate lung primary carcinomas from those of metastatic origin, accurately diagnose small cell carcinomas of lung and sub classify non small cell carcinomas into those with squamous differentiation and distinguish between malignant mesothelioma and
FACULTY: Parvin Ganjei-Azar MD Merce Jorda MD, PhD Practicing Pathologists Cytopathology Cytopathology (Non-Gynecologic) 2.0 CME/CMLE Credits Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). Credit Designation: The ASCP designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCP continuing education activities are accepted by California, Florida, and many other states for relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s Maintenance of Certification Program.
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Parvin Ganjei-Azar MD.Merce Jorda MD, PhD
Cytologic Sub-Classification of Lung CancerNew Challenge for Practicing Pathologists
Merce Jorda MD, PhD
I do not have, and have not had, any relevant financial relationship with
any commercial interests within the past 12
Disclosure
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any commercial interests within the past 12 months, as pertaining to this presentation.
Parvin Ganjei-Azar MD.Merce Jorda MD, PhD
Lung cancer is the most frequent cause ofmajor cancer incidence and mortalityworldwide.
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More people die of lung cancer than of colon, breast, and prostate cancers combined.
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• Lung cancer is the second most common cancer in both men (after prostate cancer) and women (after breast cancer)
• In 2011….
221 130 l di d
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• 221,130 newly diagnosed cases
• 156,940 deaths from lung (27% of all cancer deaths)
Incidence
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Combined data from the National Program of Cancer Registries as submitted to CDC and from the Surveillance, Epidemiology and End Results program as submitted to the National Cancer Institute in November 2009. *Rates are per 100,000 persons and are age-adjusted to the 2000 U.S. standard population
• Black men are about 40% more likely to develop lung cancer than white men
• The rate is about the same in black women and in white women
• The rate of lung cancer has been dropping
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• The rate of lung cancer has been dropping among men for many years
• The rate of lung cancer is fairly stable among women.
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• Significant decline in incidence/mortality for African American and white males
• Increase in
Mortality
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incidence/mortality for females of both races.
Source: North American Association of Central Cancer Registries (NAACCR), the National Cancer Institute (NCI), and the American Cancer Society. Journal of the National Cancer Institute, May 4, 2011.
Cytology of Lung Cancer Sampling Methods
• Sputum• Transthoracic (FNA)• Transbronchial (FNA BB BL)
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• Transbronchial (FNA, BB, BL)• Transesophageal (FNA)• Body Cavity Fluids
Cytology of Lung Cancer: Goals
• Preventive • Diagnostic
Prognostic
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• Prognostic• Predictive
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Spiral (helical) C T scans of the lungsChest X-rays
Sputum cytology
Preventive
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•They can find cancers earlier •There is little evidence that they prevent death from lung cancer
High-risk patients
The International Early Lung Cancer Action Program (I-ELCAP):–48 institutions in 9 countries
H li l C T ith f ll d bi t l
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–Helical C T scan with followed biopsy or cytology–Curability of stage I lung cancers is 80-90%–Costs of CT screening for lung cancer compare favorably with breast, cervical, and colon cancer screenings
The U.S. Preventive Services Task Force concludes that evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer with either low dose computerized tomography,
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chest x-ray, sputum cytology, or a combination of these tests.
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• Preventive• Diagnostic
Pulmonary Cytology: Goals
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• Prognostic• Predictive
Diagnostic Goals
• Malignant neoplasms• Benign neoplasms
I f ti /I fl t
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• Infectious/Inflammatory processes
Malignant Neoplasms of Lung
• Primary• Secondary
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• Secondary
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Primary L C iLung Carcinoma
WHO 1967, 1981, 1999Based on histomorphology
Primary Lung Neoplasms: Classification
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WHO 2004Based on histomorphology, genetics and
clinical information
International Multidisciplinary ClassificationIASLC/ATS/ERS, 2011
Identification of prognostic and predictive factors
Primary Lung Neoplasms: Classification
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• International Association for the study of lung cancer (IASLC)
• American Thoracic Society (ATS)• European Respiratory Society (ERS)
J Thorac Oncol. 2011; 6: 244-285
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International Multidisciplinary Classification, 2011
• Applies to – Resection specimens– Biopsies– Cytology samples
• Bronchioloalveolar carcinoma and mixed
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J Thorac Oncol. 2011; 6: 244-285
• Bronchioloalveolar carcinoma and mixed subtypes adenocarcinoma are NOT used
• Provides guidance for diagnosis in cytology samples (70% of lung cancers are diagnosed by cytology)
Primary Lung CarcinomagCytomorphology
Type Frequency 5-year survival
NSCLCAdenocarcinoma Squamous Cell
80 % 17%15%
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Small Cell 20 % 5%
Large Cell5%
11%
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Adenocarcinoma:Mixed TypeAcinarPapillarySolid
Bronchioloalveolar (non-mucinous)
Bronchioloalveolar (mucinous)
Adenocarcinoma with lepidic pattern
Mucinous adenocarcinoma
Adenocarcinoma
Adenocarcinoma(describe patterns present: Acinar, Papillary, Solid,Micro-papillary)
WHO, 2004Small Biopsy/CytologyIASLC/ATS/ERS, 2011
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Mucinous (colloid)
Fetal
Signet ring
Clear cell
No counterpart
Adenocarcinoma with fetal pattern
Adenocarcinoma with colloid pattern
Adenocarcinoma with signet ring cell features
Adenocarcinoma with clear cell features
NSCLC, favor AdenocarcinomaJ Thorac Oncol. 2011; 6: 244-285
AdenocarcinomaCytomorphology
• Cohesive groups• Acinar, papillary, micro‐papillary formations
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papillary formations• Cytoplasmic vacuoles• Mucinous background
Small Biopsy/Cytology IASLC/ATS/ERS, 2011
Gland FormingMicropapillaryLepidic growthM i diff
Cytology
YesYesYesY
YesYesNoY
BiopsyAdenocarcinoma
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Mucinous diff.“Colloid”Signet-ringClear cell
YesYesYesYes
YesYesYes?
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WHO 2004Bronchoalveolar Carcinoma, non-mucinous
IASLC/ATS/ERS, 2011Adenocarcinoma with lepidic pattern
WHO 2004Bronchoalveolar Carcinoma, non-mucinous
IASLC/ATS/ERS, 2011Adenocarcinoma
Squamous cell carcinomaPapillaryClear cellSmall cell
Squamous cell carcinomaPapillaryClear cellSmall cell
Squamous Cell Carcinoma
Small Biopsy/CytologyIASLC/ATS/ERS, 2011
WHO, 2004
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Small cellBasaloid
No counterpart NSCLC, favor Squamous Cell Carcinoma
Small cellBasaloid
J Thorac Oncol. 2011; 6: 244-285
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Squamous Cell CarcinomaCytomorphology
• Cohesive groups• Isolated pleomorphic cells
• Hyperchromatic nuclei
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• Hyperchromatic nuclei• Eosinophilic cytoplasm
• Necrotic background
WHO 2004Squamous cell carcinoma
IASLC/ATS/ERS, 2011Squamous cell carcinoma
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WHO 2004No counterpart
IASLC/ATS/ERS, 2011NSCLC, favor Squamous Cell Carcinoma
Small cell carcinoma Small cell carcinoma
Small cell carcinoma
Small Biopsy/CytologyIASLC/ATS/ERS, 2011WHO, 2004
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Small cell carcinoma Small cell carcinoma
J Thorac Oncol. 2011; 6: 244-285
Small cellCarcinoma 20%
Incidence
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Non-small cellcarcinoma 80%
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• Isolated small cells / small groups• Crushing artifact
Small Cell CarcinomaSmall Cell CarcinomaCytomorphologyCytomorphology
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• Nuclear molding• Cellular fragmentation• Tumor necrosis
WHO 2004Small Cell Carcinoma
IASLC/ATS/ERS, 2011Small Cell Carcinoma
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Small Biopsy/CytologyIASLC/ATS/ERS, 2011
Large cell carcinoma Non-small cell carcinoma, NOS
Large cell neuroendocrinecarcinoma (LCNEC)
Non-small cell carcinoma, withneuroendocrine morphology (positiveNE markers) possibly LCNEC
Large Cell Carcinoma
WHO, 2004
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NE markers) possibly LCNEC
Large cell carcinoma withneuroendocrinemorphology (LCNEM)
Non-small cell carcinoma, withneuroendocrine morphology(negative NE markers); LCNEC issuspected
J Thorac Oncol. 2011; 6: 244-285
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• No squamous or glandular differentiation• Isolated cells • Pleomorphic nuclei
Large Cell CarcinomaCytomorphology
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Pleomorphic nuclei• Macronucleoli• Binucleation
WHO 2004Large Cell Carcinoma
IASLC/ATS/ERS, 2011Non-small cell carcinoma, NOS
Small Biopsy/CytologyIASLC/ATS/ERS, 2011
AdenosquamousCarcinoma
Non-small cell carcinomawith squamous cell andadenocarcinoma patterns
Adenosquamous Carcinoma
WHO, 2004
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Non-small cell carcinoma,NOS with IHC favoring bothsquamous andadenocarcinoma patterns
No counterpart
J Thorac Oncol. 2011; 6: 244-285
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Small cell carcinomaIASLC/ATS/ERS, 2011
Sarcomatoid Carcinoma Poorly differentiated NSCLC
Sarcomatoid Carcinoma
WHO, 2004
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with spindle and or giant cellmorphology (with adeno or squamouscomponent)
J Thorac Oncol. 2011; 6: 244-285
Primary Lung Carcinomag
Immunocytochemistry
• Sub-classification of primary lung cancer
••• Distinction between primary vsDistinction between primary vsDistinction between primary vs
Malignant Neoplasms in LungImmunocytochemistry
Applications
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••• Distinction between primary vs. Distinction between primary vs. Distinction between primary vs. secondary carcinomassecondary carcinomassecondary carcinomas
••• Distinction between lung primary and Distinction between lung primary and Distinction between lung primary and malignant mesotheliomamalignant mesotheliomamalignant mesothelioma
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TTF-1 Positive
CK 7 Positive
AdenocarcinomaAdenocarcinoma Squamous CellSquamous Cell Small CellSmall Cell
p63 Positive
TTF-1 Negative
TTF-1 Positive
CK Positive (dot-like)
Immunocytochemistry in Primary Lung Immunocytochemistry in Primary Lung CarcinomasCarcinomas
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p63 Negative
CDX-2(*) Negative (*)
CK 20 Negative
(*) positive in intestinal type
Synapto Positive
Chromo Positive/Negative
p63 Negative
Ganjei, Jorda, Krishan. Effusion Cytology: A Practical Guide to Cancer Diagnosis. Demos 2011
NSCLCPrognostic and Predicti ePrognostic and Predictive
Molecular Markers
• A prognostic biomarker is a biomolecule that is indicative of patient survival independent of the treatment received
• A predictive biomarker is a biomolecule
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• A predictive biomarker is a biomolecule that is indicative of therapeutic efficacy
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• EGFR mutation:– 15% of Caucasians– 30% of Asians
• EGFR high copy number
NSCLCPrognostic and Predictive Biomarkers
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EGFR high copy number– 40% Caucasians (FISH,IHC)
• KRAS mutation: 25% • EML4-ALK translocation: 6%• BRAF mutation: 3%
•Patients with EGFR mutation respond to TKI (Erlotinib, Getifinib).
•Patients with KRAS or BRAF mutation do not
NSCLC: Target Therapy
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respond to TKI, ALKI
•Patients with EML4-ALK fusion, respond to ALK inhibitor (Crizotinib)
Secondary L C iLung Carcinoma
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Secondary Lung Carcinomas
• Metastatic carcinomas are the most common malignant neoplasms found in lung
• Adenocarcinomas are the most common secondary neoplasmsSit f i i B t l t l d t i
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• Sites of origin : Breast, colorectal , endometrium, others
• Distinction between lung primary and secondary carcinomas can not be made , based on cytomorphology alone
Secondary Lung Carcinomas
• Final diagnosis should be based on:–Clinical
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–Imaging–Cytomorphology–Immunocytochemistry
••• SubSubSub---classification of primary lung classification of primary lung classification of primary lung cancer cancer cancer
• Distinction between primary vs
Malignant Neoplasms in LungImmunocytochemistry
Applications
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• Distinction between primary vs. secondary carcinomas
••• Distinction between lung primary and Distinction between lung primary and Distinction between lung primary and malignant mesotheliomamalignant mesotheliomamalignant mesothelioma
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• TTF-1• Napsin• TGB• PSA• S100, HMB45• ER PR
Primary vs. SecondaryCommonly Used Markers
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• ER, PR• CK 7 and CK20• P63• CDX-2• HCA, RCC• Endocrine markers• Lymphoid markers
• Adenocarcinomas• Squamous cell carcinomas
Primary vs. Secondary
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• Small cell carcinomas• Large cell carcinomas
Adenocarcinoma with lepidic pattern
Mucinous adenocarcinoma
Adenocarcinoma(describe patterns present: Acinar, Papillary, Solid,Micro-papillary)
Small Biopsy/CytologyIASLC/ATS/ERS, 2011
Secondary Adenocarcinomas
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Adenocarcinoma with fetal pattern
Adenocarcinoma with colloid pattern
Adenocarcinoma with signet ring cell features
Adenocarcinoma with clear cell features
NSCLC, favor Adenocarcinoma
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Adenocarcinoma
MaleMale Lung Upper GI Colorectal
TTF-1 + - -
CDX-2 - / + + / - +
CK 7 + + -
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•Colorectal •Upper GI•Others
CK 20 - - +
Cancer Cytopathology 2002
TTF-1
Lung FNA; 76 M History of Colon Ca.
CK20Adenocarcinoma of Lung
CK7
Ganjei & NadjiSpringer 2007
2020
Lung FNA : Patient with history of colorectal carcinoma
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CK20
CDX2
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Adenocarcinoma
FemaleFemale Lung Breast Colorectal FGT
TTF-1 + - / + - -
ER - /+ +/- - + /-
CK 7 + + - +CK 20 + - + + /-
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•Breast•Colorectal•Female Genital tract•Others
CK 20 + + + /CA 125 - - - +P16 - - - +
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PF of a woman with history of breast cancer
“Cellular evidence of adenocarcinoma. ICC for further subclassification to
follow”
ER(+) “This immunophenotype is consistent with metastasis from the patient’s known primary breast carcinoma”
ER1D5
Secondary Squamous Cell
C i
Squamous cell carcinomaPapillaryClear cellSmall cell
Small Biopsy/CytologyIASLC/ATS/ERS, 2011
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Carcinomas
NSCLC, favor Squamous Cell Carcinoma
Small cellBasaloid
Squamous cell Carcinoma
Male Male Lung Head & Neck
Esophagus Urothelial
TTF-1 - - - -
P63 + + + +
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•Lung•Head & Neck•Esophagus•Urothelial•Others
P16 - - / + - - / +
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Squamous cell Carcinoma
Female Female Lung Head & Neck
Esophagus Uterine Cervix
Urothelial
TTF-1 - - - - -
P63 + + + + +
P16 / /
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•Lung•Head & Neck•Esophagus•Uterine Cervix•Urothelial •Others
P16 - - /+ - + - / +
3
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Squamous Cell Carcinomap63p63
Secondary Small Cell Carcinomas
Small Biopsy/CytologyIASLC/ATS/ERS, 2011
Small cell carcinoma
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Cell Carcinomas
Small Cell Carcinoma
MaleLung Skin (Merckel)
TTF-1 + -
CK 20 - +
Female
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•Skin•Others
CK 20 - +
•Skin•Others
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Differential DiagnosisSmall Cell Carcinoma vs.
Other Small Cell Neoplasms
CK CD45 DES CD99 SYN TTF-1
Small Cell Ca + - - - + +
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Small Cell Ca + - - - + +
Lymphoma - + - -/+ - -
Rhabdomyosarcoma - - + -/+ - -
PPNET - - - + +/- -
••• SubSubSub---classification of primary lung classification of primary lung classification of primary lung cancer cancer cancer
••• Distinction between primary vsDistinction between primary vsDistinction between primary vs
Malignant Neoplasms in LungImmunocytochemistry
Applications
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••• Distinction between primary vs. Distinction between primary vs. Distinction between primary vs. secondary carcinomassecondary carcinomassecondary carcinomas
• Distinction between lung primary and malignant mesothelioma
Lung Primary vs.Malignant Mesothelioma
CEA TTF-1 Calretinin p63
L Ad i
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Lung Adenocarcinoma + + - -
Malignant Mesothelioma - - + -
Squamous Cell Carcinoma +/Squamous Cell Carcinoma +/-- -- -- ++
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FNA: Pleural- Based Mass, 62 Male
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• Calretinin is the most useful marker for mesothelial cells
• Expression is both nuclear & cytoplasmic
• Calretinin does diff i
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not differentiate benign from malignant mesothelial cells
Ganjei & NadjiSpringer 2007
• Sarcomatoid mesotheliomas are negative for calretinin
• Lung spindle cell carcinomas & sarcomatoid mesotheliomas express
Remember….
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CK but are negative for TTF-1• Lung spindle cell carcinomas may
express p63, whereas mesotheliomas are p63 negative
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• Formulate a differential diagnosis based on clinical, imaging and cytologic findings
• Differentiate lung primary carcinomas from those of metastatic origin, and sub-classify primary carcinomas
Intended Learning Outcomes
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primary carcinomas • Application of immunocytochemistry in
cytologic material • Applicability of molecular assays