THE MAIN CHANGES
• Greater role for immunohistochemistry
• Emphasis on genetic studies
• New classification for small biopsy specimens
• New approach to adenocarcinoma (2011)
• Diagnosis of large cell CA restricted to resected specimens
• Reclassification of squamous cell carcinoma
Grouping of neuroendocrine tumors
Addition of NUT carcinoma
Sclerosing hemangioma becomes sclerosing pneumocytoma
Hamartoma becomes pulmonary hamartoma
Created PEComatous tumors group: LAM, PEComa benign, PEComa malignant
New entity: pulmonary myxoid sarcoma EWSR1-CREB1 translocation
Adding myoepithelioma, myoepithelial carcinoma – can show EWSR1 gene rearrangement
Usefulness of WWTR1-CAMTA1 fusions in diagnosis of epithelioid hemagioendothelioma
Erdheim-Chester disease added to lymphoproliferative category
New group of ectopic tumors eg germ cell tumors, intrapulmonary thymoma, melanoma, meningioma
DIAGNOSIS OF LUNG CA IN SMALL BIOPSY SPECIMENS AND CYTOLOGY
• First WHO Classification to provide criteria for lung cancer diagnosis on small biopsy specimens
• In + 2/3 cases the tumor is advanced stage so this is usually the only material available for diagnosis
• Immunohistochemical stains are required for accurate diagnosis but tissue should be spared for molecular testing (don’t waste!)
GREATER ROLE FORIMMUNOHISTOCHEMISTRY
• The 2004 WHO classification was based primarily on morphology (small cell/non small cell)
Immunohistochemistry was advised in the following situations:
- Sarcomatoid carcinoma
- Neuroendocrine tumors
- DD of mesothelioma
In the 2015 WHO Classification immuno-histochemistry has additional roles:
- Undifferentiated NSCLC – solid adenoca vs non keratinizing SCC
- Diagnosis of large cell carcinoma NOS
HOW TO SAVE TISSUE
Clear cut adenoCA or keratinizing squamous cell CA
do not require additional stains (except TTF-1 to confirm
primary adenoCA)
In poorly differentiated NSCLC egsolid adenoCA, non-keratinizing SCC, a limited optimal panel should be chosen for accurate diagnosis
Tissue should be spared for molecular testing (don’t waste!)
INTERPRETATION OF STAINS
mucin +: adenoCA (>5 +ve cells in 2 HPF)
TTF-1/napsinA +: NSCLC favor adenoCA
p40/p63 +: NSCLC favor SCC
Solid, non-NE, -ve stains NSSC NOS – consider doing a limited immuno panel to confirm CA and r/o metastasis eg CK, MART-1/LCA
Note: +ve staining for TTF-1 &/or napsinA is considered adenoCA irrespective of p40/p63
• p40 and p63 have similar sensitivity but p40has superior specificity for SCC (99-100% vs 90%)
• Note: You can suggest but not make a definite diagnosis of adenosquamous CA on small biopsy specimen
ROLE FOR IMMUNOHISTOCHEMISTRY IN PERSONALIZED/PRECISION MEDICINE
Antibodies for 3 EGFR mutations are specific but not sensitive (av. 58%)
VENTANA ALK was approved by FDA in 2015 as a companion marker together with FISH
PDL-1 – 4 drugs each with its own PDL-1 antibody
NSCC IN SMALL SPECIMENS
ADENOCARCINOMA
Describe patterns (papillary, acinic, lepidic, micropapillary, solid) and features (eg colloid features, fetal features, enteric features)
If you see LEPIDIC pattern only on a small biopsy specimen add a note that invasive adenoCA cannot be excluded
Mucinous adenocarcinoma is usually lepidic and almost always invasive
SQUAMOUS CELL CARCINOMA
2004 WHO ClassificationPapillary – rareClear cell – rare, feature, not a subtypeSmall cell – rare, confusing; the term has been dropped
2015 WHO ClassificationKeratinizingNon-keratinizingBasaloid (large cell CA in 2004 WHO Classification)
SQUAMOUS CELL CARCINOMA
Keratinizing squamous cell carcinoma can be diagnosed without stains
The non-keratinizing and basaloid types need stains – p40/p63
Note: - AdenoCAs may appear to be “squamoid”- Basaloid SCC may express NE markers
CLASSIFICATION IN RESECTED SPECIMENS
Major changes in classification of adenocarcinoma
• Terms bronchioloalveolar carcinoma and mixed adenocarcinoma are out
• Addition of adenoCA in situ - AIS (joins atypical adenomatous hyperplasia as a pre-invasive lesion)
• Addition of minimally invasive adenocarcinoma - MIA
• Classify adenoCA by major subtype (papillary, acinar, lepidic, micropapillary, solid)
The term lepidic used for non-invasive component
Invasive mucinous adenoCA (instead of mucinous BAC) – usually lepidic with minor invasive component – r/o AIS, MIA on resection specimen
colloid adenoCA (instead of mucinous cystadenoCA)
clear cell and signet ring are features, not subtypes
ADENOCARCINOMA WHO 2015
• Pre-invasive lesions
• -Atypical adenomatous hyperplasia (<5mm)
• - Adenocarcinoma in situ (<3cm)
• Minimally invasive adenocarcinoma
• (lesion <3cm with <5mm invasion)
• Invasive adenocarcinoma
• Lepidic, acinar, papillary, micropapillary, solid
• Variants
ADENOCARCINOMA IN SITUDIAGNOSTIC CRITERIA
• Small - not >3cm• Solitary• Pure lepidic growth• No stromal, vascular, pleural invasion• No invasive histologic pattern eg acinar, papillary,
micropapillary, solid, colloid • No spread through air spaces (STAS)• Non-mucinous• Minimal or absent nuclear atypia• Septal widening with sclerosis, elastosis common• 100% disease free survival if resected
LEPIDIC COMPONENT
• Lepidic pattern on a small biopsy could represent AIS, MIA, lepidic adenoCA, adenoCA with a lepidic component or even metastatic adenoCA (eg ovary, colon, pancreas) – don’t commit!
MINIMALLY INVASIVE ADENOCARCINOMA
• Small – up to 3cm
• Solitary
• Predominantly lepidic
• Invasive component not >0.5cm
• NO: lymphovascular, airspace, pleural invasion, tumor necrosis
• Non-mucinous
• 100% disease free survival if resected
•
INVASIVE ADENOCARCINOMA
• Adenocarcinoma should be classified according the predominant pattern (papillary, acinar, lepidic, micropapillary, solid ) and a semi-quantitative assessment of other patterns
Reproducability among experts is not great!
HISTOLOGIC GRADING
• No established system
• Lepidic low grade
• Acinar, papillary intermediate grade
• Solid, micropapillary high grade
SPREAD THROUGH AIRSPACES - STAS
• Additional pattern of spread is now being recognized as a prognostic factor
• Presence of STAS is considered to be invasionand excludes a diagnosis of AIS, MIA
• Thought to be responsible for recurrence after limited resection (small low stage tumors)
INVASIVE MUCINOUS ADENOCARCINOMA
• Usually predominantly lepidic with minor invasive component
• Adenocarcinoma in situ and minimally invasive adenocarcinoma of this variant are rare; can only be diagnosed/ruled out on resection specimen
• R/o metastatic mucinous carcinoma eg pancreas ovary
INVASIVE MUCINOUS ADENOCARCINOMA
• Has a different immunophenotype:
• TTF-1, napsin A negative
• CK7, CK20 positive
APPROACH TO MULTIPLE ADENOCARCINOMASmultiple primaries or intrapulmonary metastases?
• 1. Morphology may be helpful – compare growth patterns
•2. Multidisciplinary approach (clinical, radiologic, molecular, pathology) (the role of molecular studies remains to be established)
LARGE CELL CARCINOMA
• Can only be diagnosed on a resected specimen
• Exclude solid adenoCA, non-keratinizing/basaloid SCC , NEC - immunohistochemistry
• Changes from 2004 classification:
• LCNEC is now classified with other neuroendocrine tumors
• Basaloid CA is now considered a subtype of SCC
• Clear cell/rhabdoid are features rather than subtypes
NEUROENDOCRINE AND PLEOMORPHIC CARCINOMA
• SMALL BIOPSY RESECTION
• Small cell CA Small cell CA
• NSCC with NE morphology LCNEC
and +ve NE markers :
Possible LCNEC
• NSCC with NE morphology LCC with NE morphology
but -ve NE markers: NSCC –
suspected LCNEC but NE stains
are negative
• NSCC with spindle Pleomorphic, spindle cell
• &/or giant cell CA &/or giant cell CA Travis et al 2015
•