Lung Cancers

Othman Salim AkhtarDepartment of Pathology

Overview of major lung tumorsDiagnostic ChallengesIHCThe Small Biopsy

Squamous Cell CarcinomaSegmental BronchiUndergo CavitationCalcification rareCentral Cavitatory Lesion- CLASSICAL PICTURECan Occur elsewhere- even lepidic pattern

Cell Atypia InvasivenessKERATIN FORMATIONINTERCELLULAR BRIDGES

Whorl Formation/stratification

Variants & IssuesPOORLY DIFFERENTIATED tumorsSmall cell variant- Small Cell CarcinomaClear Cell variant-AdenocaBasaloid variant- Large Cell UndiffSpindle Cell variant-

IHC->>LMW/HMW Keratin, EMA, p63Negative for TTF-1, CK-7

AdenocarcinomaSolid lesions, usuallymaybe gelatinousCavitation rare65% peripheralNo more BACGrowth patternsLepidic, Acinar, Papillary, Micropapillary, SolidFormation of tubules, papillae and secretion of mucin

AAH> AIS >> MIA >>>ADENOCARCINOMA

Adenocarcinoma in Situ

What is Invasion?Histologic patterns other than LepidicAcinar, Papillary, Micropapillary, SolidTumor Cells infiltrating STROMA (only!)

MIA is EXCLUDED ifTUMOR INFILTRATES VESSELS/PLEURACONTAINS NECROSIS

Minimally Invasive AdenocarcinomaMIA is a small, solitary adenocarcinoma (

By definition- SOLITARY & DISCRETEWHAT IF multiple areas of invasion are present?Size of the largest area of invasion to be measured in largest dimension and should be less than/equal to 5mmSize of invasion is not summation of multiple fociManner of sectioning makes it impossible to calculate total area of invasionEstimate percentage of non lepidic histologyMultiply it by total tumor size(eg. A 2 cm tumor with 85% lepidic and 15% tubular growth = 15/100 X 2 = 3 mm therefore MIA

Invasive AdenocarcinomasFour patterns recognizedLepidicAcinarPapillaryMicropapillarySolid

Pathology recommendation 6For nonmucinous adenocarcinomas previously classified as mixed subtype where the predominant subtype consists of the former nonmucinous BAC, we recommend use of the term LPA and discontinuing the term mixed subtype (strong recommendation, low-quality evidence).

Lepidic Predominant Adenocarcinoma (LPA)Tumor with predominant lepidic pattern BUTAreas of invasion > 5mm in at least one focusINVASION = Other Histological Subtype Stromal InvasionIf the tumorInvades Vessels/LymphaticsHas Areas of NecrosisLPA is always Non Mucinous...!!

Pathology recommendation 8For adenocarcinomas formerly classified as mucinous BAC, we recommend they be separated from the adenocarcinomas formerly classified as nonmucinous BAC and depending on the extent of lepidic versus invasive growth that they be classified as mucinous AIS, mucinous MIA, or for overtly invasive tumors invasive mucinous adenocarcinoma (weak recommendation, low-quality evidence).

Mucinous AdenocarcinomaIn a MUCINOUS TUMOR with predominant lepidic growthInvasive Mucinous AdenocarcinomaNOT LPA!!

has a distinctive histologic appearance with tumor cells having a goblet or columnar cell morphology with abundant intracytoplasmic mucinThese tumors may show the same heterogeneous mixture of lepidic, acinar, papillary, micropapillary, and solid growth as in nonmucinous tumorsThese tumors differ from mucinous AIS and MIA by one or more of the following criteria: size (3 cm), amount of invasion (0.5 cm), lack of a circumscribed border with miliary spread into adjacent lung parenchyma, multiple nodules

Mixtures of mucinous and nonmucinous tumors may rarely occur; then the percentage of invasive mucinous adenocarcinoma should be recorded in a comment. If there is at least 10% of each component, it should be classified as Mixed mucinous and nonmucinous adenocarcinoma.They must contain goblet cells

WHY this obsession with a nonmucionus LPA?Excellent Survival despite invasion= Stage I 90% 5 yr survival rate

Other growth patterns

Pathology Recommendation 7In patients with early-stage adenocarcinoma, we recommend the addition of micropapillary predominant adenocarcinoma, when applicable, as a major histologic subtype due to its association with poor prognosis (strong recommendation, low-quality evidence).

Other stains/IHCLMW keratins, EMA, CEATTF-1, CK7, NAPSIN ACDX2 NEGATIVE- does not apply to mucinous adenocarcinomasLPA- CK7+/CK20-/TTF1 +/CDX2 Mucinous Adeno CK7-/CK20+/TTF1-IHC has its limitations

KRAS mutations- EVER SMOKERSEGFR mutations- NEVER SMOKERS

The Neuroendocrine tumors

Differentiate towards Kulchitsky cellsDivided on the basis of MitosisNecrosisLocation- central/peripheral

Typical Carcinoid> Atyp Carc. > LARGE CELL NEURO = SMALL CELL CA

Reference: Neuroendocrine Tumors of the lung: An Update- Rekhtman. Arch Pathol Lab MedVol 134, November 2010.

Typical Carcinoids- CentralSolitary Polypoid Mass within the main bronchusMostly silentSmall uniform cellsCentral nuclei, moderate cytoplasmCompact nests, ribbons festoons, pronounced vascularityMitosis

Typical Carcinoids- PeripheralPeripheral Lung often beneath the pleuraMultipleMicroscopically- Spindle Cells- DD Leiomyoma

Atypical CarcinoidShare histological/IHC featuresMitosis 2-10/10 HPF and/or focal areas of necrosisRecognizable neuroendocrine patternPleomorphism, nucleoli, but NO MOULDINGLymph node metastasis up to 70% Typical carcinoid- lymph node metastasis 5%Cytogenetic differences also exist -10q, 13q underrepresentation

Large Cell Neuroendocrine CarcinomaWHO CLASSIFICATIONHigh Grade- >10 Mit/10HPF, NecrosisMorphology- NE- organoid nests, RossettesDISCORDANT CYTOLOGY- Non Small Cell Nuclear features and/or large cell size and abundant cytoplasmPositive IHC- at least 1 NE Marker

Small Cell Lung CarcinomaKey defining feature- NUCLEAR appearanceFine granularity as opposed to Coarse (Carcinoids) and clumpy vesicular chromatin in LCNEC/NSCLC

Classification for small biopsies/cytology

Pathology Recommendation 9For small biopsies and cytology, we recommend that NSCLC be further classified into a more specific histologic type, such as adenocarcinoma or squamous cell carcinoma, whenever possible (strong recommendation, moderate quality evidence).

Greater need to differentiate Adeno from Squamous Response of Adeno to PemetrexedToxicity in case of Bevacizimab

Good Practice ConsiderationsWhen a Dx is made on LM alone or using Special Stains- mention itTry to save as much tissue for molecular testing as possibleDevelop a multidisciplinary approach for tissue management

AIS, MIA not to be used in small biopsiesLarge cell carcinoma NOT to be used- use NSCLC-NOS insteadWhen morphology, IHC are inconclusive- NSCLS- NOSConsult other disciplines for a specific DxRadiology can guide histological Dx

IHC When and How?Minimal use of stainsWhen morphology is inconclusiveTTF-1 for Adenocarinoma +/- Mucin stains (PAS)P63 for Squamous Cell CarcinomaTherefore TTF-1 main markerIf tumor is TTF-1 +ve, p63 + NSCLS Favor AdenoIf Tumor is TTF-1 ve , p63+ NSCLS Favor SqCCIf tumor is TTF-1 ve, p63- NSCLS NOS- Radiology Guides

NE morphologyIf NE MorphologyNE StainsIF NE morphology absent No stains

Good Practice RecommendationWhen Cytology specimens exist, use in conjunction with histologyReduce the NSCLC NOS typesAccuracy for definitive Dx 96% with IHC 100%

Pathology Recommendation 10We recommend that the term NSCLC-NOS be used as little as possible, and we recommend it be applied only when a more specific diagnosis is not possible by morphology and/or special stains (strong recommendation, moderate quality evidence).

When to test for EGFRAdenocarcinomaNSCLC- favor AdenocarcinomaNSCLC- NOS

Sarcomatoid CarcinomasShould be labelled as Adeno or Squamous Cell Cas if features are presentIf not- Poorly Diff NSCLS with giant and/or spindle cell features

Summary of recommendationsWe recommend discontinuing the use of the term BAC (strong recommendation, low-quality evidence).For small (3 cm), solitary adenocarcinomas with pure lepidic growth, we recommend the term Adenocarcinoma in situ that defines patients who should have 100% disease-specific survival, if the lesion is completely resected (strong recommendation, moderate quality evidence). Remark: Most AIS are nonmucinous, rarely are they mucinous.For small (3 cm), solitary, adenocarcinomas with predominant lepidic growth and small foci of invasion measuring 0.5 cm, we recommend a new concept of Minimally invasive adenocarcinoma to define patients who should have near 100%, disease-specific survival, if completely resected (strong recommendation, low-quality evidence). Remark: Most MI are nonmucinous, rarely are they mucinous.For invasive adenocarcinomas, we suggest comprehensive histologic subtyping be used to assess histologic patterns semiquantitatively in 5% increments, choosing a single predominant pattern. We also suggest that individual tumors be classified according to the predominant pattern and that the percentages of the subtypes be reported (weak recommendations and low-quality evidence).

5. In patients with multiple lung adenocarcinomas, we suggest comprehensive histologic subtyping in the comparison of the complex, heterogeneous mixtures of histologic patterns to determine whether the tumors are metastases or separate synchronous or metachronous primaries (weak recommendation, low-quality evidence).6. For nonmucinous adenocarcinomas previously classified as mixed subtype where the predominant subtype consists of the former nonmucinous BAC, we recommend use of the term LPA and discontinuing the term mixed subtype (strong recommendation, low-quality evidence).7. In patients with early-stage adenocarcinoma, we recommend the addition of micropapillary predominant adenocarcinoma, when applicable, as a major histologic subtype due to its association with poor prognosis (strong recommendation, low-quality evidence).

8. In patients with early-stage adenocarcinoma, we recommend the addition of micropapillary predominant adenocarcinoma, when applicable, as a major histologic subtype due to its association with poor prognosis (strong recommendation, low-quality evidence).9. For small biopsies and cytology, we recommend that NSCLC be further classified into a more specific type, such as adenocarcinoma or squamous cell carcinoma, whenever possible (strong recommendation, moderate quality evidence)10. We recommend that the term NSCLC-NOS be used as little as possible, and we recommend it be applied only when a more specific diagnosis is not possible by morphology and/or special stains (strong recommendation, moderate quality evidence).

Scenario 1

Scenario 1Small Bx/ Histological Specimen?Pattern?----LepidicCells? --- Non MucinousHow to report?Adenocarcinoma with lepidic pattern. Invasion cannot be ruled out

Scenario 2

Scenario 2Small BiopsyLepidic PatternMucinous CellsHow to report?Mucinous Adenocarcinoma

Scenario 3

Scenario 3Small BiopsyPattern- noneCells- undifferentiatedNext Step?IHC>>> ttf1/p63If TTF1 ve and p63 +ve (diffuse)How to reportNon Small Cell Carcinoma Favour Squamous Cell Carcinoma (p63+/TTF-ve)

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