Lung tumor are most common in cigrate smoker . Most commonly it is adenocarcinoma

1. LUNG TUMOURS
PRESENTER- DR.CHHAVI BAJPAI

2. WHO CLASSIFICATION OF LUNG
TUMORS

3. • Epithelial tumors
Precursor glandular lesions
• Atypical adenomatous hyperplasia
• Adenocarcinoma in situ
Nonmucinous, Mucinous
Adenocarcinoma
Minimally invasive adenocarcinoma
• Nonmucinous ,Mucinous
• Lepidic adenocarcinoma
• Acinar adenocarcinoma
• Papillary adenocarcinoma
• Micropapillary adenocarcinoma
• Solid adenocarcinoma
Invasive mucinous adenocarcinoma
• Mixed invasive mucinous
&nonmucinous adenocarcinoma
• Colloid adenocarcinoma
• Fetal adenocarcinoma
• Adenocarcinoma ,Enteric type
• Adenocarcinoma ,NOS
Squamous cell carcinomas
• Keratinizing squamous cell carcinoma
• Nonkeratinizing squamous cell carcinoma
• Basaloid squamous cell carcinoma
• Lymphoepithelial carcinomas
Large cell carcinoma
Adenosquamous carcinoma
Sarcomatoid carcinomas
• Pleomorphic carcinoma
• Carcinosarcoma
• Pulmonary blastoma
Other epithelial tumors
• NUT carcinoma
• Thoracic SMARC 4- deficient
undifferentiated tumour*
• Squamous cell carcinoma ,NOS
Squamous precursor lesions
• Squamous cell carcinoma in situ
• Mild, Moderate, severe dysplasia
Invasive non mucinous adenocarcinoma

4. Salivary gland-type tumors
• Mucoepidermoid carcinoma
• Adenoid cystic carcinoma
• Epithelial-myoepithelial
carcinoma
• Pleomorphic adenoma
• Hyalinising clear cell
carcinoma
• Myoepithelioma
• Myoepithelial carcinoma
Papillomas
• Squamous cell papilloma
NOS
Inverted
• Glandular papilloma
• Mixed squamous and
glandular papilloma
• Papillary adenoma
• Mucinous cystadenoma
• Mucous gland adenoma
Adenomas
• Sclerosing pneumocytoma
• Alveolar adenoma
• Bronchiolar adenoma/ciliated muconodular
papillary tumor
Neuroendocrine tumors
Small cell carcinoma
• Combined small cell carcinoma
Large cell neuroendocrine carcinoma
• Combined large cell neuroendocrine
carcinoma
Carcinoid tumors (Typical , Atypical)
Preinvasive lesion
• Diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia

5. Hematolymphoid tumors
• MALT lymphoma
• Diffuse large cell Bcell lymphoma NOS ,
• Lymphomatoid granulomatosis ,NOS
Grade1,Grade2, Grade3
• Intravascular large B cell lymphoma
• Pulmonary Langerhans cell histiocytosis
• Erdheim–Chester disease
Tumors of ectopic origin
• Melanoma
• Meningioma
Metastatic tumors
• Pleuropulmonary blastoma
• Intimal sarcoma
• Pulmonary myxoid sarcoma with EWSR1-CREB1 fusion
Mesenchymal tumors
• Pulmonary hamartoma
• Diffuse lymphangiomatosis*
• Chondroma
• PEComatous tumors
Lymphangioleiomyomatosis*
PEComa, benign
PEComa, malignant
• Congenital peribronchial myofibroblastic tumor

6. •New entities or terminology:
- Thoracic SMARCA4-deficient undifferentiated tumor
- Bronchiolar adenoma/ciliated muconodular papillary tumor
- Lymphoepithelioma-like carcinoma → Lymphoepithelial
carcinoma
- Enteric adenocarcinoma → Enteric-type adenocarcinoma
CHANGES IN WHO 2021 CLASSIFICATION OF LUNG
TUMOURS

7. HISTOLOGICAL SUBTYPE OF LUNG
CARCINOMAS
•Small cell lung cancer (SCLC)
•Non-small cell lung cancer (NSCLC)
– Squamous cell cancer
– Adenocarcinoma
– Large cell carcinoma
– Other subtypes

8. ADENOCARCINOMA
Preinvasive lesions
 Atypical
adenomatous
hyperplasia
 Adenocarcinoma
in situ
- Nonmucinous
- Mucinous
Invasive mucinousADC,
variants
• Mixed invasive mucinous &
nonmucinous
adenocarcinoma
Minimally
invasiveADC
(MIA)
- Nonmucinous
-Mucinous
InvasiveADC
Invasivenonmucinous
ADC
• LepidicADC
• AcinarADC
• PapillaryADC
• MicropapillaryADC
• SolidADC

9. ADENOCARCINOMA : Molecular /
cytogenetics :
EGFR mutation
KRAS mutation
ALK rearrangement
TP53 point mutation
ROS1 gene fusions
BRAF mutation, V600E most common
NTRK mutation
PDL1mutation
STK11 mutation
KEAP 1 mutation
HER2 amplification
MET amplification
SMARCA4 loss of function

10. ADENOCARCINOMA : Molecular / cytogenetics
Genetic abnormalities seen in epidermal growth factor receptor (EGFR) and
downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-
kinases (PI3K) signaling pathways.
ALK gene translocation with EML4 at 2p chromosome is also seen.
ALK translocated pulmonary adenocarcinoma shows solid growth pattern, often with
signet ring cell morphology.
Occur in young age ,non smokers and lacks mutation of EGFR,KRAS,TP53.

11. ATYPICAL ADENOMATOUS
HYPERPLASIA(AAH)
• This is defined as a small ,localised
proliferation of atypical pneumocytes
usually ≤ 5 mm lining the alveoli forming
small peripheral nodule .
• It is recognised as precursor lesion to invasive
adenocarcinoma.

12. ATYPICAL ADENOMATOUS
HYPERPLASIA(AAH)
•Atypical pneumocytes showing mild to
moderate atypia with enlarged cell and
increased N:C ratio; hyperchromatic nuclei.
• Atypical cells form a discontinuous
monolayer of cells c/a (skip lesion)
lining the alveoli.
• Mitotic activity is typically minimal
• There is minimal/no septal widening
and absence of septal inflammation
or fibrosis.
• Positive for TTF1

13. ADENOCARCINOMA IN
SITU(AIS)
•Defined as a localised (≤3cm) neoplastic
lesion growing along existing alveolar walls
in a lepidic growth pattern.
•Atypical cells form a continuous monolayer
of cells along alveoli ,no stromal invasion; no
necrosis
• shows mild to moderate cytologic atypia,
hyperchromasia, small nucleoli, increased
N:C ratio, hob nailing may be present.
Mucinous type adenocarcinoma in situ are
extremely rare
D/D-Minimally invasive adenocarcinoma-
invasive foci present

14. D/D OF ATYPICAL ADENOMATOUS
HYPERPLASIA (AAH)
•ADENOCARCINOMA IN SITU - is >0.5cm ( unlike AAH <0.5 cm) in size lesion, shows
cellular crowding and more abrupt transition to adjacent normal alveolar lining than AAH
and Columnar cells form a continuous monolayer along the alveoli.
•REACTIVE PNEUMOCYTE HYPERPLASIA- shows parenchymal inflammation and
fibrosis and the atypical pneumocytes tend to be more diffuse and do not form well
defined nodular areas. (unlike AAH.)

15. Minimally Invasive
Adenocarcinoma
• MIA is adenocarcinoma with lepidic growth pattern
predominantly with foci of invasion measuring
≤0.5 cm in greatest dimension and invasive
component should be non lipidic , as it can be
Acinar, papillary, micropapillary, solid , colloid,
fetal or mucinous.
• Acinar Pattern is the commonest invasive pattern
seen here.
• Image shows small invasive component consisting
of well differentiated glands (acinar pattern)seen
infiltrating through desmoplastic stroma.

16. The Entire Tumor Must Be Sampled for Diagnosis of AIS orMIA
 Minimally invasive adenocarcinoma should be excluded if the tumor
 Invades lymphatics, blood vessels, or pleura or
 contains tumor necrosis
 shows tumour spread through air spaces.
If multiple microinvasive areas are found in 1 tumor, the size of the
largest invasive area should be measured in its greatest dimension
and it should be 5 mm or less in size.
•Invasive adenocarcinoma, lepidic predominant pattern:
• Invasive foci must be 0.5 cm or more in size
•Adenocarcinoma in situ / Atypical adenomatous
hyperplasia
• No invasive component
Differential diagnosis of MIA

17. INVASIVEADENOCARCINOMA
• It is m/c lung cancer in nonsmokers and females , usually peripheral in location .
• Invasion should be present in at least 1 focus, measuring more than 5 mm in greatest
dimension .
(1) Histologic pattern of invasion should be other than lepidic pattern (ie,
acinar,papillary, micropapillary, and/or solid, colloid, fetal, enteric type).
(2) Document percentage (>5%) of each type present( lepidic to papillary to
acinar, micropapillary) as they are usually composed of complex heterogenous
mixture of patterns.

18. INVASIVE
ADENOCARCINOMA
shows peripherally located poorly circumscribed
mass containing a large area of central scarring.
•Greyish yellow on cut .
• There is a strong tendency for
multicentric, multilobar, and bilateral
lung involvement, which may reflect
aerogenous spread.

19. Lepidic Invasive
Adenocarcinoma
• Defined as non mucinous
adenocarcinoma that has lepidic
growth as its predominant
component means tumor cells
grow along the alveolar walls
• Tumor with lepidic predominant
pattern usually have good
prognosis.

20. Acinar Predominant
Adenocarcinoma
• Shows round / oval closely
packed glands with visible
lumen seen invading in to
desmoplastic stroma .
• Individual cells are round to
oval shows high N:C ratio,
pleomophism, hyperchromatic
nuclei, prominent nucleoli with
moderate amount of cytoplasm
and peripheral nuclear
polarization and apical
cytoplasm can be seen.
• Desmoplastic stroma is usually
present.

21. PapillaryAdenocarcinoma
• Presence of papillary structures with
true fibrovascular cores replacing the
alveolar lining or present within the
alveolar spaces
• The fibrovascular cores are lined by
cuboidal to columnar neoplastic cells

22. MicropapillaryAdenocarcinoma
Characterized by tumor cells growing in
small papillary tufts that lack fibrovascular
cores, these may be detached and/ or
connected to alveolar walls.
• The tumor cells are usually small
and cuboidal with mild to
moderate nuclear atypia.
• Small glandular structures may ‘‘float’’
within alveolar spaces .Vascular and
stromal invasion is frequent.
• Associated with poor prognosis.

23. SolidAdenocarcinoma
• Shows polygonal shaped tumor cells
arranged in sheets that lack recognizable
patterns of adenocarcinoma
• If the tumor is 100% solid, intracellular mucin
should be present in 5 or more tumor cells in
each of 2 hpf, confirmed with histochemical
stains for mucin
• Solid adenocarcinoma must be distinguished
from squamous cell carcinomas and large cell
carcinomas, both of which may show rare
cells with intracellular mucin
• Associated with poor prognosis.

27. Invasive mucinous
adenocarcinoma
• Large glands filled with mucin are characteristic of the
mucinous adenocarcinoma
• Comprising of columnar epithelium and shows
intracytoplasmic mucin ,minimal cytological atypia.
• These tumors may show the same heterogeneous
mixture of lepidic, acinar, papillary, micropapillary, and
solid growth as in non mucinous tumors
• If there is at least 10% of each component, it
should be classified as ‘‘mixed invasive
mucinous and non mucinous adenocarcinoma

28. Colloid
Adenocarcinoma
• This is characterised by extracellular mucin
lakes that can expand and destroy existing
alveolar spaces.
• Contains malignant mucinous epithelium
which is of tall columnar type , growing along
the alveolar septa in a lepidic pattern,is often
difficult to visualise. Tumor cell clusters are
seen floating in pools of mucin.

29. Enteric Type
adenocarcinoma
• Is an extremely rare tumor that has a
striking resemblance to colorectal
adenocarcinomas.
• It is composed of moderate to well-
differentiated glands, often with cribriform
pattern, lined by eosinophilic tall columnar
cells with nuclear pseudostratification, dirty
necrosis and nuclear debris.
• Presence of other subtypes of primary lung
adenocarcinomas & CK7 negativity
facilitates distinction from metastatic
colorectal adenocarcinoma , frequently
express some or all markers of enteric
differentiation such as CDX2, MUC2 and
CK20, in addition to the pulmonary markers.

30. Fetal adenocarcinoma
• This is characterised by Irregular tubular
structures lined by columnar epithelial
cells with clear cytoplasm and oval
nuclei, optically clear nuclei rich in
biotin.
• Resembles fetal lung in pseudoglandular
stage
• Morular metaplasia, as in endometrioid
adenocarcinoma, can also be seen
• AFP+ ,PAX 8 – differentiate it from
endometrioid carcinoma.

31. IHC: ADENOCARCINOMA
Positive stains
•TTF1, Napsin A , CK7, beta catenin, cytokeratin AE1/3
,EMA ,surfactant apoprotein(PE-10)
Negative stains
•p53, p40, p63, CK5/6, WT1, D2-40, calretinin,

32. D/D OF ADENOCARCINOMA
•Squamous cell lung carcinoma
• Is positive for p40 or p63; negative for TTF1
• shows large, more eosinophilic cells with intracellular bridges and contains keratin
•Small cell lung carcinoma
• Is positive for neuroendocrine markers, shows Small round blue cells, usually in sheets .
•High grade neuroendocrine tumor
• Increased mitotic activity (> 10/high power field), necrosis
• Positive for neuroendocrine markers and nuclear chromatin is clumped / salt and pepper
appearance
•Metastatic adenocarcinoma
• Negative for TTF1 (unless thyroid),Positive for markers from primary site(CDX2+ metastatic
colorectal adenoca, ER+ breast ca, GATA3+ urothelial ca)
•Metastatic papillary thyroid carcinoma
• psammoma bodies, nuclear features of PTC (orphan Annie)
• PAX8 and thyroglobulin positive

33. SQUAMOUS CELL CARCINOMA
•They have a strong association with cigarette smoking.
•SCC usually presents as a central tumour close to the hilum.
• They tend to produce symptoms earlier than adenocarcinoma and commonly show direct
spread into adjacent structures, in particular hilar lymph nodes. However, they are late to
metastasize compared with adenocarcinoma .
• can occur as endobronchial growth - associated with bronchial obstruction and post
obstructive pneumonia.

34. SQUAMOUS CELL CARCINOMA: MOLECULAR
ALTERATIONS
TP53 mutation
CDKN2A inactivating mutation (deletion at 3p&9p)
NOTCH1 & NOTCH 2 mutation
FGFR1 amplification

35. SQUAMOUS CELL CARCINOMA
•Usually present as hilar or perihilar mass.
•Demonstrates central cavitation.

36. Well-differentiated squamous cell
carcinoma showing keratinization
Sheets or islands of large polygonal malignant cells and
intercellular bridges

37. Basaloid variant : SCC
The tumor cells have a basophilic appearance and
are arranged in lobules with peripheral
palisading.
It is high-grade poorly-differentiated
variant that lacks obvious squamous
morphology ( like keratinization, keratin pearls,
intercellular bridges) but expresses squamous cell
markers (p40, p63) by immunohistochemistry.
Tumors with obvious squamous differentiation but a
majority basaloid component (>50%) are also
classified as Basaloid variant of SCC.

38. Basaloid variant : SCC
Basaloid squamous cell carcinoma
composed of inter anastamosing
cords of basaloid cells having central
areas of typical squamous cell
carcinoma.
Compressed lung parenchyma can be
seen at the top of the image.
It is characterized by a very
aggressive clinical course.

39. LYMPHOEPITHELIAL
CARCINOMA
•Lymphoepithelial carcinoma shows
syncytial growth pattern
•Large polygonal cells , round to oval
vesicular nuclei with multiple prominent
nucleoli and variably abundant
eosinophilic cytoplasm along with
lymphoid infiltrate and variable mitosis
•Squamous markers: CK5/6, p40, p63 +
•EBER1 +: desirable diagnostic criteria

40. IHC: Squamous cell carcinoma
•SCC strongly positive for p40, p63 and high molecular weight cytokeratin– CK 5/6
,Thrombomodulin .
•Always negative for TTF-1 and Napsin-A, Vimentin .

41. Differential Diagnosis of squamous cell
carcinoma
Metastatic squamous cell carcinoma( positive for markers
of origin.)

42. LARGE CELL CARCINOMA
LCCs are undifferentiated malignant epitheial carcinomas lacking cytologic features
of small-cell carcinoma and glandular or squamous differentiation.
They represent approximately 10% of Non Small Cell Lung Ca and have a strong
association with cigarette Smoking.
They commonly present as large peripheral tumours that shows a
fleshy, necrotic cut surface without cavitation.
This is a diagnosis of exclusion that can only be accurately made on a surgical
specimen rather than biopsy due to the heterogeneity of lung carcinomas“

43. LARGE CELL CARCINOMA : MOLECULAR ALTERATIONS
KRAS mutation
NRAS mutation
MET amplification
STK11mutation
PIK3CA Amplification & mutation

44. Large cell
carcinoma
Tumor cells are large,pleomorphic,
with abundant cytoplasm &
prominent nucleoli.
Atypical mitotic figures are usually
present.

45. IHC:LARGE CELL CARCINOMA
Low molecular weight cytokeratin -CAM 5.2 +
TTF1-
p40 -
Synaptophysin -
Chromogranin –

46. D/D OF LARGE CELL CARCINOMA
• Large cell Neuroendocrine carcinoma – synaptophysin, chromogranin, NSE +
• Solid variant of adenocarcinoma –TTF1, NAPSIN +
• Basaloid squamous cell carcinoma – P40 +
• Metastatic carcinoma – positive markers for site of origin.

47. SARCOMATOID CARCINOMA
• Sarcomatoid carcinomas are a group of poorly differentiated non-small cell
carcinomas
• Strongly associated with tobacco smoking ,Classified into
Pleomorphic carcinoma
variants- Spindle cell carcinoma
Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma

48. • usually aggressive, poorly differentiated malignant
epithelial neoplasm composed of cells with significant
cytologic atypia and nuclear pleomorphism
•Contains at least 10% spindle cells and / or giant cells
Pleomorphic carcinoma
•Giant cells usually bizarre with multilobulated nuclei,
abundant eosinophilic cytoplasm accompanied by heavy
neutrophilic infiltrate
•Stroma is often myxoid, with collagen fibers, numerous
mitotic figures
•Massive necrosis common, Vascular invasion is
common, characterized by the presence of pleomorphic,
undifferentiated cells and numerous giant cells.

49.  Subtype of Sarcomatoid carcinoma
 Majority of cases are diagnosed in adults over the age
of 65 years
 Carcinoma composed exclusively
of spindle-shaped tumor cells
 Tumor cells often obliterate vessels
Spindle cell carcinoma
 These tumors consist of spindle-shaped tumor cells
haphazardly arranged in irregular fascicles and
whorls.

50. Pulmonary giant cell
carcinoma
Consists of discohesive, pleomorphic,
mononucleated or multinucleated giant cells
,frequently intermingled with a rich
inflammatory infiltrate predominantly
composed of neutrophils. Prominent
Mitosis also seen

51. Pulmonary blastoma
• Usually seen in adults ,peripherally located, large
mass, characterised by well differentiated glands
resembling fetal lung lined by pseudostratified
columnar cells with subnuclear and supranuclear
glycogen vacuoles
• Cellular stoma composed of undifferentiated small
blastematous spindle cells with variable cellular atypia,
possible heterologous differentiation (skeletal muscle,
cartilage and bone)
 Morules which are clusters of cells with
abundant acidophilic cytoplasm & ground
glass nuclei due to accumulation of biotin
are common
Positive stains
 PAS (glycogen in epithelial cells)
Molecular Genetics
 CTNNB1mutation,aggressive tumor with poor prog.

52. D/D OF Pulmonary blastoma
• Fetal type adenocarcinoma- no blastematous stroma
•Pleuropulmonary blastoma –occur in age <4 years, no epithelial component,DICER1 mutation
•Synovial sarcoma –TTF1- ,TFEL1 +
•Carcinosarcoma – absence of morules , CTNNB1 mutation -

53.  More common in male with
smoking history & older age
 Sites - Large airway and
peripheral lung
 Biphasic tumor composed of a
mixture of well differentiated adenocarcinoma
and heterologous sarcomatoid differentiation
 Rare tumor with poor prognosis
 Osteosarcoma, chondrosarcoma, and
rhabdomyosarcoma are the
most common components, sometimes intermingled in the
same tumor.
Carcinosarcoma

54. ADENOSQUAMOUS
CARCINOMA
•Defined as carcinoma showing both squamous and
glandular differentiation, with each component
comprising at least 10%.
•Associated with cigarette smoking.
• They often present as a peripheral mass and can
show central scar formation .
•On immunohistochemistry, the adenocarcinoma
component should express TTF-1 and CK7, while the
squamous component is usually stained by p63 and
CK5/6.

55. OTHER EPITHELIAL TUMOURS
• Thoracic SMARCA4-Deficient ( WHO update)
Undifferentiated Tumor
• NUT carcinoma

56. Thoracic SMARCA4-Deficient
Undifferentiated Tumor
• occur in middle age, male & in smokers
•It is rapidly progressive tumor
• Present as large mass in mediastinum or pulmonary
hilum or pleura with or w/o chest wall involvement
•Often present with metastases.

57. SMARCA4-UT
•Poorly differentiated tumor usually with
rhabdoid morphology.
•Diffuse sheets of variably cohesive, large
,round to epithelioid cells,with large
eccentric nuclei with vesicular
chromatin & prominent nucleoli and
large paranuclear intracytoplasmic
inclusions & abundant eosinophilic
cytoplasm .
•Focal myxoid or desmoplastic stroma
can be seen
•Epithelial architecture(glands) should be
absent.

58. SMARCA4-UT
Loss of BRG1 (& BRM) expression .
Preserved INI-1 expression.
Commonly positive for SOX2, CD34 and/or SALL4.
• Negative or focal positivity for- Keratin (focal), claudin 4 (rare), TTF-1 (rare),
synaptophysin.
SMARCA4 (BRG1) - is a member of BAF chromatin- remodelling complex
 Regulates transcription , promotes cell differentiation.
Biallelic inactivation of SMARCA4 gene.
TP53 mutation can also be seen .

59. SMARCA4-UT - Differential Diagnosis
•NUT carcinoma
•Neuroendocrine carcinoma
•Lymphoma
•Melanoma
•Sarcomas
•SMACRA4-deficient NSCLC – CK++(unlike SMARCA4-UT),epithelial architecture
present.
•Metastatic SMACRA4-deficient carcinoma (uterus, ovary, stomach, kidney, pancreas)

60. NUT carcinoma
NUT carcinoma is an aggressive malignancy characterized by NUT gene
rearrangements
Somatic NUT reciprocal translocation leading to expression of an oncogenic NUT fusion
gene
Positive stains
NUT speckled nuclear positivity.
Keratins, particularly high molecular weight +
p63 and p40 ,MYC ,p16 +
Negative stains
CD99, synaptophysin, FLI1, EGFR, HER2, focal TTF1

61. NUT carcinoma
•Diffuse architecture with occasional spacing
and dyscohesion of tumor cells is present
• Cells are primitive looking, monotonous,
medium sized cells with frequent
cytoplasmic clearing ,prominent nucleoli.
•Scattered foci of abrupt keratinization can be
seen
•Background can shows necrosis with
prominent neutrophils.

62. D/D OF NUT carcinoma
•Focally keratinizing or basaloid squamous cell carcinoma :
NUT immunohistochemistry is important in differentiating these tumors
•Thymic carcinoma :
Thymic carcinomas usually express all of CD5, GLUT1 and CD117
•Small cell carcinoma:
Occasional positivity for synaptophysin and nuclear molding in NUT carcinoma is a diagnostic
pitfall
NUT immunohistochemistry can help differentiate
•Ewing sarcoma:
Occasional positivity for CD99 in NUT carcinoma is a pitfall
Ewing sarcomas express NKX2.2 by immunohistochemistry and harbor EWSR1 gene
rearrangement

63. Bronchial Adenoma / Ciliated
Muconodular Papillary Tumor
•Benign tumor
•Peripheral, peribronchiolar in location , not
associated with proximal bronchi
• affects middle age to elderly, no sex
predilection
•Tumor diameter is usually <2.5 cm

64. BA / CMPT
• shows papillary or glandular architecture
•Luminal epithelial cells may contain mucous
and or ciliated cells or cuboidal cells
•Shows continuous basal cell layer
surrounding luminal cells.→ p40 and TTF-1
positive.
•No nuclear atypia; rare mitoses
•Potential molecular alterations are: BRAF,
EGFR, KRAS, HRAS, ALK, AKT1

66. BA/CMPT
Differential Diagnosis
•Adenocarcinoma (including AIS) – lacks continuous basal cell layer.
•Papilloma -central, endobronchial( unlike BA/CMPT which shows
parenchymal involvement)
•Peribronchiolar metaplasia
Lack of expression of BRAF, ALK
Often multicentric, no discrete nodule formation ( in contrast to
BA/CMPT.)
Occur in background of Interstitial lung ds or small airways disease.

67. Neuroendocrine Neoplasms
• Precursor lesion of neuroendocrine tumors
Diffuse idiopathic neuroendocrinal cell hyperplasia
• Neuroendocrine carcinomas
Small cell carcinoma
Large cell neuroendocrine carcinoma
• Neuroendocrine tumours
Carcinoid tumor , NOS
TYPICAL
ATYPICAL

69. Small Cell Carcinoma
• Arises from neuroendocrine cells.
• Centrally located masses , extension to lung
parenchyma can be seen.
• Tan-white ,soft, friable mass, extensively necrotic.
• Involvement of hilar & mediastinal nodes

70. MUTATIONS: SMALL CELL CARCINOMA
Tp53 mutation
Ch.3p deletion
Loss of function mutation of RB gene
L-MYC amplification
Telomerase activation
Small cell carcinomas have highest mutational burden.

71. Paraneoplastic syndromes
Due to abnormal production of:
– increased ACTH secretion (Cushing's syndrome)
– increased ADH (SIADH - hyponatremia)
– Superior venacava syndrome.( obstruction of svc -facial &limb edema)
– Encephalomyelitis
– Lambert-Eaton syndrome (ab against voltage gated calcium channels,ms
weakness)
– Carcinoid sx (due to serotonin &bradykinin-flushing,wheezing, diarrhoea)
– Subacute sensory neuropathy
Small cell carcinoma is very aggressive tumor with early distant
metastasis

72. Shows sheets and clusters of small round
,hyperchromatic cells with dispersed finely
granular( salt & pepper) chromatin,
inconspicuous nucleoli and scant cytoplasm
and forming rossette
Small cell carcinoma
• shows nuclear moulding, high mitotic rate.
• Stroma: thin, delicate, scant, fibrovascular.
• Necrosis and apoptosis of individual cells
common

73. Crushed elongated deformed small blue cells
along with chromatin diffusion c/a “Crush
artifact” or “chromatin smearing or
streaming” is commonly seen
Azzopardi phenomena:
Basophilic nuclear DNA from necrotic tumor cells
gets deposited in the walls of vessels
small cell carcinoma

74. IHC: SMALL CELL CARCINOMA
Positive stains
Low molecular weight keratin CK7 +(weak) ,TTF1 +
NSE ,SYNAPTOPHYSIN ,CHROMOGRANIN,CD56 ,INSM1 +
Negative stains
NAPSIN, PAX-8, P40, P63

75. Differential diagnosis of small cell carcinoma
• Carcinoid tumors –ki67(MIB-1) Negative ( positive only < 10% cases).
• Large cell Neuroendocrine carcinoma - prominent nucleoli, abundant cytoplasm,
large nucleus.
• Lymphoma –Low molecular weight keratin negative.
• Basaloid variant of squamous cell carcinoma - HMW keratin + (Ck5/6,p63,p40 ),
TTF1 & Neuroendocrine markers negative.
• Poorly differentiated lung adenocarcinoma – CK 7++ (Strong),Neuroendocrine
markers -

76. Large cell neuroendocrine carcinoma
• Neuroendocrine architecture may include organoid, nesting,
palisading, trabecular, solid patterns and rosette-like
structures
• Large cells (~3x size of small cell carcinoma) with abundant
cytoplasm, nuclear pleomorphism, salt pepper
chromatin,prominant nucleoli.
• >10 mitoses / 2 mm2, extensive necrosis
• Chromogranin, synaptophysin, CD56, CD117 Cam5.2,
TTF1 + , High Ki67 index- helpful to differentiate from
carcinoid tumors, especially in small biopsies

77. Diffuse idiopathic neuroendocrinal cell
hyperplasia
•It is considered a preinvasive lesion that may progress into tumorlets or carcinoid
tumors (usually typical carcinoid).
•Histologic features comprise a diffuse intramucosal proliferation of pulmonary
neuroendocrine cells in monolayers or small groups that can penetrate through the
bronchial basement membrane to form tumorlets.
•Must be differentiated from secondary DIPNECH, which is a localized neuroendocrine
proliferation secondary to another chronic lung disease.

78. Diffuse idiopathic
neuroendocrinal cell hyperplasia
It is proliferation of neuroendocrine cells arise from
terminal bronchioles.
Cells are round, oval or spindle shaped, have a
moderate amount of eosinophilic cytoplasm and
have round to oval nuclei with a salt and pepper
chromatin.
Cells do not cross the mucosal basal lamina.

79. CARCINOID TUMORLET
• Tumorlet presenting as a small poorly defined
nodule of neuroendocrine cells that cross
beyond mucosal basal lamina
• They are benign,poorly defined nodules with
infiltrative margins in a fibrotic stroma, usually
found in relation to an airway.
• Tumor size < 5 mm with minimal mitosis &
absence of necrosis.

80. Differential diagnosis of carcinoid tumorlet
Typical carcinoid:
Tumor size 5 mm or more with < 2 mitoses/2 mm² and absence of necrosis
Atypical carcinoid:
Tumor size 5 mm or more with > 2 mitoses/2 mm² or presence of necrosis

81. • Typical Carcinoid tumor have central & peripheral
variants, mostly asymptomatic.
• Central carcinoids- present with recurrent
pneumonias or hemoptysis.
• association with (MEN)1 syndrome in 5%
• Grossly, carcinoids are usually >5mm or more in
size , well-circumscribed, round to oval mass
filling up the bronchial lumen. Appear as yellow
or fleshy, polypoid masses.
• tumor can infiltrate between cartilaginous
rings to extensively involve the bronchial
submucosa.
Carcinoid tumor

82. • Tumor cells are arranged in nested
pattern ,composed of intermediate
sized uniform polygonal cells,having
central nuclei, inconspicuous nucleoli,
moderate amount of granular
cytoplasm.
• characteristic of neuroendocrine tumor is
chromatin that is finely dispersed granular
or classically described as “salt and
pepper” chromatin.
• Ocassionally nuclear pleomorphism and
hyperchromasia can be seen but without or
<2 mitosis per 2 mm2 and lacks
necrosis.
Typical Carcinoid tumor

83. •Different patterns of Typical carcinoid
A. organoid nesting arrangement
B. Prominent spindle cell pattern
C. Trabecular pattern
D. Oncocytic features with abundant eosinophillic cytoplasm

84. Atypical carcinoid
• Histologic patterns similar to typical carcinoids: organoid,
trabecular, papillary.
• Tumor cells shows ,greater pleomorphism than typical
carcinoid , nuclei with salt and pepper chromatin and
inconspicuous nucleoli, along with moderate to abundant
eosinophilic cytoplasm. Spindle cells and clear cell
features can be seen
• Stroma is fine and highly vascularized; hyalinization,
cartilage or bone formation are possible
• shows 2 - 10 mitoses per 2 mm² or presence of
necrosis
Mitotic rate should be counted in the area with the highest
proliferation rate .

85. M
Mitoses
ATYPICAL CARCINOID
large
zones
necrosis
Punctate
necrosis
with LVI

86. IHC : Carcinoid Tumour
• NE markers strong positivity.
(NSE ,SYNAPTOPHYSIN ,CHROMOGRANIN,CD56 +)
•TTF-1 +/- , ck+

87. Differential diagnosis of carcinoid tumour
•Small cell carcinoma –ki67(MIB-1) strongly ++
•Metastatic carcinoid – CDX2 + ,PAX8+ (unlike carcinoid).

88. MUTATIONS: CARCINOID TUMOR
• MEN1 gene mutation
• ARID2 , SETD1B & STAG1 gene mutation

90. Perivascular epithelioid cell tumor (PEComatous
tumours)
Benign PEComa
Malignant PEComa
Lymphangioleiomyomatosis
MESENCHYMAL TUMORS

91. BENIGN PEComa /
SUGAR TUMOR
 Also called as- Clear cell tumor
 Benign peripheral lung mass derived from
perivascular epithelioid cells, occurs in
adults >40 years of age.
Gross- Small sharply outlined
glistening ,red- tan mass
c/s -shows foci of necrosis

92. SUGAR TUMOR
 Microscopy :
Clear to eosinophilic, finely granular
cytoplasm containing abundant PAS+
glycogen.
Small, uniform, round nuclei with small
nucleoli, prominent sclerotic
vasculature.
There is absence of cellular atypia,
necrosis, and mitotic activity.
“Spider cells” with nuclear condensation
of eosinophilic cytoplasm with extensions
to the cell membrane.

93. Malignant PEComa
Gray-white, circumscribed tumor
confined to the lower lobe under the
pleura

94. Malignant PEComa

95. Gross
Numerous uniform thin-walled cysts and
bullae throughout the lungs creating
a honeycomb appearance.
Lymphangioleiomyomatosis

96. Lymphangiomyomatosis (LAM) is a low-grade
destructive tumor that diffusely
involves lungs in women of reproductive age.
About 15% of patients with LAM have tuberous
sclerosis.
Cytological features are same as other pecomatous
tumours. The tumor cells may invade lymphatics and
blood vessel walls causing secondary hemorrhage and
destruction of the septal wall.
This results in formation of cystically-dilated airspaces
Lymphangioliomyomatosis

97. LAM shows proliferation of plump spindle-shaped
cells arranged in short fascicles around arterioles,
venules, and lymphatics which cause thickening of
alveolar septa.
Lymphangioleiomyomatosis

98. • Mutations in tuberous sclerosis genes
TSC1 and TSC2
• TFE3 (transcription factor 3 ) rearrangement –
associated PEComa shows aggressive
behaviour and poor prognosis
IHC : PEComatous Tumor

99. HMB45, MART1/MelanA , MITF, SMA, desmin, S100
CD1a , synaptophysin, NSE
Negative stains
Keratins, EMA
Positive stains
PEComatous Tumours

100. Differential Diagnosis of PEComatous
Tumor
•Renal cell carcinoma - ck7+ ,EMA +,NAPSIN +,HNF1Beta +,AMACR +
•Metastatic clear cell sarcoma - BCL2+ , SMA-, desmin - ,Synaptophysin - ,CD56 –
,more prominant nucleoli, giant cells +
•Metastatic melanoma – SMA - ,desmin -, synaptophysin-, NSE-
•Paraganglioma - HMB45 -, Melan A -, S100 (focal)+

102. PROGNOSIS
Histologic type
Tumor size and location
Involvement of pleura
Surgical margins
Status and location of lymph nodes by station
Tumor grade
Lymphovascular invasion
Identification of gene mutations in lung cancer
Spread Through Airspace (STAS)

103. Spread Through Airspace (STAS)
• It is defined as tumor cells within airspaces beyond the edge of main tumor
•Present in 15-56% of NSCLC
• composed of 3 morphological Patterns: Micropapillary structures, Solid tumor
cell nests , Discohesive single tumor cells
•Spread through air spaces is more commonly associated with
adenocarcinomas
•SQCC, neuroendocrine neoplasms (all subtypes), pleomorphic carcinoma
can also show stas but less commonly
•Not included in total % of pattern or tumor size for staging because its just a
pattern of tumor spread.

104. Spread Through Airspace (STAS)
The extent of STAS was graded according to the distance from the edge of tumor with
a two-tiered system.
When all tumor clusters were present within 2500 μm (equivalent to one field of ×10
objective lens) from the edge of the tumor, STAS was graded as I, while it was graded
as II when any of tumor clusters were seen equal or greater than 2500 μm away from
the edge of tumor .
To differentiating STAS from artifacts. Artifacts were defined as; (1) tumor cell clusters
with jagged edges owing to tumor fragmentation or knife cuts during specimen
processing; (2) linear strips of cells that were lifted off the alveolar walls; (3) rare
isolated tumor clusters found at a distance rather than spreading in a continuous
manner.

105. Spread Through Airspace (STAS)
•Reduced recurrence free and overall survival in any
stage lung adenoCa
•Associated with aggressive pathologic features, KRAS
mutations
•Limited resection shows –
possibly higher risk for recurrence than lobectomy

106. Spread Through Airspace
(STAS)

108. Common Sites of Metastasis of Lung Cancer
• Lymph node
• Adrenal
• Liver
• Bone
• Brain
• Kidney
• Spleen

109. Tumors metastatic to the Lungs
• Colon
• Breast
• Kidney
• Head n neck
• Bone
• Thyroid
• Bladder
• Prostate