Neuroendocrine Lung Tumors Myers€¦ · ATYPICAL CARCINOID TUMOR Ha et al. Lung Cancer 2013; 80: 146 “moderate” “marked” “invasion to the adjacent lung parenchyma with

Neuroendocrine Lung Tumors – Myers

Jeffrey L. Myers, M.D.

A. James French Professor Director, Anatomic Pathology & MLabs University of Michigan, Ann Arbor, MI

[email protected]

Diagnosis and Classification of Neuroendocrine Lung Tumors

Lost In Processing

As a result of this presentation, attendees who were fully engaged will be able to,

• apply criteria for separating low grade from high grade neuroendocrine tumors, and

• articulate the clinical, biological, histologic, immunohistochemical, and molecular overlap between them.

Neuroendocrine Lung Neoplasms


Classification

WHO* Other

Typical carcinoid Well differentiated/

low grade

Ne

uro

en

do

crin

e

ca

rcin

om

a

Atypical carcinoid Moderately differentiated/

intermediate grade

Small cell carcinoma

Poorly differentiated/

high grade Large cell

neuroendocrine

carcinoma

*Travis et al (editors). WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2004.



Classification

WHO* Other


low grade

Ne

uro

en

do

crin

e

ca

rcin

om

a


intermediate grade




neuroendocrine

carcinoma


TYPICAL CARCINOID TUMOR

~ 75% central ~ 25% peripheral

TYPICAL CARCINOID TUMOR Definition*

• “neuroendocrine” growth pattern

“organoid, trabecular, insular, palisading, ribbon, rosette-like”







uniform cytology ± “atypia”

TYPICAL CARCINOID TUMOR Definition*


• uniform cytology ± “atypia”

• < 2 mits/2 mm2

• no necrosis



Classification

WHO* Other


low grade

Ne

uro

en

do

crin

e

ca

rcin

om

a


intermediate grade




neuroendocrine

carcinoma



ATYPICAL CARCINOID TUMOR Definition*



• 2-10 mits/2 mm2, and/or

• necrosis


TYPICAL VS. ATYPICAL CARCINOID TUMOR Ha et al. Lung Cancer 2013; 80: 146

Histology

Typical

(40)

Atypical

(23) p value

rosettes 0 6 (26%) .001

parenchymal invasion* 5 (13%) 9 (39%) .01

vascular invasion 0 3 (13%) .04

lymphatic invasion 2 (5%) 6 (26%) .04

abundant basophilic

cytoplasm 10 (25%) 0 .01

*“invasion to the adjacent lung parenchyma with an infiltrative border”



“moderate” “marked”

“invasion to the adjacent lung parenchyma with an

infiltrative border”

*

ATYPICAL CARCINOID TUMOR Comparison with Typical Carcinoid

typical carcinoid

atypical carcinoid

Survival 5 years 10 years

89-99% 82-93%

61-78% 35-67%

from Garcia-Yuste et al. Eur J CV Surg 2007 (n = 661 surgical patients)



• 2-10 mits/2 mm2



97 (91.5%) of 106 cases had ≥ 2 mits/2 mm2

Beasley et al Hum Pathol 2000; 31: 1255



Mitoses



• 2-10 mits/2 mm2

• ± necrosis



71 (67%) of 106 cases had necrosis

Beasley et al Hum Pathol 2000; 31: 1255


Classification

WHO* Other


low grade

Ne

uro

en

do

crin

e

ca

rcin

om

a


intermediate grade




neuroendocrine

carcinoma



SMALL CELL CARCINOMA General

• cigarette smoking

• ~ 15% of incident cases

• men ≥ women (~1-2:1)

• central >> peripheral


clinical stage (n=7,960†)

I 7%

II 4%

III 32%

IV 57%

limited 45%

extensive 55%


†from Shepherd et al. J Thorac Oncol 2007

†from Shepherd et al. J Thorac Oncol 2007

Survival (n = 7,960†)

cStage % of pts 1 year 5 years

I 7% 41% 28%

II 4% 73% 21%

III 32% 54% 11%

IV 57% 22% 1%


limited 45%

extensive 55%



SMALL CELL CARCINOMA WHO Definition

malignant epithelial tumor consisting of,

• small cells with scant cytoplasm, ill-defined cell borders

“usually less than the size of three small resting lymphocytes”

WHO “size rule” ≤ 3 x lymphocyte diameter





• finely granular nuclear chromatin, and absent or inconspicuous nucleoli


• finely granular chromatin • absent/inconspicuous nucleoli

“In 29 cases, a varying percentage of cells demonstrated nucleoli that were conspicuous but small.” Nicholson et al. AJSP 2002




• cells are round, oval and spindle-shaped; nuclear molding is prominent


round, oval and spindle-shaped

nuclear molding is prominent


nuclear spooning is prominent

“spooning”

high mitotic count (>10/2 mm2)




• cells are round, oval and spindle-shaped; nuclear molding is prominent

• mitotic count is high (>10/2 mm2)


CLASSIFICATION OF LUNG TUMORS Rates of Diagnostic Agreement†

0% 25% 50% 75% 100%

SCLC

LCC

Adca

SqCC

Reg

ion

al P

ath

olo

gis

ts

Central Pathologist

SCLC

SqCC

Adca

LCC

Mixed

Other

N = 668 (tissue ± cytology specimens) SCLC highest rates of agreement (92%, Κ = 0.82)

†Stang et al. Lung Cancer 2006; 52: 29-36

WHO IASLC WHO (1981) (1988) (1999-2004)

oat cell small cell small cell

intermediate cell

mixed small/large cell

combined combined combined

small cell small cell small cell

SMALL CELL CARCINOMA Histologic Variants


& adenocarcinoma small cell


Classification

WHO* Other


low grade

Ne

uro

en

do

crin

e

ca

rcin

om

a


intermediate grade




neuroendocrine

carcinoma


LARGE CELL CARCINOMA WHO 2004

• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation


• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation

• 5 variants: – large cell neuroendocrine – basaloid carcinoma – lymphoepithelioma-like carcinoma – clear cell carcinoma – large cell ca with rhabdoid phenotype

LARGE CELL CARCINOMA WHO 2004

LARGE CELL NEUROENDOCRINE CARCINOMA

Definition

• neuroendocrine morphology



• necrosis (extensive)

• >10 mitosis/2 mm2 (10 hpf)

• cytologic features of NSCLC: – large size, low N:C, nucleoli, coarse

chromatin


Definition






chromatin

• immunohistochemical confirmation


Definition

chromogranin


Comparison with Atypical Carcinoid

atypical carcinoid LCNEC

NE morphology

necrosis ±

atypia mitotic rate 2-10/2 mm2 >10/2 mm2

Asamura et al. J Clin Oncol 2006; 24: 70-6


LCNEC atypical carcinoid

10 mits/2 mm2


Comparison with Atypical Carcinoid

LCNEC small cell ca

≤ 3 x lymphocytes, nucleoli, cytoplasm


Comparison with Small Cell Carcinoma

Hypothesis: LCNEC & SCLC are different

They look (and stain) differently.

They behave differently.

They are genetically distinct.


Large Cell Neuroendocrine Carcinoma Definition





chromatin

• immunohistochemical confirmation LCNEC vs

SCLC

Is cell size a reliable criterion for separating large cell

neuroendocrine carcinoma from

small cell carcinoma?


† Marchevsky et al. Am J Clin

Pathol 2001; 116: 466.

0

50

100

1 2 3 4 5 6 7

e.g. type A (peak TC/L = 2)

• n = 12 LCNEC and 16 SCLC

• measured tumor cell (TC) and lymphocyte (L) nuclear areas

• histograms for each peak TC/L: A = 2 B = 3 C = 4 D = 5 E = 6 F no peak

SCLC vs LCNEC Nuclear Size Overlap†


†Marchevsky et al. Am J Clin Pathol 2001; 116: 466.

0

1

2

3

4

5

6

7

8

TC/L = 2

(Type A)

TC/L = 3

(Type B)

TC/L = 4

(Type C)

TC/L = 5

(Type D)

TC/L = 6

(Type E)

no peak

(Type F)

SCLC

LCNEC

5 (31%) of 16 “SCLC” had predominant population of cells 4-6 times larger than

lymphocytes

* * *

“small”

“large”

SCLC vs LCNEC Nuclear Size Overlap†

0%

50%

100%

typical

carcinoid (16)

atypical

carcinoid (6)

small cell ca

(7)

LCNEC (14)

c-kit pos

bcl-2 pos

c-kit/bcl-2 pos

†LaPoint et al. Appl IHC Mol Morphol 2007; 15: 401-6

c-kit/bcl-2 expression in

SCLC & LCNEC

SCLC vs LCNEC Role of Immunohistochemistry†

0%

30%

60%

90%

typical carcinoid

(44)

atypical

carcinoid (7)

small cell ca

(26)

LCNEC (3)

Diffuse (> 10%)

2-3+ intensity

PAX-5 expression in

SCLC & LCNEC

†Sica et al. Am J Clin Pathol 2008; 129: 556-62



CRMP5 expression in

SCLC & LCNEC

†Meyronet et al. Am J Surg Pathol 2008; 32: 1699-708

0%

20%

40%

60%

80%

100%

typicalcarcinoid

(31)

atypicalcarcinoid

(15)

small cell ca(54)

LCNEC (4)

POSITIVE EQUIVOCAL

NEGATIVE


†Hiroshima et al. Mod Pathol 2006; 19: 1358

0%

20%

40%

60%

80%

100%

CRG SYN CD56 mASH1 NeuroD TTF p63 p16 PTEN

SCLC

LCNEC

p .0018

p .0422

p .0022 p .0369

p .0150


†Ha et al. Histopathology 2012; 60: 731-9

0%

20%

40%

60%

80%

100%

TC (19) AC (6) LCNEC (17) SCLC (18)

FoxM1

p27kip1(high)

p21waft1/cip1(+)



Large Cell Neuroendocrine Carcinoma Conclusion

Neither cell size nor immunohistochemistry reliably

separate large cell neuroendocrine carcinoma

from small cell carcinoma.






chromatin

• immunohistochemical confirmation

LCNEC vs other NSCLC

organoid?

squamous cell carcinoma


trabecular?

CK5/6 POS

p63 POS

TTF1 NEG

squamous cell carcinoma, basaloid variant

ribbons?


small cell?

CD56

SYN

LCNEC?

†den Bakker et al. Histopathol 2010; 56: 356

0

40

80

120

SCLC LCNEC Comb Carcinoid OtherNSCLC

Unsuitable

n = 170 large bxs, resections, mets 9 assessors (“special interest in lung cancer”)

20 (12%) = unanimous 117 (69%) = consensus (≥ 5)

Neuroendocrine Lung Tumors Diagnostic Reproducibility†


SCLC & LCNEC accounted for the largest number of outliers compared to the

consensus diagnosis

†den Bakker et al. Histopathol 2010; 56: 356

Neuroendocrine Lung Tumors Diagnostic Reproducibility†




LCNEC versus SCLC? Survival

J Clin Oncol 2006; 24: 70-6

Asamura, 2006

P = .9147


LCNEC versus SCLC?

Survival in Stage I Disease

Takei 2002

P =.1851

Asamura 2006

†Varlotto et al. J Thorac Oncol 2012; 6: 1050

“multivariate Cox analysis

demonstrated no significant differences between SCLC and

LCNELC . . . or between OLC

and LCNELC.”

LCNEC versus SCLC?

Survival in Stage I Disease†

Lung cancer-specific survival by histology for patients undergoing lobectomy or bilobectomy without

radiation for pT1N0 tumors

SEER database 2000 – 2007

†Rossi, G. et al. J Clin Oncol 2005; 23: 8774-8785

†Fig 5. Kaplan-Meier curves for overall survival stratified according to chemotherapeutic

protocols in the adjuvant setting and tumor stage

LCNEC is more likely to respond to chemotherapeutic strategies targeting

SCLC

“SCLC-based” = platinum-etoposide






neuroendocrine

tumors (38)

typical (12) & atypical (1)

carcinoids

“pure” small cell ca (15)

small cell & adca (2)

“pure” LCNEC (6)

LCNEC & adca (2)

large cell carcinoma (13)

well differentiated adenocarcinoma (12)

normal (30)

2,803 differentially expressed genes

unsupervised hierarchical clustering

Lancet 2004; 363 (9411): 775

Most SCLC & LCNEC were co-

mingled in 2 related but

distinct groups

HGNT1 4 “pure” SCLC

1 SCLC & adca

1 “pure” LCNEC

HGNT2 8 “pure” SCLC

4 “pure” LCNEC

HGNT3

2 “pure” SCLC

1 “pure” LCNEC

1 LCC

Lancet 2004; 363 (9411): 775


Lancet 2004; 363 (9411): 775

genetic profiles, but not histologic classification, separated patients with high grade NE tumors

into prognostically distinct groups





Large Cell Neuroendocrine Carcinoma Comparison with Small Cell Carcinoma

LCNEC small cell ca

≤ 3 x lymphocytes, nucleoli, cytoplasm


Large Cell Neuroendocrine Carcinoma Practical Approach?

LCNEC?

any way to make this

SCLC? • finely dispersed chromatin? • inconspicuous nucleoli? • scant cytoplasm? • is cell size the only issue? • clinical context?

– central mass in smoker with mediastinal adenopathy?


SCLC? YES!

SCLC



SCLC?

NO

compelling reason to

acknowledge neuroendocrine differentiation?

• LCNEC already diagnosed • IHC stains and it really, really looks

neuroendocrine but ≠ atypical carcinoid • been called SCLC but it isn’t



LCNEC


SCLC?

NO



YES!


LCC, sq cell

ca, adca


SCLC?

NO



NO


As a result of this presentation, attendees who were fully engaged will be able to,

• apply criteria for separating low grade from high grade neuroendocrine tumors, and

• articulate the clinical, biological, histologic, immunohistochemical, and molecular overlap between them.


Documents

Neuroendocrine Lung Tumors Myers€¦ · ATYPICAL CARCINOID TUMOR Ha et al. Lung Cancer 2013; 80: 146 “moderate” “marked” “invasion to the adjacent lung parenchyma with