Pulmonary Neuroendocrine Neoplasms

Cesar A. Moran, MD

Definition: Typical carcinoid: <2mitoses x 10hpf and lack of necrosisAtypical Carcinoid: 2-10 mitoses x 10hpf and/or foci of necrosis

Thanks – Conference is over

1.5

Pulmonary Neuroendocrine Neoplasms

• It has been estimated that approximately 65-70% of neuroendocrine neoplasms occur in the gastrointestinal tract: appendix 40%, rectum 14%, ileum 11%, duodenum 2-5%

• On the contrary, these tumor in the lung represent only approximately 10-15%.

Pulmonary Neuroendocrine Neoplasms

• In general, the nomenclature of these tumors has been debated for a considerable number of years.

• Different parameters have been used to assess clinical behavior including: morphology alone, IHC, molecular biology.

• Regardless, aggressive behavior has been estimated in 10-15% of these tumors.

In 1972, Arrigoni popularized the term “ Atypical Carcinoid”

• Carcinoid– Nesting pattern, ribbons– Glandular or alveolar

appearance– Well organized growth pattern

• Atypical Carcinoid– Mitotic activity 5-10x10hpf– Nuclear pleomorphism– Hyperchromasia– N/C ratio abnormal– Necrosis

Let us start our analysis

W h a t a bou t B iop sies

Is it really reproducible

• The 40 cases were carefully chosen by one of these pathologists.

• Unanimous agreement was reached in only 55% of the cases.

• The most common disagreement was between LCNEC and Atypical carcinoid

Total cases of the TC and AC: 113 cases

The Larger Problem

The goal of this paper was to disprove the analysis by Arrigoni of 5-10 m x 10hpf

On the Mitoses Issue !!!

Mitosis - Recurrence Free Survival (RFS)

• Random count:– 0 = 95%– 1 = 87%– 2 = 75 %– 3 = 100%

• Hot Spot (mitotically active area):– 0 = 100%– 1 = 90%– 2 = 100%– 3 = 100%

Mitosis - Overall Survival (OS)

• Random count:– 0-1 = 100%– 2-10 = 96.6%

• Hot Spot– 0-1= 100%– 2-10 = 95.5%

Project

• 17 different medical centers from 12 different countries participated in the collection of all the cases diagnosed as Carcinoid and Atypical carcinoid.

• We were able to collect approximately 890 cases.• Of the 890 cases available, in 783, we were able

to obtain enough clinical follow-up of no less than 12 months. Therefore, for statistical analysis only 783 cases were included.

Results

• Total cases 890 – 323 men and 567 women.• Ages: 13 to 97 years (mean: 58 – median: 61)• Symptomatology: non specific – 100 patients

were asymptomatic; 11 patients had another associated malignancy.

Results• The tumor size varied from 0.6 to 9.0 cm in

largest diameter.• Distribution:

– Left main bronchus: 30 cases– Right main bronchus: 34 cases– LLL: 180 cases– LUL: 132 cases– RLL: 200 cases– RML: 177 cases– RUL: 137 cases

Results

• The histopathological parameters evaluated included:– Necrosis: present in 81 cases– Mitoses: varied from 0 to 10 x 10hpf– Lymphatic permeation: present in 723 cases– Tumor outside of the lung proper: 33 cases

Results

• Clinical Follow up was obtained in 783 patients (ranged: 12 to 208 months), which represented the cohort that was statistically analyzed:– 94 patients died (12%) due to tumor (median fetal

outcome: 56 months)– 689 patients were alive.

Approach• Contrary to previous assessment of these tumors,

we set histopathological parameters without creating any bias regarding specific grading. Thus, we more objectively set the following clinical and histological parameters:– Tumor size– # of mitoses– Presence of necrosis– Presence of lymphatic invasion– Age and gender of the patients

Mitoses

Necrosis

Metastases

Lymphatic Invasion

Tumor Size

Age of the Patients

Analysis• Based on this analysis, we can state without

equivocation:– The current histological assessment to separate TC

from AC (Travis/WHO) are incorrect.– The new proposal for staging is faulty at best

(there is not a single study addressing this issue, until now).

– The SEER manuscript supporting the TNM is not based on actual review of cases but on the review of diagnosis only.

Low Grade NE Ca (Carcinoid)

Final Analysis for Low and Intermediate grade NE Carcinomas

Favorable Features• Clinical Features

– Younger than 40 years

• Histological features:– Tumors < 3cm– Up to 4 mitoses x 10hpf– Absence of necrosis– Absence of lymphatic

invasion– Tumors limited to the lung

proper.

Unfavorable Features• Clinical Features• Histological Features

– Tumors > 3cm– >4 mitoses x 10 hpf– Presence of necrosis– Presence of lymphatic

invasion– Tumor outside of the lung

proper.

Regarding small cell carcinoma• The diagnosis can be

made without the Travis/WHO criteria of 10 mitotic figures.

• There is no need for IHC for the diagnosis of small cell carcinoma

Large Cell NE Carcinoma

It is an Immuno diagnosis

synaptophysin chromogranin

LCNEC

LCC with NE Pattern

Non-Small Cell Ca - NE Diff

Molecular Biology and IHC• Ki-67: it has been stated that can separate

TC from AC with a 4% cutoff.– Bx or Resection? Which histologic criteria?

• Both AC and TC have shown deletions of 11q and losses of 10q and 13q.

• RB is also present in both AC and TC.• K-ras-2 , p53, and C-raf-1 suggest that

they represent two different tumors.

Conclusions

• The current Travis/WHO grading and definitions of pulmonary NE carcinomas (low –intermediate - and high grade) is poor at the best, if not flat out incorrect.

• The TNM system of staging is likely not the proper way to provide the best clinical outcome for patients with low and intermediate grade NE Ca.

All we can do is to make suggestions