Pulmonary Neuroendocrine Neoplasms - Pathology...Pulmonary Neuroendocrine Neoplasms • In general,...
Transcript of Pulmonary Neuroendocrine Neoplasms - Pathology...Pulmonary Neuroendocrine Neoplasms • In general,...
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Pulmonary Neuroendocrine Neoplasms
Cesar A. Moran, MD
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Definition: Typical carcinoid: <2mitoses x 10hpf and lack of necrosisAtypical Carcinoid: 2-10 mitoses x 10hpf and/or foci of necrosis
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Thanks – Conference is over
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1.5
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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%.
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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.
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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
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Let us start our analysis
W h a t a bou t B iop sies
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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
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Total cases of the TC and AC: 113 cases
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The Larger Problem
The goal of this paper was to disprove the analysis by Arrigoni of 5-10 m x 10hpf
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On the Mitoses Issue !!!
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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%
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Mitosis - Overall Survival (OS)
• Random count:– 0-1 = 100%– 2-10 = 96.6%
• Hot Spot– 0-1= 100%– 2-10 = 95.5%
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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.
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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.
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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
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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
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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.
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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
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Mitoses
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Necrosis
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Metastases
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Lymphatic Invasion
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Tumor Size
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Age of the Patients
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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.
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Low Grade NE Ca (Carcinoid)
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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.
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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
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Large Cell NE Carcinoma
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It is an Immuno diagnosis
synaptophysin chromogranin
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LCNEC
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LCC with NE Pattern
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Non-Small Cell Ca - NE Diff
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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.
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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.
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All we can do is to make suggestions