Ki-67 index cutoff value of 1% is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. Our data also provide strong evidence for clinical variables such as age, stage, smoking status, and LN involvement as clinical prognostic factors in pulmonary carcinoids. A prognostic calculator incorporating Ki-67 and clinical variables is under development.

Conclusions

Pulmonary carcinoid tumors [typical carcinoid (TC) and atypical carcinoid (AC)] account for up to 5% of all lung cancers and for unclear reasons they have shown the greatest increase in incidence from 1973 to 2004 according to the SEER database. TC is commonly indolent and well differentiated, while AC is usually highly aggressive and poorly differentiated. The evaluation of the prognostic factors and biomarkers of carcinoid tumors of the lung is limited due to the rarity of the disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients.

Background WHO Criteria Results

Tumor Tracing Technique & Imaging Analysis of Ki-67 Expression

A Ki-67 proliferation index cutoff value of 1% accurately predicts 5-year RFS and OS in patients with pulmonary carcinoid tumorsReungwetwattana T.1, 2, Mandrekar SJ.1, Kroneman TN.1 , Foster NR.1, Aubry MC.1, Yi JE. 1, Kerr SE. 1, Yang P. 1,

Grothey A .1, Shridhar V.1, Voss JS.1, Kipp BR.1, Molina JR.1

1 Mayo Clinic, Rochester, MN, USA, 2 Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

• Median follow-up on alive-patients is 5 years (range: 0.006-5). • Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were

significant prognostic factors in RFS and OS for pulmonary carcinoids.• Tumor with the longest dimension of > 2 cm had significant worse RFS compared with

the smaller tumor size (≤ 2 cm) with HR of 2.03 (95% CI; 1.14, 3.63 and P = 0.014).• Gender, presenting symptoms, location of tumor, type of surgery, number of resected LN, status of tumorlets, and status of multicentric foci were not significant prognostic factors.

Objectives

To study the impact of Ki-67 expression (proliferative index) and the other clinical variables as the prognostic factors of pulmonary carcinoids on survival outcomes (RFS and OS).

Methods

A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were centrally reviewed by 1 of 3 pathologists according to WHO criteria. With respect to the original diagnosis, 19 AC patients were revised to TC, and 13 TC patients were revised to AC. Statistical analyses were performed based on the original and revised diagnosis. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators in half of the specimen. The concordance between two operators was observed then the rest of specimens were performed by one operator. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index.

Abstract ID: 11119

Pathological Features Typical carcinoid

Atypical carcinoid

Organoid pattern 

Yes Yes

Mitoses 

< 2/2 mm2 2-10/2 mm2

Necroses 

None +/-

Nuclear/cytoplasmicratio

Moderate Moderate

Nucleoli Occasional CommonNuclear chromatin Finely granular Finely granular

Correlation Curve Between Two Operators for Ki-67 Analysis

Outcomes 

RFS OSHR; 95% CI

(P-value)C-index HR; 95% CI

(P-value)C-index

Ki-67 ≥ 1% vs. < 1% 

3.69; 2.08-6.53(<0.0001)

0.65 3.69; 1.73-7.90(0.0007)

0.66

AC vs. TC (original diagnosis)

3.85; 2.17-6.84(<0.0001)

0.62 2.72; 1.23-6.02(0.0214)

0.59

AC vs. TC (central-reviewed diagnosis)

4.24; 2.40-7.48(<0.0001)

0.63 4.02; 1.90-8.50(0.0007)

0.64

Variable N Deaths

OS Log-rank P-value

OS

Hazard Ratio

(95% CI)

RFS

Events

RFS Log-rank

P-value

RFS

Hazard Ratio (95% CI)

Age     0.0441     0.0144     <= 50) 69      3    --      6    --   51-60 61      4    1.56 (0.35,6.99)      8    1.54 (0.53,4.44)   61-70 72      10    3.34 (0.92,12.13)      19    3.29 (1.31,8.23) > 70 60      11    4.46 (1.25,16.00)      16    3.33 (1.30,8.50)Staging     <0.0001     <0.0001     I 169      9    --      17    --   II 31      4   2.27 (0.70,7.37)      7    2.16 (0.90,5.22)   III 32      7    4.78 (1.78,12.84)      12    4.45 (2.12,9.33)   IV 15      5    7.92 (2.65,23.67)      8    8.34 (3.57,19.46)Smoking Status     0.0181     0.0355     Never Smokers 139      9    --      20    --   Former Smokers 87      12    2.31 (0.97,5.48)      19    1.64 (0.87,3.07)   Current Smokers 36      7    3.72 (1.39,10.01)      10    2.58 (1.21,5.52)Status of Metastatic LN

    <0.0001     <0.0001  

   Negative 187      9    --      20    --   Positive 45      11    5.61 (2.32,13.55)      19    4.75 (2.53,8.91)

Univariable Cox PH Model for RFS and OS

Table: Pulmonary Carcinoids Categorized by Ki-67 at cut point of 1%

% Ki-67 by operator # 2