Lung carcinoid tumours: histology and Ki‐67, the eternal rivalry

Centonze, Giovanni; Madelenat, P.; Simbolo, Michele; Lagano, Vincenzo; Grillo, Federica; Fabbri, Alessandra; Prinzi, Natalie; Garzone, Giovanna; Filugelli, Martina; Pardo, Carlotta; Mietta, Alessia; Pusceddu, Sara; Sabella, G; Bercich, Luisa; Mangogna, Alessandro; Rolli, Luigi; Grisanti, Salvatore; Benvenuti, Mauro Roberto; Pastorino, Ugo; Roz, Luca; Scarpa, Aldo; Berruti, Alfredo; Capella, Carlo; Milione, Massimo

doi:10.1111/his.14819

Cited by 15 publications

(16 citation statements)

References 23 publications

(54 reference statements)

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“…OTP was found to be an independent prognostic marker but better predicted patient outcome when combined with CD44, a stem cell marker and cellsurface glycoprotein. These findings were later validated by several other researchers resulting in the addition of coexpression of nuclear OTP and CD44 as a prognostic factor in the current WHO classification (1,10,(15)(16)(17).…”

Section: Value Of Orthopedia Homeobox Protein (Otp) Immunohistochemis...mentioning

confidence: 58%

“…This suggests that OTP activation may be an important step for carcinoid tumorigenesis. However, downregulation seems to be related to tumor progression since loss of OTP protein expression correlates with prognosis ( 8 , 10 , 15 , 16 ). Recently, the authors of the paper commented on, examined DNA methylation data and found that that changes in DNA methylation patterns were associated with the difference in OTP expression levels ( 18 ).…”

Section: Value Of Orthopedia Homeobox Protein (Otp) Immunohistochemis...mentioning

confidence: 99%

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Orthopedia homeobox protein (OTP) in the diagnostic and prognostic workup of pulmonary carcinoid tumors

Vesterinen¹,

Arola²

2023

Transl Lung Cancer Res

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Lung neuroendocrine neoplasms (NENs) account for approximately one fifth of all lung malignancies. They are a heterogenous group of neoplasms that can be classified as low-and intermediate-grade PCs and high-grade large-cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). PCs are further divided into typical carcinoid (TC) and atypical carcinoid (AC) tumors based on the number of mitoses and presence of necrosis (1).PCs are rare, well-differentiated tumors that account for <2% of all lung cancers. The only curative treatment for PC tumors is a complete surgical resection. Resected PC tumor patients generally have a good prognosis with a 5-year overall survival 87-100% for TC patients and 60-70% for AC patients (2,3). However, PCs show a risk for late recurrence and distant metastasis. The risk is higher for ACs (20-35% metastasize) and lower for TCs (5-10% metastasize). Clinical management of metastatic disease remains challenging and a curative treatment strategy is not available (1,4). Thus, the aim of treatment is to control tumor growth and possible functioning syndromes to improve both quality of life and survival. Challenges in the histopathological evaluation of pulmonary carcinoid tumorsDiagnosis of a PC requires a careful histological evaluation. Here, distinguishing between PCs and high-grade LCNEC and SCLC is crucial as it impacts subsequent surgical management and additional therapeutic management and has a significant impact on prognosis. Typically, a biopsy or fine-needle aspiration is the first sample the pathologist receives. Evaluating these small specimens can be challenging, which created a need for specific immunohistochemical markers that can assist in differential diagnostics (5).On the other hand, occurrence of PC tumor recurrence or metastasis cannot be reliably predicted with the current WHO classification. This leads to clinical and radiological surveillance, which causes unnecessary radiation exposure, is a constant reminder of the disease for the patients, and results in additional health care costs. Previous studies have reported several clinical and molecular markers associated with the risk of developing metastases and poor outcome (3). These include e.g., age, gender, performance status, TNM staging, mitotic index, and Ki-67 proliferation index at the

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Section: Value Of Orthopedia Homeobox Protein (Otp) Immunohistochemis...mentioning

confidence: 58%

Section: Value Of Orthopedia Homeobox Protein (Otp) Immunohistochemis...mentioning

confidence: 99%

Orthopedia homeobox protein (OTP) in the diagnostic and prognostic workup of pulmonary carcinoid tumors

Vesterinen¹,

Arola²

2023

Transl Lung Cancer Res

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“…Proliferative analysis also showed a specific role of Ki‐67 ≥10%, which was associated with reduced DFS. As previously proposed, Ki‐67 could represent an independent prognostic marker for carcinoids 23–26 . A recent study carried out by Marchiò et al .…”

Section: Discussionmentioning

confidence: 70%

“…As previously proposed, Ki-67 could represent an independent prognostic marker for carcinoids. [23][24][25][26] A recent study carried out by Marchi o et al showed a clinical role of Ki-67 10% cutoff for stratification of all lung carcinoid tumours and suggested that this cutoff is also reliable specifically for ACs identifying a subgroup with a dismal prognosis. 7 Our results underline that Ki-67 at 10% cutoff is a strong prognostic marker for ACs in univariate analysis, strongly associated with postoperative recurrence.…”

Section: Discussionmentioning

confidence: 99%

Ascl1 and OTP tumour expressions are associated with disease‐free survival in lung atypical carcinoids

et al. 2023

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Aims: According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2-10 mitoses/ 2 mm 2 and/or foci of necrosis (usually punctate). Besides morphological criteria, no further tools in predicting AC clinical outcomes are proposed. The aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. Methods and results: Three hundred-seventy lung carcinoids were collected and centrally reviewed by two expert pathologists. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP,

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“…24 However, there are some studies that did not find any significant association between hot spot Ki-67 and disease-free survival 25 or overall survival. 23 It is also interesting to note that Ki-67 is an independent predictor in multivariate models of some [26][27][28] but not all studies, 20,29 and thus the "added value" of Ki-67 in resected tumors remains ambiguous. The current WHO classification is certainly a strong predictor of outcome, 2,30,31 and its performance in predicting ds-PFS in the present study was statistically significant and comparable to Ki-67.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Immunohistochemistry for Ki-67 and OTP on Small Biopsies of Pulmonary Carcinoid Tumors

Naso,

Jenkins,

Roden

et al. 2024

American Journal of Surgical Pathology

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Prognostic stratification of pulmonary carcinoids into “typical” and “atypical” categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS (P<0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% (P=0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology (P=0.06) but not with ds-PFS (P=0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.

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Lung carcinoid tumours: histology and Ki‐67, the eternal rivalry

Cited by 15 publications

References 23 publications

Orthopedia homeobox protein (OTP) in the diagnostic and prognostic workup of pulmonary carcinoid tumors

Orthopedia homeobox protein (OTP) in the diagnostic and prognostic workup of pulmonary carcinoid tumors

Ascl1 and OTP tumour expressions are associated with disease‐free survival in lung atypical carcinoids

Prognostic Immunohistochemistry for Ki-67 and OTP on Small Biopsies of Pulmonary Carcinoid Tumors

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