Cancer Res Treat.  2015 Oct;47(4):813-822. 10.4143/crt.2014.238.

Prognostic Significance of Defining L-Cell Type on the Biologic Behavior of Rectal Neuroendocrine Tumors in Relation with Pathological Parameters

• The Gastrointestinal Pathology Study Group of Korean Society of Pathologists
• Sohn JH
• Cho MY
• Park Y
• Kim H
• Kim WH
• Kim JM
• Jung ES
• Kim KM
• Lee JH
• Chan HK
• Park DY
• Joo M
• Kim S
• Moon WS
• Kang MS
• Jin SY
• Kang YK
• Yoon SO
• Han H
• Choi E

• KMID: 2403401
• DOI: http://doi.org/10.4143/crt.2014.238

Abstract

PURPOSE
In 2010, the World Health Organization categorized L-cell type neuroendocrine tumors (NETs) as tumors of uncertain malignancy, while all others were classified as malignant. However, the diagnostic necessity of L-cell immunophenotyping is unclear, as are tumor stage and grade that may guide diagnosis and management. To clarify the predictive markers of rectal neuroendocrine neoplasms (NENs), 5- and 10-year overall survival (OS) was analyzed by pathological parameters including L-cell phenotype.
MATERIALS AND METHODS
A total of 2,385 rectal NENs were analyzed from our previous multicenter study and a subset of 170 rectal NENs was immunophenotyped.
RESULTS
In univariate survival analysis, tumor grade (p < 0.0001), extent (p < 0.0001), size (p < 0.0001), lymph node metastasis (p=0.0063), and L-cell phenotype (p < 0.0001) showed significant correlation with the prognosis of rectal NENs; however, none of these markers achieved independent significance in multivariate analysis. The 10-year OS of tumors of NET grade 1, < 10 mm, the mucosa/submucosa was 97.58%, 99.47%, and 99.03%, respectively. L-Cell marker, glucagon II (GLP-1&2), with a cut off score of > 10, is useful in defining L-Cell type. In this study, an L-cell immunophenotype was found in 83.5% of all rectal NENs and most, but not all L-cell type tumors were NET G1, small (< 10 mm) and confined to the mucosa/submucosa.
CONCLUSION
From these results, the biological behavior of rectal NENs does not appear to be determined by L-cell type alone but instead by a combination of pathological parameters.

Keyword

Rectal neoplasms; Neuroendocrine tumors; L cells; Immunohistochemistry; Survival; International Classification of Diseases

MeSH Terms

Diagnosis
Glucagon
Immunohistochemistry
Immunophenotyping
International Classification of Diseases
Lymph Nodes
Multivariate Analysis
Neoplasm Metastasis
Neuroendocrine Tumors*
Phenotype
Prognosis
Rectal Neoplasms
World Health Organization
Glucagon

Figure

• 

  Fig. 1. Five- and 10-year overall survival rates in patients with rectal neuroendocrine neoplasms (NENs) according to the grade (A), size group (B), lymph node (LN) metastasis (C), extent (D) and L-cell type (E). Rectal neuroendocrine tumors (NETs) with < 2 mitoses per 10 high-power field’s (World Health Organization G1), confined to the mucosa-submucosa, with no lymph node metastases, and of L-cell type showed excellent prognosis. In particular, 10-year survival rate of NETs G1 confined to mucosa-submucosa was more than 99%.

• 

  Fig. 2. Survival analysis according to lymph node metastasis (LN_Mets) in all samples (A), and neuroendocrine tumors (NET) G1 and G2 (B). LN_Mets was significantly related with poor prognosis in all rectal neuroendocrine neoplasms examined (p < 0.0001), but it was not if NET G1 and G2 tumors were selectively analyzed (p=0.4830).

• 

  Fig. 3. Patterns and distribution of immunohistochemical expression of L-cell markers. The arrows (A) indicate L-cell marker cytoplasmic staining in normal endocrine cells of associated benign rectal mucosa that serves as a positive control. L-Cell immunohistochemical staining of rectal neuroendocrine neoplasms (NENs) was either focal/localized (B, C) or diffuse (D). L-Cell NEN type is defined by one or more positive markers (immunoscore > 10) (A-D, ×400).

• 

  Fig. 4. Survival analysis according to L-cell marker expression. Five- and 10-year overall survival rates (OS) in patients with immunoscore group 0 was significantly shorter than that of others (A). The survival curve according to the immunoscore groups strongly supports the reliability of using a cutoff score group of more than 0 for defining the L-cell type (B). (immunoscore group 1: p=0.0061; hazard ratio [HR], 0.226; 95% confidence interval [CI], 0.078 to 0.654; immunoscore group 2: p=0.0059; HR, 0.120; 95% CI, 0.026 to 0.544; immunoscore group 3: p ≤ 0.0001; HR, 0.051; 95% CI, 0.016 to 0.205).

• 

  Fig. 5. Distribution of L-cell immunoscore groups by tumor grade (A), size (B), extent (C), and lymph node (LN) metastasis (D). Most neuroendocrine tumor (NET) G1 were L-cell type but seven out of 21 NET G2 (33.33%) and three out of 29 neuroendocrine carcinomas (NECs) (10.34%) were in the highest score group 3 for L-cell markers. L-Cell type tumors were rarely found in large size, invasive and even node positive tumor.

Reference

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