title: Primary large-cell neuroendocrine carcinoma of the parotid gland: immunohistochemical and molecular analysis of two cases.
abstract: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a newly proposed clinicopathologic entity; a few cases of LCNEC have been reported in other sites, such as the uterine cervix and the thymus. In the salivary glands, LCNEC is extremely rare and is not recognized as a specific entity in the World Health Organization classification. We retrospectively reviewed from our files 1675 cases of surgically resected primary parotid gland tumors and found 2 cases of LCNEC that fulfilled the criteria of pulmonary LCNEC. These cases occurred in 72- and 73-year-old men who had short histories of enlarging parotid gland tumors. The tumors were composed of large cells that exhibited organoid, solid, trabecular, and rosette-like growth patterns with a high mitotic rate and a conspicuous tendency for necrosis. The tumor cells were polygonal and characterized by a moderate nuclear:cytoplasmic ratio, coarse chromatin, and conspicuous nucleoli. Immunohistochemical examination revealed that the tumor cells were positive for six general neuroendocrine markers, cytokeratin, p53, bcl-2, epidermal growth factor receptor, and cyclin D1. Markedly reduced expressions of p21Waf1 and p27Kip1 were also noticed. The Ki-67 labeling index was more than 50% in both cases. One case showed loss of heterozygosity at TP53 accompanied by a p53 gene point mutation. Loss of heterozygosity at chromosome 9p21 was detected in both cases; one was accompanied by a p16 gene silent point mutation. Both patients died of the disease, with recurrence 5 months and 4 years after surgery, respectively. These findings indicate that LCNEC is a rare but distinct salivary gland tumor with highly aggressive biologic behavior. Multiple alterations of cell cycle regulators and tumor suppressor genes may play an important role in presenting the biologic characteristics of this rare parotid gland tumor.
authors.affiliation: Department of Surgical Pathology, Teikyo University, School of Medicine, Ichihara Hospital, Chiba, Japan. t-nagao@med.teikyo-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Nagao
authors.forename: I
authors.initials: I
authors.lastname: Sugano
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: Y
authors.initials: Y
authors.lastname: Tajima
authors.forename: S
authors.initials: S
authors.lastname: Munakata
authors.forename: A
authors.initials: A
authors.lastname: Asoh
authors.forename: K
authors.initials: K
authors.lastname: Yamazaki
authors.forename: H
authors.initials: H
authors.lastname: Muto
authors.forename: A
authors.initials: A
authors.lastname: Konno
authors.forename: Y
authors.initials: Y
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Nagao
mesh_terms: D000368:Aged; D001483:Base Sequence; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019938:Cyclin D1 / Q000032:analysis; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D003937:Diagnosis, Differential; D066246:ErbB Receptors / Q000032:analysis; D006801:Humans; D007633:Keratins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D010307:Parotid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017354:Point Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D007633:Keratins; D066246:ErbB Receptors