A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases
Introduction
High-grade neuroendocrine carcinoma of the uterine cervix (HGNCUC) is a rare disease making up 1–5% of cervical cancers. Compared with other histologic types of cervical cancer, HGNCUC gives rise to hematogenous metastases from an early stage and shows a poor prognosis [1], [2], [3], [4]. The 5-year survival rate for the International Federation of Gynecology and Obstetrics (FIGO) stage IB1 is approximately 90% for ordinary cervical cancers, but has been estimated as only 55–63% for HGNCUC [2], [3], [4], [5]. As the biological characteristics of HGNCUC differ from those of other histologic types of cervical cancer, the therapeutic strategy must also differ. Systemic chemotherapy even in the early stages has been suggested as necessary to achieve complete control of a local HGNCUC lesion [2], [6]. Small cell lung cancer is a typical classical example of high-grade neuroendocrine carcinoma, representing a significant percentage (14–20%) of all lung cancers, and this tumor is typically thought to be the histologic type showing the poorest prognosis. Regarding the National Comprehensive Cancer Center Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®), the primary treatment of small cell carcinoma (SmCC) and large cell neuroendocrine carcinoma (LCNEC) of sites other than the lung is generally recommended to follow the regimen for small cell lung cancer [7], [8]. Given the above, both the diagnosis of HGNCUC, which tends to metastasize even in the early stage, and the selection of a different therapeutic strategy need to be made quickly and precisely. However, diagnosis may be difficult using only staining with hematoxylin and eosin. Immunohistochemistry using conventional neuroendocrine (NE) markers is often problematic because of their low sensitivity or low specificity in some cases.
Insulinoma-associated protein 1 (INSM1), a zinc-finger transcription factor related to NE differentiation, was recently reported to be frequently expressed in NE tumors [9], [10], [11]. INSM1 was identified by Goto et al. [9] in 1992 using a human insulinoma tissue subtraction library, and is strongly and temporarily expressed during the prenatal period, but exists only locally in normal tissues in adulthood. Fujino et al. [10] and Rosenbaum et al. [11] confirmed most recently by immunostaining that INSM1 was located in the nuclei of NE tumor cells in the lung [10] and gastrointestinal tract [11]. As INSM1 appears likely to represent a superior marker to the chromogranin A (ChrA), synaptophysin (Syn) and neural cell adhesion molecule (NCAM) that have conventionally been used, verification is needed through immunohistochemical studies of more cases.
Human papillomavirus (HPV) infection is a crucial event in the path to cervical cancer [12], [13]. HPV may also be associated with the development of HGNCUC [14], [15], [16]. On the other hand, smoking has been closely implicated in the development of NE carcinoma of the lung [17], [18]. The cause of NE carcinoma is thought to differ between organs. To know whether the same transcription factor works in NE carcinoma of different organs in which different causes may have developed them, it seems to be important to clarify expression frequencies of the transcription factor for every primary organ. Interestingly, transcription factors related to NE differentiation such as INSM1 may become the targets of future treatments [19], [20].
In this study, we examined the following points: 1) whether differences exist in the expression of INSM1 among HGNCUC and other histologic types or organs; 2) whether INSM1 can be a useful NE marker in the histological diagnosis of HGNCUC; 3) whether immunohistochemical expression of INSM1 can be a prognostic factor; and 4) frequency and genotype of HPV infections of HGNCUC.
Section snippets
Case selection
This study was approved by the ethics committees at Shizuoka Cancer Center Hospital, Shizuoka, Japan, and Keio University Hospital, Tokyo, Japan. The present study covered patients diagnosed with FIGO stage IB1 to IVB cervical cancer with SmCC, LCNEC and NE carcinoma that could be classified as HGNCUC between 1985 and 2013 at Shizuoka Cancer Center and Keio University Hospital. Thirty-seven cases were retrieved, comprising 19 from Shizuoka Cancer Center (biopsy only, 9 cases; radical
Patients' characteristics
We analyzed 37 HGNCUC cases, 20 cases of non-HGNCUC (SqCC, AD and ADSq of the cervix), and each 5 cases of both SmCC and SqCC of the lung (Table 2). Among 37 HGNCUC cases, 29 cases were SmCC (pure type, 24 cases; combined type, 5 cases) and 8 cases were LCNEC (pure type, 6 cases; combined type, 2 cases). Among the 7 combined-type cases, 5 cases were combined with AD, and 2 cases were combined with SqCC (Table 2). Follow-up period, age and FIGO stage were shown in Table 2.
Immunohistochemical results
INSM1 immunoreactivity
Discussion
INSM1, a zinc-finger transcriptional factor, has been reported to play an important role in the development of pancreatic and intestinal NE cells, adrenal medulla cells, and basal neuronal progenitor cells in the neocortex and in the neurogenesis of the embryonic olfactory epithelium. INSM1 is abundantly expressed in fetal developing neuronal and NE tissue, but is significantly reduced or restricted in adult tissues [9], [10]. In normal adult tissues, expression has been confirmed in endocrine
Conflict of interest statement
The authors have no conflict of interest to declare.
Acknowledgments
We thank Drs. Nobutaka Takahashi, Masakazu Abe, Aki Tanaka, Norihiro Kado and Yuka Kasamatsu, (Division of Gynecology, Shizuoka Cancer Center Hospital, Shizuoka, Japan) for their valuable cooperation; Dr. Takashi Nakajima (Head, Division of Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan) for allowing the use of histologic materials stored at Shizuoka Cancer Center; Dr. Takaaki Ito (Department of Pathology and Experimental Medicine, Kumamoto University, Kumamoto, Japan) for
References (37)
- et al.
Natural history and outcome of neuroendocrine carcinoma of the cervix
Gynecol. Oncol.
(2016) - et al.
Diagnosis, clinicopathologic features, treatment, and prognosis of small cell carcinoma of the uterine cervix; Kansai Clinical Oncology Group/Intergroup study in Japan
Gynecol. Oncol.
(2013) - et al.
Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy
Gynecol. Oncol.
(2009) - et al.
A novel human insulinoma-associated cDNA, IA-1, encodes a protein with “zinc-finger” DNA-binding motifs
J. Biol. Chem.
(1992) - et al.
Insulinoma-associated protein 1 is a crucial regulator of neuroendocrine differentiation in lung cancer
Am. J. Pathol.
(2015) - et al.
P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix
Hum. Pathol.
(2003) - et al.
Molecular abnormalities associated with endocrine tumors of the uterine cervix
Gynecol. Oncol.
(1999) - et al.
hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors
Mod. Pathol.
(2004) - et al.
A subset of small cell lung cancer with low neuroendocrine expression and good prognosis: a comparison study of surgical and inoperable cases with biopsy
Hum. Pathol.
(2014) - et al.
Achaete-scute homolog 1 as a marker of poorly differentiated neuroendocrine carcinomas of different sites: a validation study using immunohistochemistry and quantitative real-time polymerase chain reaction on 335 cases
Hum. Pathol.
(2013)