Human papillomavirus-associated small cell carcinoma/neuroendocrine carcinoma of the oropharynx: a report of two cases
© The Author(s) 2016
Received: 3 May 2016
Accepted: 10 October 2016
Published: 22 October 2016
Small cell carcinoma/neuroendocrine carcinoma (SCNEC) of the oropharynx is uncommon. Two cases of SCNEC in an 81-year-old woman and in a 54-year-old man are presented here.
We have documented two cases of SCNEC arising in the oropharynx with evidence of high-risk human papillomavirus (HPV) infection. Histologically, both cases were classified as poorly differentiated SCNEC with high nuclear-to-cytoplasmic ratios and nuclear molding. Observations using a transmission electron microscope revealed membrane-bound neuroendocrine granules in some tumor cells. Both tumors expressed high levels of p16, a surrogate marker for high-risk HPV infection. HPV infection was confirmed in both cases using HPV polymerase chain reaction analysis; HPV subtype 16 was identified in one case and HPV subtype 18 in the other.
Discussion and Evaluation
SCNEC of the oropharynx is a rare and novel HPV-associated disease with neuroendocrine granules and aggressive clinical behavior.
Herein, we present two cases of SCNEC, focusing on its histologic features and treatment modalities. More studies are required to elucidate the pathophysiology of HPV-associated SCNEC in different organ systems.
Primary malignant tumors of the oropharynx are usually squamous cell carcinomas (SqCCs). Over the past decade, human papillomavirus (HPV) infection has been recognized as a significant etiological factor for a subset of oropharyngeal SqCCs. Primary small cell carcinoma/neuroendocrine carcinoma (SCNEC) of the oropharynx is rare. The larynx is the most commonly involved site, followed by the nasal cavity, paranasal sinuses, salivary glands, and oral cavity (Renner 2007; Mineta et al. 2001). Approximately 75 cases of SCNEC in the primary nasal/paranasal cavities and 180 cases in the larynx have been reported (Sirsath et al. 2013). The prognosis of SCNEC in the nasal cavity and larynx is poor (Chai et al. 2014). Recently, SCNEC of the uterine cervix and anus have been shown to be associated with HPV infection, and aggressive behavior of HPV-positive SCNEC in the female genital tract has been documented (Mills 2002). Herein, we present the clinical courses of two patients with oropharyngeal HPV-associated SCNEC.
Summary of the demographic details, immunohistochemistry profiles, and results of HPV tests for Cases 1 and 2
Year of diagnosis
Age at diagnosis (years)
Base of tongue
Irradiation (70 Gy) + chemotherapy (cisplatin + etoposide)
Follow-up interval (month)
Dead of disease
Dead of disease
Transmission electron microscopy studies
DNA extraction, HPV polymerase chain reaction, and HPV type sequencing
DNA was isolated from the SCNEC elements of specimens obtained during surgery. Genomic DNA was extracted from frozen tumor specimens using the QIAamp DNA Mini Kit (QIAGEN, Hilden, Germany), according to the manufacturer’s instructions.
The worldwide incidence and prevalence of HPV-associated oropharyngeal cancer have been increasing over time. Among the head and neck regions, SCNEC most commonly arises in the larynx, but it has also been reported in the sinonasal tract and salivary glands (Renner 2007; Mineta et al. 2001). SCNECs of the oropharynx are extremely rare, and only 40 cases have been reported since it was first identified by Koss et al. (1972) (Wang et al. 2014; Watson et al. 2013; Kraft et al. 2012; Bishop and Westra 2011). Recently, an association between oropharyngeal SCNEC and high-risk HPV infection was reported (Watson et al. 2013; Kraft et al. 2012; Bishop and Westra 2011). An oncogenic HPV status has been described in 14/19 (73.7 %) cases of oropharyngeal SCNEC (Watson et al. 2013; Kraft et al. 2012; Bishop and Westra 2011). HPV infection confers a better prognosis for patients with oropharyngeal SqCC and basaloid SqCC (Gillison et al. 2000; Jacobi et al. 2015). However, the prognosis of patients with SCNEC of the oropharynx is poor, as the majority of patients die of the disease mainly due to systemic metastasis (Renner 2007; Wang et al. 2014).
Gynecologic extrapulmonary SCNECs most commonly arise in the cervix, and SCNECs of the uterine cervix comprise less than 3 % of cervical cancers (Cohen et al. 2010). SCNECs of the uterine cervix are highly aggressive with extensive local invasion and distant metastases. Most small cell carcinomas of the uterine cervix exhibit neuroendocrine differentiation and ultrastructural examination may be considered the most reliable method for confirming this feature (Ishida et al. 2004). HPV has been detected in more than 90 % of SCNEC tumors through PCR sequencing analysis (Wang and Lu 2004; Horn et al. 2006; Masumoto et al. 2003; Ishida et al. 2004). Many studies have shown that SCNECs that express the HPV oncoproteins E6 and E7 have high levels of p16 (Wang and Lu 2004; Horn et al. 2006; Masumoto et al. 2003). In general, all SCNECs tend to be locally aggressive and have a strong propensity for both regional and distant metastases (Renner 2007).
The diagnosis of SCNEC requires immunohistochemical or ultrastructural studies. With routine hematoxylin and eosin staining, SCNEC exhibits morphology similar to that of nonkeratinizing SqCC. A case with a histopathologic finding of small round cells with scant cytoplasm should be evaluated for synaptophysin, chromogranin A, and CD56 expression, followed by ultrastructural analysis to detect neurosecretory granules in the tumor cells (Mineta et al. 2001). Recently, Alos et al. reported an inverse association between p16 expression and expression of Rb and cyclin D1 in SCNEC. The most prevalent phenotype was high p16-positive/Rb-low or -negative/cyclin D1-low or -negative expression (14/19, 73.7 %). Thus, patchy p16 positivity/strong Rb nuclear staining/strong cyclin D1 nuclear staining was observed in 5/19 cases (26.3 %) (Alos et al. 2016).
Owing to the rarity of these tumors, recommendations for the management of SCNEC of the oropharynx have not been established (Barbeaux et al. 2006). Most patients die within 2 years of diagnosis, despite being treated with adjuvant radiation and chemotherapy (Aggarwal et al. 2010). On the basis of comparative treatments for SCNEC of the larynx and lungs, various modalities have been indicated for patients with SCNEC of the oropharynx (Jaiswal and Hoang 2004).
In conclusion, SCNEC of the oropharynx is extremely rare and highly aggressive, with a poor prognosis. Herein, we present two cases of SCNEC, focusing on its histologic features and treatment modalities. More studies are required to elucidate the pathophysiology of HPV-associated SCNEC in different organ systems.
KM and TY performed the medical treatment and evaluated the patient. YM, DM, and SE revised the manuscript and evaluated the patient. AI, RM, KS, and HM reviewed the charts and published literature. HK and KM performed pathological investigations and electron microscopy analysis. All authors read and approved the final manuscript.
The authors would like to thank Ms. Yuko Mohri for her excellent technical support.
The authors declare that they have no competing interests.
The patients consented to the publication of this case report (IRB of Hamamatsu University School of Medicine).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Aggarwal G, Jackson L, Sharma S (2010) Primary combined small cell carcinoma of larynx with lateralized histologic components and corresponding side-specific neck nodal metastasis: report of a unique case and review of literature. Int J Clin Exp Pathol 4(1):111–117PubMedPubMed CentralGoogle Scholar
- Alos L, Hakim S, Larque AB, de la Oliva J, Rodriguez-Carunchio L, Caballero M, Nadal A, Marti C, Guimera N, Fernandez-Figueras MT, Quint W, Ordi J (2016) p16 overexpression in high-grade neuroendocrine carcinomas of the head and neck: potential diagnostic pitfall with HPV-related carcinomas. Virchows Arch Int J Pathol 469(3):277–284. doi:10.1007/s00428-016-1982-1 View ArticleGoogle Scholar
- Barbeaux A, Duck L, Weynand B, Desuter G, Hamoir M, Gregoire V, Baurain JF, Machiels JP (2006) Primary combined squamous and small cell carcinoma of the larynx: report of two cases and discussion of treatment modalities. Eur Arch Otorhinolaryngol 263(8):786–790. doi:10.1007/s00405-006-0060-8 View ArticlePubMedGoogle Scholar
- Bishop JA, Westra WH (2011) Human papillomavirus-related small cell carcinoma of the oropharynx. Am J Surg Pathol 35(11):1679–1684. doi:10.1097/PAS.0b013e3182299cde View ArticlePubMedPubMed CentralGoogle Scholar
- Chai L, Ying HF, Wu TT, Zhou SH, Bao YY, Yao HT, You QH (2014) Clinical features and hypoxic marker expression of primary sinonasal and laryngeal small-cell neuroendocrine carcinoma: a small case series. World J Surg Oncol 12:199. doi:10.1186/1477-7819-12-199 View ArticlePubMedPubMed CentralGoogle Scholar
- Cohen JG, Kapp DS, Shin JY, Urban R, Sherman AE, Chen LM, Osann K, Chan JK (2010) Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol 203(4):341–346. doi:10.1016/j.ajog.2010.04.019 View ArticleGoogle Scholar
- Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, Zahurak ML, Daniel RW, Viglione M, Symer DE, Shah KV, Sidransky D (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92(9):709–720View ArticlePubMedGoogle Scholar
- Horn LC, Lindner K, Szepankiewicz G, Edelmann J, Hentschel B, Tannapfel A, Bilek K, Liebert UG, Richter CE, Einenkel J, Leo C (2006) p16, p14, p53, and cyclin D1 expression and HPV analysis in small cell carcinomas of the uterine cervix. Int J Gynecol Pathol Off J Int Soc Gynecol Pathol 25(2):182–186. doi:10.1097/01.pgp.0000185406.85685.df View ArticleGoogle Scholar
- Ishida GM, Kato N, Hayasaka T, Saito M, Kobayashi H, Katayama Y, Sasou S, Yaegashi N, Kurachi H, Motoyama T (2004) Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study. Int J Gynecol Pathol Off J Int Soc Gynecol Pathol 23(4):366–372View ArticleGoogle Scholar
- Jacobi C, Ayx I, Fritsche K, Piontek G, Hoffmann D, Weirich G, Knopf A (2015) Potential impact of human papilloma virus on survival of basaloid squamous carcinoma of the head and neck. Oncotarget 6(5):3462–3470. doi:10.18632/oncotarget.3062 View ArticlePubMedGoogle Scholar
- Jaiswal VR, Hoang MP (2004) Primary combined squamous and small cell carcinoma of the larynx: a case report and review of the literature. Arch Pathol Lab Med 128(11):1279–1282. doi:10.1043/1543-2165(2004)128<1279:PCSASC>2.0.CO;2 PubMedGoogle Scholar
- Koss LG, Spiro RH, Hajdu S (1972) Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 30(3):737–741View ArticlePubMedGoogle Scholar
- Kraft S, Faquin WC, Krane JF (2012) HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol 36(3):321–330. doi:10.1097/PAS.0b013e31823f2f17 View ArticlePubMedGoogle Scholar
- Masumoto N, Fujii T, Ishikawa M, Saito M, Iwata T, Fukuchi T, Susumu N, Mukai M, Kubushiro K, Tsukazaki K, Nozawa S (2003) P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix. Hum Pathol 34(8):778–783View ArticlePubMedGoogle Scholar
- Mills SE (2002) Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Modern Pathol Off J US Can Acad Pathol 15(3):264–278. doi:10.1038/modpathol.3880522 Google Scholar
- Mineta H, Miura K, Takebayashi S, Araki K, Ueda Y, Harada H, Misawa K (2001) Immunohistochemical analysis of small cell carcinoma of the head and neck: a report of four patients and a review of sixteen patients in the literature with ectopic hormone production. Ann Otol Rhinol Laryngol 110(1):76–82View ArticlePubMedGoogle Scholar
- Renner G (2007) Small cell carcinoma of the head and neck: a review. Semin Oncol 34(1):3–14. doi:10.1053/j.seminoncol.2006.10.024 View ArticlePubMedGoogle Scholar
- Sirsath NT, Babu KG, Das U, Premlatha CS (2013) Paranasal sinus neuroendocrine carcinoma: a case report and review of the literature. Case Rep Oncol Med 2013:728479. doi:10.1155/2013/728479 PubMedPubMed CentralGoogle Scholar
- Wang HL, Lu DW (2004) Detection of human papillomavirus DNA and expression of p16, Rb, and p53 proteins in small cell carcinomas of the uterine cervix. Am J Surg Pathol 28(7):901–908View ArticlePubMedGoogle Scholar
- Wang HY, Zou J, Zhou GY, Yan JQ, Liu SX (2014) Primary small cell neuroendocrine carcinoma of the tonsil: a case report and review of the literature. Int J Clin Exp Pathol 7(5):2678–2682PubMedPubMed CentralGoogle Scholar
- Watson RF, Chernock RD, Wang X, Liu W, Ma XJ, Luo Y, Wang H, El-Mofty SK, Lewis JS Jr (2013) Spindle cell carcinomas of the head and neck rarely harbor transcriptionally-active human papillomavirus. Head Neck Pathol 7(3):250–257. doi:10.1007/s12105-013-0438-z View ArticlePubMedPubMed CentralGoogle Scholar