{"paper_id":"24b4b3cd-a03e-4745-a289-92dc018969f9","body_text":"Ȉ http://www.e-crt.org Ȉ954 Copyright ⡋ 2015 by  the Korean Cancer Association\nThis is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)\nwhich permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nCancer Res Treat. 2015;47(4):954-957\npISSN 1598-2998, eISSN 2005-9256\nhttp://dx.doi.org/10.4143/crt.2014.111  \nOpen Access\nHPV-Related Retroperitoneal Squamous Cell Carcinoma of Unknown\nPrimary: A Case Report\nCase Report\nA 56-year-old female was referred to our hospital due to a mass measuring 5 cm in\nsize in the left pelvic cavity, which was found incidentally during a health examination\nby ultrasonography. Exploratory laparotomy was performed and the mass was located\nat the left retroperitoneal parametrium without invasion of the uterus and ovary. The\npathology report confirmed squamous cell carcinoma. Even after further studies, we\ndid not find any other primary lesion. Human papillomavirus (HPV) DNA chip test (HPV\n9G DNA Membrane Kit, Biometrixtechnology Inc.) showed that the surgical specimen\nwas positive for HPV 18. She received adjuvant chemotherapy and would receive \nradiation therapy for the possibility of occult gynecologic cancer. Retroperitoneal squa-\nmous cell carcinoma of unknown primary is extremely rare and little is known about\nit. It is reported that HPV may be associated with the disease. Hence, the result of\nHPV test could have an impact on finding a suspicious primary lesion and treatment\nmodality in this case.\nKey words\nRetroperitoneal neoplasms, Squamous cell carcinoma, \nHuman papillomavirus\nIntroduction\nRetroperitoneal neoplasms, defined as solid or cystic \ntumors that arise within the retroperitoneal space, are rare\nand estimated to represent approximately 0.1%-0.2% of all\nmalignant tumors, where most frequent entities include \nlymphoproliferative tumors, soft tissue tumors, and extrag-\nonadal germ cell tumors [1]. Retroperitoneal squamous cell\ncarcinoma (SCC) of unknown primary is extremely rare and\nlittle is known about its etiology, pathogenesis, and optimal\ntherapy. Human papillomavirus (HPV), first discovered in\nthe 1980s as a carcinogen, is usually associated with gyneco-\nlogic malignancies. In this paper, we report on a case of HPV\npositive retroperitoneal squamous carcinoma of unknown\nprimary. To the best of our knowledge, retroperitoneal squa-\nmous carcinoma of unknown primary has been reported\nonce in Korea, and our case represents the first report of HPV\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  \n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\n+  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +  +\nCorrespondence: Jong-Youl Jin, MD, PhD\nDivision of Hematology/Oncology, \nDepartment of Internal Medicine, \nBucheon St. Mary's Hospital, \nCollege of Medicine, \nThe Catholic University of Korea, \n327 Sosa-ro, Wonmi-gu, Bucheon 14647, Korea\nTel: 82-32-340-2114\nFax: 82-32-340-7227\nE-mail: drjin@catholic.ac.kr\nReceived  April 28, 2014\nAccepted  August 13, 2014\nPublished online  February 17, 2015\nHyun Jin Oh, MD1\nEun Hye Park, MD1\nYeong Bok Lee, MD1\nJooyeun Hu, MD1\nGuk Jin Lee, MD1\nSang Hoon Chun, MD1\nMi Yeong Lee, RN1\nDae Woo Lee, MD2\nJeana Kim, MD, PhD3\nJong-Youl Jin, MD, PhD1\nDepartments of 1Internal Medicine, \n2Obstetrics and Gynecology, \nand 3Hospital Pathology, \nBucheon St. Mary’s Hospital, \nCollege of Medicine, \nThe Catholic University of Korea, \nBucheon, Korea\n\n\nHyun Jin Oh, HPV and Retroperitoneal Squamous Cell Carcinoma\nVOLUME 47  NUMBER 4  OCTOBER  2015 955\npositive retroperitoneal squamous carcinoma. Here, we \nreport our case with a review of the literature.\nCase Report\nA 56-year-old female was admitted to our hospital, due to\nabnormal abdominal ultrasound findings that were found\nincidentally during a regular check-up. The patient denied\nany symptoms and the presence of any specific medical or\nfamily history. She had reached her menopause 2 years ago\nand her regular Papanicolaou (Pap) smear tests had been\nnormal so far.\nThe patient was hemodynamically stable on admission. On\nphysical examination, her abdomen was soft and non-tender\nwith no palpable mass. The laboratory findings were all\nwithin normal limits.\nOn gynecological examination, the cervix was normal and\nPap test was negative. Transvaginal ultrasound demon-\nstrated a left pelvic mass with complex echogenicity of 5.18\ncm!3.68 cm (Fig. 1A). Pelvic magnetic resonance imaging\nshowed a solid and cystic, heterogeneous enhanced mass\nmeasuring 5.5 cm in size in the left pelvic cavity (Fig. 1B).\nAround the mass, there were suspicious metastatic lymph\nnodes in the left internal iliac region. Fluorodeoxyglucose\npositron emission tomography (FDG-PET) showed no other\nfocus with increased glucose metabolism which excluded\nother origins of carcinoma or any metastatic location \nexcept the left pelvic mass. Endoscopy, colonoscopy, and \ncystoscopy were also normal. We also performed computed\ntomography (CT) of head, neck, and chest, which showed no\nabnormality. Tumor markers including carcinoembryonic\nantigen, cancer antigen (CA) 125, CA 19-9, alpha-fetoprotein,\n!-subunit of human chorionic gonadotropin, and SCC anti-\ngen were normal.\nSubsequently, the patient underwent an exploratory \nlaparotomy. The upper abdominal organs were grossly \nnormal and the pelvic cavity was clean, with normal uterus\nFig. 1.  (A) Transvaginal ultrasound demonstrated a left pelvic mass with complex echogenicity of 5.18 cm!3.68 cm. (B) T2\nweighted pelvic magnetic resonance imaging showed a solid and cystic, heterogeneous enhanced mass measuring 5.5 cm in\nsize in the left pelvic cavity.\nA B\nFig. 2.  (A) Microscopic examination shows a well capsulated retroperitoneal mass (H&E staining, !40). (B) Microscopic \nexamination shows poorly differentiated squamous cell carcinoma (H&E staining, !400). (C) Immunohistochemical staining\nof p63 shows strong nuclear positivity (!200).\nA B C\n\n956 CANCER  RESEARCH  AND  TREATMENT\nCancer Res Treat. 2015;47(4):954-957\nand bilateral adnexa. The mass was firm, well circumscribed,\nmeasuring 5.2!4.5!3.5 cm and located in the left retroperi-\ntoneal parametrium adjacent to the common iliac vessel, \nobturator nerve, and external iliac vessel. There was no \ninvasion to the uterus and ovary. We performed complete\nresection of the tumor with left pelvic lymph node dissection.\nThe tissue was poorly differentiated carcinoma. Immunohis-\ntochemistry of cytokeratin (CK) 7, CK 20, and thyroid tran-\nscription factor 1 were negative and CK 5/6 was positive. To\ninvestigate the focal lesion with squamous differentiation,\nadditional immunohistochemistry staining of p63 was \nperformed, which showed strong nuclear positivity. Consid-\nering the result, we concluded the final pathology as poorly\ndifferentiated SCC (Fig. 2A-C). The lymph nodes were \nnegative for malignancy. In addition, HPV DNA chip test\nwas performed using the HPV 9G DNA Membrane Kit \n(Biometrixtechnology Inc., Seoul, Korea) and the specimen\nwas positive for HPV 18. Postoperative CT of the abdomen\nwas performed and showed no remaining retroperitoneal\nmass. The patient underwent adjuvant chemotherapy with\n5-fluorouracil (5-FU; 1,000 mg/m2) for four days and \ncisplatin (60 mg/m2) for one day every 4 weeks. After four-\ncycles of chemotherapy, we performed CT of neck, chest, and\nabdomen as follow-up evaluation, and it showed no \nevidence of disease. We planned additional radiotherapy.\nDiscussion\nTo the best of our knowledge, the case presented here is\nthe first description of a primary retroperitoneal SCC with\nthe positivity of HPV 18 in South Korea. Currently, FDG-PET\nis one of the preferred imaging modalities used in detection\nof carcinoma of unknown primary origin. In this patient,\nFDG-PET did not show any occult carcinoma. Other studies\nincluding endoscopy, colonoscopy, cystoscopy, and chest CT\nwere normal and all tumor markers were negative. It has \npreviously been reported that SCC from the head and neck\nregion rarely metastasizes as a solitary pelvic mass [2]. We\nperformed CT of the head and neck, and laryngoscopy, but\ncould not find any lesions. Because all of the imaging test \nresults were negative, and a retroperitoneal mass was located\nadjacent to the urogenital organs, we performed additional\nmolecular examination by HPV DNA chip test, which \nrevealed HPV 18 positive.\nIt is believed that HPV contributes to development of a \ncarcinoma through a combination of loss of cell cycle differ-\nentiation and genomic instability. It is established that HPV\ninfection is associated with anal, cervical, vulvar, penile, and\nvaginal cancer. In addition, HPV infection is implicated in\nhead and neck SCC, particularly oropharyngeal cancer [3].\nHPV test has been used to differentiate primary gynecologic\nmalignancies when the etiology is unclear. In a study by Stae-\nbler, HPV testing was used to differentiate endometrial from\nendocervical cancer [4]. HPV was positive in 16 out of 24 \nendocervical cases (66.7%) compared to 0 out of 24 endome-\ntrial cases. Our case appears to be the first case describing\nretroperitoneal pelvic masses with unknown primary that\nare HPV 18-positive, despite normal cervical examination\nand cytology.\nDirect exposure and infection by HPV are thought to be\nthe main routes. In a malignancy that does not arise from \nsurface or mucosal tissues, the route of transmission is less\nclear. However, in many reports, transmission of HPV has\nbeen reported to occur through many routes, including \nsexual transmission, oral cavity, lymphatic or hematogenous\nspread [5-7]. In this case, we could not find the exact route\nof HPV-infected tumor cells because of unknown primary\norigin. However, we could hypothesize that multiple routes\ncould be possible and that HPV infection played an impor-\ntant role in carcinogenesis.\nThe importance of complete surgical resection has been\nemphasized in the literature as it is believed to be directly \nrelated to patient survival [1,8,9]. In order to exclude metas-\ntasis from primary gynecological malignant lesions, total\nhysterectomy with bilateral salpingo-ophorectomy is often\nperformed. In addition, pelvic lymphadenectomy, paraaortic\nlymphadenectomy, and omentectomy could be considered\n[10-12]. In our patient, no lesion was observed on PET-CT\nwith negative tumor markers and complete resection was\nconsidered possible and was therefore performed.\nHPV test affects the modality of treatment and increases\nthe likelihood of performing radiotherapy or chemoradio-\ntherapy, which improves clinical outcome. The role of radi-\nation or chemoradiation in the treatment of cervical cancer\nis well known. We found that HPV-positive head and neck\nSCC, when treated with chemoradiation has better clinical\noutcomes than HPV-negative cancers [13,14]. Due to the \nrarity of retroperitoneal SCC, there is no well-established\nchemotherapy or radiotherapy regimen. In some case series\nand reports, retroperitoneal SCC treated with chemoradia-\ntion had better prognosis compared with patients who were\nnot treated with additional radiation [5,8]. In our case, the\npatient underwent adjuvant chemotherapy with the use of\n5-FU/cisplatin for four cycles to prevent systemic relapse\n[13,14]. We also plan to perform additional radiotherapy\nafter chemotherapy because of high local recurrence rate and\npoor prognosis of primary retroperitoneal SCC.\nWe have presented a case of retroperitoneal SCC of \nunknown primary that was HPV-positive. Surgical resection\nwas performed followed by adjuvant chemotherapy with \n5-FU/cisplatin. Complete surgical resection in our case is \n\nHyun Jin Oh, HPV and Retroperitoneal Squamous Cell Carcinoma\nVOLUME 47  NUMBER 4  OCTOBER  2015 957\nexpected to produce a good result, although further obser-\nvation for local recurrence and metastasis is needed. HPV\nmay be associated with pelvic masses of unknown primary,\neven in patients with normal cervical examination results.\nHence, the result of HPV test could have an impact on find-\ning suspicious primary lesion and treatment modality in our\ncase.\nConflicts of Interest\nConflict of interest relevant to this article was not reported.\n1. Ryu MJ, Chung YW, Bae HS, Lee JK, Lee NW, Song JY. Pri-\nmary squamous cell carcinoma arising from the pelvic\nretroperitoneum. Korean J Obstet Gynecol. 2012;55:782-6.\n2. Hofmann U, O'Connor JP, Biyani CS, Harnden P, Selby P, \nWeston PM. Retroperitoneal metastatic squamous cell carci-\nnoma of the tonsil (with elevated beta human chorionic \ngonadotrophin): a misdiagnosis as extra-gonadal germ cell \ntumour. J Laryngol Otol. 2006;120:885-7.\n3. Munoz N, Castellsague X, de Gonzalez AB, Gissmann L.\nChapter 1: HPV in the etiology of human cancer. Vaccine.\n2006;24 Suppl 3:S3/1-10.\n4. Staebler A, Sherman ME, Zaino RJ, Ronnett BM. Hormone \nreceptor immunohistochemistry and human papillomavirus\nin situ hybridization are useful for distinguishing endocervical\nand endometrial adenocarcinomas. Am J Surg Pathol. 2002;26:\n998-1006.\n5. Clements A, Euscher E, Lacour R, Merritt W, Klopp A, \nRamondetta L. The presence of human papillomavirus or p16\nin six cases of retroperitoneal carcinoma. Obstet Gynecol. 2010;\n116:1042-6.\n6. Capone RB, Pai SI, Koch WM, Gillison ML, Danish HN, \nWestra WH, et al. Detection and quantitation of human papil-\nlomavirus (HPV) DNA in the sera of patients with HPV-asso-\nciated head and neck squamous cell carcinoma. Clin Cancer\nRes. 2000;6:4171-5.\n7. Kan CY, Iacopetta BJ, Lawson JS, Whitaker NJ. Identification\nof human papillomavirus DNA gene sequences in human\nbreast cancer. Br J Cancer. 2005;93:946-8.\n8. Chen CH, Yeh SD, Chiou JF, Lin YH, Chang CW. Optimum\ntreatment for primary squamous cell carcinoma of the pelvic\nretroperitoneum. J Exp Clin Med. 2011;3:304-6.\n9. Boneschi M, Erba M, Cusmai F, Eusebio D, Miani S, Bortolani\nEM. Primary retroperitoneal tumors: treatment modality and\nprognostic factors. Minerva Chir. 1999;54:763-8.\n10. Carabias E, Garcia Munoz H, Dihmes FP, Lopez Pino MA,\nBallestin C. Primary mucinous cystadenocarcinoma of the\nretroperitoneum. Report of a case and literature review. \nVirchows Arch. 1995;426:641-5.\n11. Dore R, La Fianza A, Storti L, Babilonti L, Preda L, Di Maggio\nEM, et al. Primitive mucinous cystadenocarcinoma of the\nretroperitoneum: case report and diagnostic considerations.\nClin Imaging. 1996;20:129-32.\n12. Caruncho M, Pombo F, Arnal-Monreal F. Primary retroperi-\ntoneal serous cystadenocarcinoma of 'ovarian-type': US and\nCT findings. Eur J Radiol. 1993;17:115-6.\n13. Ramshankar V, Krishnamurthy A. Human papilloma virus in\nhead and neck cancers-role and relevance in clinical manage-\nment. Indian J Surg Oncol. 2013;4:59-66.\n14. Zandberg DP, Bhargava R, Badin S, Cullen KJ. The role of\nhuman papillomavirus in nongenital cancers. CA Cancer J\nClin. 2013;63:57-81.\nReferences","source_license":"CC0","license_restricted":false}