Resection of a retroperitoneal cancer of unknown primary site after chemoradiation therapy: a case report

Background: Complete recovery from retroperitoneal squamous cell carcinoma of unknown primary site treated by multidisciplinary therapy is extremely rare. Case presentation: A 78-year-old man was referred to our hospital due to a mass measuring 8 cm in size in the left pelvic retroperitoneal area, which was diagnosed as a cancer of unknown primary site. The pathological type was squamous cell carcinoma. The left iliac artery/vein and ureter were involved in the tumor, and the tumor caused severe left leg pain. Although inammation and symptoms were severe, palliative radiotherapy was considered. After that, biweekly combined therapy with docetaxel, cisplatin, and uorouracil was planned. After 5 courses of chemotherapy, the tumor diameter reduced from 11.6 cm to 4 cm in size. In addition, the border between the iliac vessels, urinary tract and tumor became apparent. The patient underwent radical resection of the tumor 8 months after the treatment started. The left ureter and the external/internal iliac artery were preserved, but the external iliac vein was sacriced because of the possibility of tumor invasion. The postoperative course was free of complications, and the patient was discharged 10 days after the operation. The histopathological ndings showed no residual viable tumor cells or foreign body-type giant cells with necrosis. The pathological effect of chemotherapy was dened as Grade 3 (pathological complete response). The patient has experienced no recurrence or distant metastasis for 4 years. Conclusions: Multidisciplinary therapy succeeded in treating a retroperitoneal squamous cell carcinoma of unknown primary site with preservation of organ function. of

postoperative course was free of complications, and the patient was discharged 10 days after the operation. The histopathological ndings showed no residual viable tumor cells or foreign body-type giant cells with necrosis. The pathological effect of chemotherapy was de ned as Grade 3 (pathological complete response). The patient has experienced no recurrence or distant metastasis for 4 years.
Conclusions: Multidisciplinary therapy succeeded in treating a retroperitoneal squamous cell carcinoma of unknown primary site with preservation of organ function.

Background
Cancer of unknown primary site (CUP) is de ned as a histologically proven metastatic malignant tumor whose primary site cannot be identi ed during pretreatment evaluation [1]. These tumors are not rare; they represent 3-5% of all malignancies diagnosed in oncology practice. However, squamous cell carcinoma of unknown primary site (SCCUP) is a relatively rare malignant tumor [2]. Moreover, although these patients are usually treated with aggressive multidisciplinary therapy similar to patients with locally advanced head and neck cancer, the expected median survival time in previous reports is only [6][7][8][9] months [1,2]. We report a case of SCCUP located in the retroperitoneum that was treated with multidisciplinary therapy and in which long survival was obtained without recurrence.

Case Presentation
A 78-year-old man was referred to the Department of Surgical Oncology, Gifu University Hospital due to a mass measuring 8 cm in size in the left pelvic retroperitoneal area that was causing left leg pain.
Computed tomography (CT) showed that the left iliac artery/vein and ureter seemed to be involved in the mass. Ureteral dilatation due to obstruction of the ureter by the mass was also observed (Fig. 1). Fluorine-18 uorodeoxyglucose positron emission tomography showed no other focus with increased glucose metabolism, which excluded other origins of carcinoma or any metastatic location except the left pelvic mass (Fig. 2). Even after further studies such as esophagogastroduodenoscopy, colonoscopy, and cystoscopy, we could nd no other primary lesion. Endoscopic ultrasound-guided ne needle aspiration was performed during colonoscopy. Immunohistochemical studies (Fig. 3) showed positive epithelial markers in pan-cytokeratin AE1/AE3 with differential expression of cytokeratin 7 rather than cytokeratin 20. However, leukocyte common antigen and S100 were negative. The origin of the tumor could not be detected. Laboratory data revealed a high level of C-reactive protein at 8.99 mg/dL, white blood cell count of 30,450/µL, squamous cell carcinoma antigen (SCC Ag) of 11.1 ng/mL and prostate-speci c antigen of 9.629 ng/mL. Based on these results, he was diagnosed as having SCCUP. Because the mass aggravated his symptoms, he was started on palliative radiotherapy before inducing chemotherapy. After he started radiation therapy, the pain in his left leg improved. Although he needed to start chemotherapy immediately, we were concerned about renal dysfunction due to the left ureteral stenosis and performed a left nephrostomy before chemotherapy. Combined chemotherapy with paclitaxel and carboplatin was chosen as the rst-line treatment according to the National Comprehensive Cancer Network (NCCN) clinical guideline, but infusion reaction occurred after injection of the paclitaxel. Therefore, he needed to be changed to a regimen without paclitaxel, and we chose combined chemotherapy of biweekly docetaxel, cisplatin and 5-uorouracil (5FU) (Bi-DCF). After ve courses of Bi-DCF, the tumor diameter had decreased from 11.6 cm to 4 cm in size. In addition, the border between the iliac vessels, ureter and tumor became apparent (Fig. 4). Tumor marker SCC Ag had decreased to within normal range. So, radical resection was performed 8 months after starting treatment. The left urinary tract and the external/internal iliac artery were preserved, but the external iliac vein was sacri ced at the time of surgery because of the possibility of tumor invasion (Fig. 5). His postoperative course was without complications, and he was discharge from hospital 10 days after surgery. One month after surgery, the left nephrostomy was closed because his ureter function was maintained. The histopathological ndings showed only necrotic tissue or brotic changes, and there were no residual viable tumor cells. The pathological effect of chemotherapy was de ned as complete response (Fig. 6). The patient has experienced no recurrence or distant metastasis for 4 years.

Discussion
CUP is a histologically proven metastatic malignant tumor with a primary site that cannot be identi ed during pretreatment evaluation [1]. CUP, with its variety of biological characteristics, accounts for 3-5% of all malignancies, approximately 50% of which are diagnosed as well-to moderately differentiated metastatic adenocarcinoma, 30% as undifferentiated or poorly differentiated carcinoma, 15% as SCC and the remaining 5% as undifferentiated neoplasms [2].
A detailed medical history and physical ndings are important for diagnosis, followed by various examinations such as blood biochemical tests including tumor markers, chest X-ray and whole-body CT [2,3]. Furthermore, if tumor tissue can be collected, immunohistochemical staining is necessary for exclusion of occult primaries and for suggesting tissues of origin [4].
CUP remains an extremely aggressive disease with a poor prognosis. The median survival time is between 4 and 12 months [2,5], and select patients with favorable subsets of CUP have median overall survival times ranging from 12 to 36 months [6]. It is thought that more than half of patients with CUP have multiple lesions [7], and chemotherapy has a main role in the treatment of CUP. Although no regimen has been established as a standard rst-line therapy [8,9], a combination of platinum plus taxane-based chemotherapy obtained a superior response rate and survival in the reported phase II trials [8,[10][11][12].
However, multiple phase II studies have found no superior combination of cytotoxics, and there remains no standard second-line therapy [9].
Radiation therapy is also an option for localized tumors. In some cases, radical irradiation may be considered, and in others, palliative treatment. In the present case, although it was necessary to begin chemotherapy immediately, there was concern about renal dysfunction due to the left ureteral stenosis. Therefore, a left nephrostomy was performed before chemotherapy to preserve his renal function. Besides, left leg pain due to the tumor was severe, and palliative radiation therapy was started for a total of 10 Gy before the induction of chemotherapy. Furthermore, because radiation monotherapy could also cause metastasis, it was essential that the patient begin early systemic chemotherapy, and he initially underwent combination therapy of weekly paclitaxel plus carboplatin. However, because of the infusion reaction caused by the paclitaxel at the rst injection, a different combination regimen of taxane plus platinum was needed. Thus, the patient was administered Bi-DCF chemotherapy [13], , which is used for advanced esophageal squamous cell carcinoma in our institution, after ethics committee approval was received.
A regimen combining docetaxel, cisplatin and 5FU is also used for esophageal cancer, gastric cancer and head and neck cancers, and is also described in the NCCN guidelines. It offers a prolonged prognosis compared to conventional cisplatin plus 5FU combination therapy although there is concern about renal dysfunction [14][15][16][17]. Hara et al. also reported that the same regimen was used as preoperative chemotherapy for esophageal cancer, with a response rate of 64%, Grade 3/4 leukopenia of 45% and neutropenia of 83% [18]. In our institution, we performed Bi-DCF therapy as neoadjuvant chemotherapy for esophageal cancer and reported Grade3/4 leukopenia of 12.5%, neutropenia of 31.4%, and no instances of renal dysfunction while maintaining a high response rate of 90.3% compared with previous reports [19]. Bi-DCF therapy can be safely performed even in patients with potential high risk of renal dysfunction such as in this case, and it is thought that high effects can be expected.
Although there is no uni ed opinion regarding surgical treatment for CUP, it is often considered when a single, resectable tumor is present. If the tumor can be resected without tumor remnants, a favorable prognosis can be expected.
In the present case, tumor shrinkage due to chemotherapy following palliative radiotherapy was obtained and clari ed the margin between the tumor and iliac artery, vein and ureter. Therefore, surgical treatment could be performed without tumor remnants although the left external iliac vein was sacri ced because of suspected tumor invasion. Moreover, the resected tissue was brous tissue with extensive necrosis without viable cells, and granulation formation and the accumulation of foamy histiocytes were observed. All of these were changes that occurred due to the therapeutic effect after the tumor was reduced in size. The patient has experienced no recurrence or distant metastasis for 4 years.

Conclusions
We report a rare case of SCCUP in which an outstanding outcome was achieved. CUP remains an extremely aggressive disease, so early diagnosis and multidisciplinary therapy including radiation therapy, chemotherapy and radical surgery should be considered while maintaining organ function and the general condition of the patient.

Consent for publication
Consent for publication was obtained from the patient included in this study.

Availability of data and materials
All data generated or analyzed are included in this published article Competing interests K. Yoshida has received grants, personal fees and non nancial support from Chugai Pharmaceutical Co., Ltd. during the conduction of the study; grants and personal fees from Taiho Pharmaceutical Co., Ltd., P zer Inc., and Yakult Honsha Co., Ltd.; grants from Bristol-Myers Squibb; grants from Kyowa Hakko Kirin Co., Ltd. outside the submitted work; honoraria from Taiho Pharmaceutical Co., Ltd., P zer Inc., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Yakult Honsha Co., Ltd.; and had a consultant or advisory relationship with Taiho Pharmaceutical Co., Ltd. and La Roche, Ltd. T. Takahashi has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd. All remaining authors declare that they have no con ict of interest.      After tumor resection, the external iliac vessels and internal iliac artery were preserved, but the iliac vein was sacri ced because of the possibility of tumor invasion. The ureter was preserved (yellow vessel tape) (c) Intraoperative urography. The left ureter was displaced by the tumor, but the tumor had not directly invaded the ureter, and the ureter was preserved without injury