Article信州医学雑誌 69(3) : 121-126(2021)departmental bulletin pape

Fukushima, Toshirou

Kanda, Shintaro

Kobayashi, Takashi

Koizumi, Tomonobu

Matsushita, Hirohide

Ozawa, Takesumi

Sekiguchi, Nodoka

English

Shinshu University Institutional Repository

Ⅰ　Introduction　Malignant tumors of the sinonasal tract are ex­tremely rare, accounting for only 3 ％ of all head and neck cancers1）. Sinonasal tumors show similar clinical manifestations, such as nasal obstruction and epistax­is, but a wide range of histological features, including histogenesis and differentiation of tumor cells2）. Sin­onasal undifferentiated carcinoma (SNUC), originally described by Frierson et al. in 19863）, is an extremely rare and high-grade neoplasm arising in the nasal cavity with highly aggressive clinical behavior and poor prognosis1）-7）. In a study of 36 cases of SNUC, Jeng et al.8） reported that 17 ％ and 31 ％ of patients presented with cervical lymph node and distant me­tastasis, respectively, and had a median survival pe­riod of 10 months. Multimodal therapies have been proposed for SNUCs, including surgery, radiothera­py, and chemotherapy, but a standard treatment strategy has not been determined because of its rarity. We encountered a case of locally advanced SNUC treated with cisplatin＋etoposide chemothera­py combined with radiotherapy, which showed a survival period of＞5 years without recurrence. Here, we describe the clinical course of this case along with a brief review of the relevant literature, focus­ing on diagnosis and treatment. Ⅱ　Case Presentation　A 71-year-old woman had presented with nasal obstruction and intermittent epistaxis from the left nasal cavity for the previous 3 months. She visited another hospital as she also had headache in addition to these symptoms. Computed tomography (CT) indi­cated a tumor mass in the left nasal cavity and the patient was referred to our hospital. On physical examination, swelling and hypoesthesia of the left upper jaw were observed. Cervical lymph nodes were not palpable. Laboratory findings, including A Case of Sinonasal Undifferentiated Carcinoma Sucessfully Responding to ChemoradiotherapyHirohide Matsushita1）, Takesumi Ozawa1）, Nodoka Sekiguchi2）, Toshirou Fukushima2） Takashi Kobayashi2）, Shintaro Kanda2）＊ and Tomonobu Koizumi2）1）　Department of Radiology, Shinshu University School of Medicine　　　　　　　　　　2）　Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine　　Sinonasal undifferentiated carcinoma is an extremely rare and high-grade neoplasm arising in the nasal cavity, with highly aggressive clinical behavior and poor prognosis. Multimodal therapies have been proposed, including surgery, radiotherapy, and chemotherapy, but a standard treatment strategy has not been determined because of its rarity. Here, we present a case of sinonasal undifferentiated carcinoma treated with cisplatin＋etoposide chemotherapy combined with radiotherapy (2 Gy×30 fractions, total 60 Gy). The patient achieved complete remission and is still alive without recurrence for over 5 years. A beneficial therapeutic outcome by chemoradiotherapy alone is extremely rare in patients with sinonasal undifferentiated carcinoma.  Shinshu Med J 69 : 121―126, 2021(Received for publication June 16, 2020 ; accepted in revised form January 5, 2021)　Key words : undifferentiated carcinoma, FDG-PET, cisplatin VP-16, nasal cavity, complete remission＊ Corresponding author : Shintaro Kanda Department of Comprehensive Cancer Therapy,  Shinshu University School of Medicine,  3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan E-mail : skanda@shinshu-u.ac.jp121No. 3, 2021Shinshu Med J, 69⑶：121～126, 2021tumor markers (CEA, CA19-9, SCC, NSE, and Pro-GRP), were within normal limits. CT and magnetic resonance imaging (MRI) showed a hypervascular mass occupying the left nasal cavity and infiltrating the bones of the paranasal sinus (Fig. 1). Tumor biopsy was performed, and the histological findings showed groups of atypical small round cells with hyperchromatic nuclei beneath the epithelium (Fig. 2A, B). The results of immunohistochemical analy­sis indicated that the atypical cells were negative for S-100 protein (Fig. 2C), chromogranin A (Fig. 2D), synaptophysin, neuron-specific enolase, mela­noma-associated antigen 45 (Fig. 2E), CD 20, CD 34, CD 56 and α-smooth muscle antigen, and positive for cytokeratin AE1/AE3, (Fig. 2F). In addition, tumor cells were negative for nuclear protein in testis and p63 on immunohistochemical examination. Based on these histological findings, a diagnosis of SNUC was made. There were no regional lymph nodes and distant metastases on systemic radiographic exam­ination including positron emission tomography with fluorodeoxyglucose-computed tomography (FDG-PET/CT). However, during the examinations, she developed further worsening and painful swelling of the left upper jaw. Left exophthalmos and diplopia were also present because of tumor growth. Surgical excision was impossible because of the locally ad­vanced nature of the tumor. Chemotherapy was initiated with cisplatin at 80 mg/m2 intravenously on day 1 and etoposide at 100 mg/m2 intravenously on DCBAFig. 1 　Magnetic resonance imaging (MRI) at admission. Fat suppressed contrast-enhanced T1- weighted (A ; axial, B ; coronal), and T2-weighted (C ; axial, D ; coronal) images showing a heterogenous contrast-enhanced mass occupying the left nasal cavity and infiltrating the bones of the paranasal sinus.122 Shinshu Med J　Vol. 69Matsushita・Ozawa・Sekiguchi et al.days 1-3 (PE chemotherapy) every 3-4 weeks. Three cycles of PE chemotherapy were effective and resulted in tumor reduction (Fig. 3A, B) . Subsequently, concurrent radiotherapy at a dose of 60 Gy in 30 frac­tions of 2.0 Gy each combined with PE chemotherapy was performed (Fig. 3C, D). Irradiation fields included primary tumor and bilateral neck as elective neck treatment. During the chemoradiotherapy, the patient developed febrile neutropenia but recovered with appropriate antibiotic therapy. The patient refused a fifth round of PE chemotherapy. FDG-PET/CT re­vealed negative FDG uptake after the chemoradio­therapy (Fig. 3F) and was considered to show com­plete remission (Fig. 3D, F). Based on the FDG-PET findings, salvage surgery for the residual mass was not undertaken and close observation has been per­formed. The patient is still alive without recurrence for over 5 years. Ⅲ　Discussion　There are no specific clinical and radiographic findings that could be useful for differential diagnosis among nasal malignancies8）9）. Therefore, a histological diagnosis is essential for high-grade malignancies because of the broad and complex histological find­ings in tumors arising from the sinonasal tract1）-6）. Fig. 2 　Hematoxylin and eosin staining ; (A) low-power (x 2) and (B) high-power fields (×40). Immunohistochemical findings indicated that malignant cells were negative for (C) S-100, (D) chromogranin A and (E) melanoma-associated antigen, and positive for (F) cytokeratin AE1/AE3.AFDECB123Sinonasal undifferentiated carcinoma responding to chemoradiotherapyNo. 3, 2021The differential diagnoses of small round cell tumors include squamous cell carcinoma, small cell neuroen­docrine carcinoma, rhabdomyosarcoma, Ewing sarcoma, lymphoma, malignant melanoma, etc. Im­munohistological markers are useful for differential diagnosis4）-6）, and the tumor cells in the present case were of epithelial origin and lacked any evidence of neuroendocrine, muscle, melanocyte, or leukocyte differentiation. The histological findings in our case were consistent with those in other reports of SNUCs. 　Multimodality therapy has been adopted for SNUC, but the optimal treatment has yet to be determined because of its rarity. Smith et al.6） reported six pa­tients with SNUCs initially treated with surgical resection followed by radiation therapy. Only two cases had disease-free survival of 6 and 18 months at last follow-up. On the other hand, Musy et al.7） reported the clinical outcomes of 20 cases of SNUCs initially treated with chemoradiotherapy or radio­therapy. Ten cases were followed by craniofacial resection and the 2-year survival was 64 ％ in the treatment group. The study suggested that the re­sponse to initial chemoradiotherapy was important for long-term survival. Recently, Faisal et al10） sum­marized clinical data of 255 published patients with SNUCs and reported that the locoregional control rate was 63.9 ％ undergoing trimodality (surgery plus radiotherapy with and without chemotherapy), 49.2 ％ in bimodality (chemoradiotherapy), and 31.3 ％ in surgery alone. There was no significant difference in the locoregional control rate between trimodality and bimodality in their study, however, the data suggested that surgical resection for residual tumor after chemoradiotherapy could be added for the best suitable management in the present case. However, several cases indicated that viable tumor cells in the resected specimens were absent after chemoradio­therapy and associated with relatively long survival6）-8）. In addition, the negative FDG-PET finding after chemoradiotherapy in our case suggested a complete remission. Several clinical studies suggested that if PET scan is negative by FDG-PET, salvage surgery or subsequent chemotherapy can be omitted safety in patients with seminoma11）12） and/or malignant lym­phoma13）. Thus, treatment options in the present case including surveillance or salvage surgery, were em­BA  DCFEFig. 3 　Serial contrast-enhanced computed tomographies are shown, (A) before, (B) after three cycles of cisplatin plus etoposide chemotherapy, (C) after chemoradiotherapy by 4th cycle cisplatin plus etoposide combined with radiotherapy (60Gy) and (D) 4 years after the chemoradiotherapy. Positron emission tomography with fluorodeoxyglucose-computed tomography (FDG-PET/CT) (E) before and (F) after chemoradiotherapy. Positive FDG uptake in the nasal mass was completely diminished after the chemoradiotherapy, suggested complete remission after chemoradiotherapy.124 Shinshu Med J　Vol. 69Matsushita・Ozawa・Sekiguchi et al.ployed and we selected close observation, resulting in long-term survival without recurrence over 5 years. Our case suggests that FDG-PET can be a useful tool for making a decision regarding optimal treat­ment choice for the residual mass in patients with SNUC. We need further clinical experience about the FDG-PET information and prognosis in patients with SNUC.　Faisal et al.10） also performed a meta-analysis assess­ing regional (neck) relapse with and without elective neck treatments (neck dissection or irradiation) and reported that the elective neck treatment was associ­ated with an 80 ％ decreased risk for regional recurrence. Thus, elective neck treatment should be considered in patients with SNUC even in initial stage N0, as done in the present case. 　In the present case, radiotherapy for all involved tumor lesions would have been difficult because of the wide fields, especially when including the left orbit area. Therefore, we selected PE chemotherapy alone as the initial therapy. The efficacy of this PE chemotherapy was remarkable and concurrent chemoradiotherapy was available after three cycles of PE chemotherapy. No information is available in the literature regarding the usefulness of chemother­apy in SNUCs. Various chemotherapeutic regimens, including CDDP＋5-FU, cyclophosphamide, vincris­tine, doxorubicin (CAF), or PE, were used in previous case series4）-8）. However, these studies did not evaluate the response. PE combined with concurrent radio­therapy has been widely accepted in limited cases of small cell lung cancer14）. In addition, radiotherapy combined with PE chemotherapy was used in the treatment of other nasal tumors15）-17）. Our experience suggested that PE is a useful novel chemotherapy regimen for SNUC. Further clinical studies of SNUC and evaluation of the response to chemoradiotherapy or chemotherapy are required.Ⅳ　Conclusion　We described a case of SNUC successfully treated with chemoradiotherapy alone, resulting in complete remission and disease-free survival for over 5 years. The disease of SNUC should be recognized and dif­ferential diagnosis of this distinct tumor from other nasal tumors is important. FDG-PET may be a useful for making a decision regarding optimal treatment choice in patients with SNUCs.Conflict of Interest　The authors declare no potential conflicts of inter­est with respect to the research, authorship, and/or publication of this article.References 1）　Goel R, Ramalingam K, Ramani P, Chandrasekar T : Sino nasal undifferentiated carcinoma : A rare entity. J Nat Sci Biol Med 3 : 101-104, 2012 2）　Devi CP, Devi KM, Kumar P, Amrutha Sindhu RV : Diagnostic challenges in malignant tumors of nasal cavity and paranasal sinuses. J Oral Maxillofac Pathol 23 : 378-382, 2019 3）　Frierson HF Jr, Mills SE, Fechner RE, Taxy JB, Levine PA : Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from schneiderian epithelium and distinct from olfactory neuroblastoma. Am J Surg Pathol 10 :  771-779, 1986 4）　Ejaz A, Wenig BM : Sinonasal undifferentiated carcinoma : clinical and pathologic features and a discussion on classification, cellular differentiation, and differential diagnosis. Adv Anat Pathol 12 : 134-143, 2005 5）　Enepekides DJ : Sinonasal undifferentiated carcinoma : an update. Curr Opin Otolaryngol Head Neck Surg 13 : 222-225, 2005 6）　Smith SR, Som P, Fahmy A, Lawson W, Sacks S, Brandwein M : A clinicopathological study of sinonasal neuro­endocrine carcinoma and sinonasal undifferentiated carcinoma. Laryngoscope 110(10 Pt 1) : 1617-1622, 2000 7）　Musy PY, Reibel JF, Levine PA : Sinonasal undifferentiated carcinoma : the search for a better outcome. Laryngoscope 112(8 Pt 1) : 1450-1455, 2002125Sinonasal undifferentiated carcinoma responding to chemoradiotherapyNo. 3, 2021 8）　Jeng YM, Sung MT, Fang CL, et al : Sinonasal undifferentiated carcinoma and nasopharyngeal-type undifferentiated carcinoma : two clinically, biologically, and histopathologically distinct entities. Am J Surg Pathol 26 : 371-376, 2002 9）　Phillips CD, Futterer SF, Lipper MH, Levine PA : Sinonasal undifferentiated carcinoma : CT and MR imaging of an uncommon neoplasm of the nasal cavity. Radiology 202 : 477-480, 1997 10）　Faisal M, Seemann R, Lill C, et al : Elective neck treatment in sinonasal undifferentiated carcinoma : Systematic review and meta-analysis. Head Neck 42 : 1057-1066, 202011）　 Bachner M, Loriot Y, Gross-Goupil M, et al : 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions : a retrospective validation of the SEMPET trial. Ann Oncol 23 : 59-64, 201212）　Sakaguchi Y, Isowa N : Successful resection of mediastinal seminoma evaluated the response to induction chemo­therapy with fluorodeoxyglucose-positron emission tomography. Ann Thorac Cardiovasc Surg 18 : 45-47, 201213）　Johnson P, Federico M, Kirkwood A, et al : Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med 374 : 2419-2429, 2016 14）　Stinchcombe TE, Gore EM : Limited-stage small cell lung cancer : current chemoradiotherapy treatment paradigms. Oncologist 15 : 187-195, 201015）　Gomi D, Sasaki S, Sekiguchi N, Kobayashi T, Sakamoto A, Koizumi T : A case of olfactory neuroblastoma (esthesio­neuroblastoma) presenting with anemia due to nasal bleeding. Shinshu Med J 64 : 247-252, 201616）　Lucas JT Jr, Ladra MM, MacDonald SM, et al : Proton therapy for pediatric and adolescent esthesioneuroblastoma. Pediatr Blood Cancer 62 : 1523-1528, 2015 17）　Nakamura Y, Suzuki M, Ozaki S, et al : Sinonasal inverted papilloma associated with small cell neuroendocrine carcinoma : A case report and literature review of rare malignancies associated with inverted papilloma. Auris Nasus Larynx 46 : 641-650, 2019 （2020. 6. 16 received ; 2021. 1. 5 accepted）　126 Shinshu Med J　Vol. 69Matsushita・Ozawa・Sekiguchi et al.

A Case of Sinonasal Undifferentiated Carcinoma Sucessfully Responding to Chemoradiotherapy

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A Case of Sinonasal Undifferentiated Carcinoma Sucessfully Responding to Chemoradiotherapy

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