Introduction
Extrapulmonary small cell carcinoma is rare and has unique histopathological characteristics that make it difficult to diagnose and treat. In this study, we adapted the Japanese Lung Cancer Treatment Guidelines to treat three patients with small cell carcinoma of the head and neck, and we evaluated outcomes.Reference Pignon, Arriagada, Ihde, Johnson, Perry and Souhami1–Reference Ebi, Kubota, Nishiwaki, Hojo, Matsumoto and Kakinuma10
When a head and neck tumour was diagnosed as small cell carcinoma, we determined whether the patient had limited or extensive disease and then developed an appropriate treatment plan (i.e. chemoradiotherapy plus surgery, chemoradiotherapy alone or chemotherapy alone). The chemotherapy regimen comprised four courses of platinum 80 mg/m2 for 1 day each plus etoposide 100 mg/m2 for 3 days. For chemoradiotherapy, a standard fractionation radiotherapy dosage (50 to 60 Gy) was given concurrently with chemotherapy.
Upon completion of treatment, we evaluated its effect according to the Response Evaluation Criteria in Solid TumorsReference Eisenhauer, Therasse, Bogaerts, Schwartz, Sargent and Ford11 and developed a management plan (i.e. ‘wait and scan', chemotherapy, surgery, or best supportive care).
Case reports
Case one
Our first patient was a 56-year-old man whose chief complaint was right nasal bleeding. The patient presented at another hospital with right nasal bleeding, and a tumour was discovered in his nasal cavity. After a biopsy revealed small cell carcinoma, he was referred to our hospital. The tumour completely filled his right nasal passage.
Magnetic resonance imaging (MRI) of the nasal cavity revealed a tumour limited to the inside of the right nasal cavity (Figure 1a). No abnormalities were detected upon computed tomography (CT) scanning of other regions, bronchoscopy, biopsy of the pulmonary hilum, or cranial MRI. Bone scintigraphy showed accumulation only in the right nasal cavity.
Fig. 1 Imaging studies for case one. (a) Axial, gadolinium-enhanced, T1-weighted magnetic resonance imaging (MRI) scan before treatment. (b) Axial, gadolinium-enhanced, T1-weighted MRI scan after initial treatment. (c) Axial, T2-weighted MRI scan taken 31 months after treatment. Arrowheads indicate the tumour.
The tumour was diagnosed as stage I small cell carcinoma (tumour-node-metastasis (TNM) classification T1 N0 M0), limited disease, with a primary lesion in the right nasal cavity.
Chemotherapy was undertaken, following a regimen of platinum 110 mg for 1 day and etoposide 140 mg for 3 days, for a total of four courses. A total radiotherapy dose of 50 Gy was given in 25 fractions, commencing with the second course of chemotherapy.
Upon completion of treatment, imaging revealed a 71.4 per cent reduction in tumour size, which was classified as a partial response according to the Response Evaluation Criteria in Solid Tumors system (Figure 1b). Adverse effects of treatment included grade IV bone marrow toxicity and grade II mucositis.
One month after the final chemotherapy treatment, removal of the middle turbinate was performed under general anaesthesia.
Thirty-one months after treatment, there was no sign of recurrence (Figure 1c).
Case two
Our second patient was a 55-year-old woman whose chief complaint was protrusion of her left eyeball. She presented initially at a neighbourhood clinic, with a protruding left eyeball. An MRI revealed a tumour in the left ethmoid sinus, which led to her referral to our institution.
Upon examination, the patient's left eyeball was noticeably protuberant. An enlarged lymph node was detected upon palpation of the submandibular region of the neck. A biopsy of the tumour via the left middle nasal passage revealed small cell carcinoma.
Magnetic resonance imaging revealed a tumour centred within the left ethmoid sinus. The mass extended to the nasal cavity, orbit and cranium, but with no evidence of brain metastasis (Figure 2a). A CT revealed metastasis to submandibular lymph nodes but no abnormalities in other regions. Bone scintigraphy showed accumulation only in the left nasal cavity.
Fig. 2 Imaging studies for case two, showing coronal, gadolinium-enhanced, T1-weighted magnetic resonance imaging scans (a) before treatment and (b) after initial treatment. Arrowheads indicate the tumour.
The tumour was diagnosed as stage IV-B small cell carcinoma (T4b N2b M0), limited disease, with a primary lesion in the left ethmoid sinus.
Chemotherapy was commenced, following a regimen of platinum 120 mg for 1 day and etoposide 150 mg for 3 days, for a total of four courses. A total radiotherapy dose of 60 Gy was given in 30 fractions, commencing with the second course of chemotherapy.
Upon completion of treatment, imaging revealed a 64.4 per cent reduction in tumour size, which was classified as a partial response (Figure 2b). Adverse effects of treatment included grade IV bone marrow toxicity and grade II mucositis. Following treatment, we opted for ‘wait and scan' management.
Two months after treatment, the patient developed disseminated intravascular coagulation. Histological examination revealed tumour cells in the peripheral blood. These findings indicated that the cancer had metastasised to bone marrow. Additional treatment was contraindicated due to the patient's poor general condition. She died two weeks after diagnosis of metastasis.
Case three
Our final patient was a 58-year-old man who presented at another hospital complaining mainly of swelling in the left submandibular area. After an open biopsy revealed small cell carcinoma, the patient was referred to our hospital.
Palpation revealed a hard mass approximately 60 mm in size at the location of the left submandibular gland, with strong adhesion to the mandibular bone. There was reduced sensitivity in the area of the lesion.
An MRI revealed a tumour centred within the left submandibular area (Figure 3a). A CT scan revealed metastases in submandibular and submental lymph nodes. There were no visible abnormalities in other regions. Bone scintigraphy showed accumulation only under the left mandible.
Fig. 3 Imaging studies for case three, showing axial, gadolinium-enhanced, T1-weighted magnetic resonance imaging scans (a) before treatment and (b) after initial treatment. Arrowheads indicate the tumour; arrows indicate an enlarged lymph node.
The tumor was diagnosed as stage IV-A small cell carcinoma (T4a N2b M0), limited disease, with a primary lesion in the left submandibular gland.
The patient underwent a chemotherapy regimen of platinum 140 mg for 1 day and etoposide 170 mg for 3 days, for a total of three courses. A total radiotherapy dose of 60 Gy was given in 30 fractions, commencing with the second course of chemotherapy. Because of adverse effects, including febrile neutropenia and drug-induced renal dysfunction, the final course of chemotherapy was changed from platinum to carboplatin (area under the curve, 5.0 mg·min/ml), and the etoposide dosage was reduced to 80 mg/m2. The fourth course was therefore carboplatin 450 mg for 1 day (carboplatin dosage as per Calvert: (creatinine clearance 65 ml/min + 25) × area under the curve 5 mg·min/ml) plus etoposide 135 mg for 3 days.Reference Calvert, Newell, Gumbrell, O'Reilly, Burnell and Boxall12
Upon completion of treatment, imaging revealed a 31.1 per cent reduction in tumour size, which was classified as a partial response (Figure 3b). The tumour was no longer detectable by palpation, and the overlying reduced sensitivity had disappeared. Adverse effects of treatment included grade IV bone marrow toxicity and grade IV mucositis.
Following treatment, we opted for 'wait and scan' management.
Thirteen months after completion of treatment, there had been no tumour progression.
Discussion
The Japanese Lung Cancer Treatment Guidelines are now commonly used for treating small cell lung carcinoma; however, there are no guidelines for the treatment of extrapulmonary small cell carcinoma.Reference Galanis, Frytak and Lloyd13–Reference Gregory15 Some reports have suggested that extrapulmonary small cell carcinoma is pathologically dissimilar from small cell lung carcinoma and should therefore be treated as an entirely different condition.Reference Ferlito, Barnes, Rinaldo, Gneep and Milroy16 Nevertheless, extrapulmonary small cell carcinoma is typically treated using the guidelines for small cell lung carcinoma, which are strongly supported by evidence.Reference Rosenthal, Barker and EL-Naggar17, Reference Barnes, Eveson, Reichert and Sidransky18 Thus, it is reasonable to adapt the Japanese Lung Cancer Treatment Guidelines for treatment of small cell carcinoma of the head and neck.
In the above patient series, we selected full-body CT scan and bone scintigraphy to diagnose small cell carcinoma of the head and neck. Furthermore, due to the histological characteristics of this cancer, we would advise MRI scanning of both the affected area and the cranium.Reference Barnes, Eveson, Reichert and Sidransky18, Reference Mills19
Figure 4(a) shows the strategy for treating small cell lung carcinoma, while Figure 4(b) shows our proposed strategy for treating small cell carcinoma of the head and neck. First, it is necessary to classify the extent of the carcinoma: either limited disease or extensive disease.Reference Pignon, Arriagada, Ihde, Johnson, Perry and Souhami1, Reference Warde and Payne2 Limited disease is defined as disease ‘limited to an area for which radiotherapy is potentially curative'.Reference Micke, Faldum, Metz, Beeh, Bittinger and Hengstler20 If this criterion was used to classify small cell carcinoma of the head and neck, all but stage IV-C cases would be classified as limited disease. Because simple chemotherapy is unusual for cancers of the head and neck, we maintain that chemoradiotherapy is indicated even for stage I disease.Reference Galanis, Frytak and Lloyd13, Reference Kim, Lee, Chun, Shin, Kim and Lee14, Reference Mills19 Many reports emphasise that small cell carcinoma should be treated as systemic rather than localised disease; thus, we believe that chemoradiotherapy is the appropriate first-line treatment for stage I disease, and that the decision to undertake surgical treatment should be based on the results of chemoradiotherapy.Reference Barnes, Eveson, Reichert and Sidransky18, Reference Lee and Lin21, Reference Muller, Gani, Weinmann, Mayer, Sipos and Bamberg22
Fig. 4 (a) Treatment outline for small cell lung carcinoma, as specified in the Japanese Lung Cancer Treatment Guidelines. (b) Proposed treatment outline for small cell carcinoma of the head and neck. (c) Chemoradiotherapy regimen for small cell carcinoma of the head and neck. LD = limited disease; ED = extensive disease; Cx = chemotherapy; CRT = chemoradiotherapy; CDDP = platinum; VP-16 = etoposide; Rx = radiotherapy; fr = fractions
In the Japanese Lung Cancer Treatment Guidelines, the first-line chemotherapy regimen used within chemoradiotherapy is four courses of platinum plus etoposide.Reference Noda, Nishiwaki, Kawahara, Negoro, Sugiura and Yokoyama3 These Guidelines recommend concurrent radiotherapy and chemotherapy.Reference Jeremic, Shibamoto, Acimovic and Milisavljevic4, Reference Takada, Fukuoka, Kawahara, Sugiura, Yokoyama and Yokota5 However, because our centre required approximately 10 days to plan and prepare a course of radiotherapy, we commenced patients on chemotherapy immediately, and began standard fractionated radiotherapy concurrently with the second course of chemotherapy. As regards radiotherapy dose fractionation, the Guidelines recommend 45 Gy of accelerated hyperfractionation.Reference Choi, Herndon, Rosenman, Carey, Chung and Bernard6 However, several studies have reported that accelerated hyperfractionation can lead to spinal cord toxicity, and there is insufficient evidence to support the use of the same radiotherapeutic dose employed for carcinoma of the head and neck (i.e. 50–60 Gy).Reference Macbeth, Wheldon, Girling, Stephens, Machin and Bleehen7 Thus, we selected standard fractionation of 50 to 60 Gy in 25 to 30 fractions over five to six weeks (Figure 4c).
With regard to treatment planning, the Japanese Lung Cancer Treatment Guidelines recommend that if initial treatment produces a partial response or better, then the usual approach should be to simply ‘wait and scan'. In cases with tumour reduction of less than 30 per cent, or in the event of a relapse, the approach should comprise chemotherapy, extensive surgical removal or best supportive care.Reference Ettinger, Finkelstein, Abeloff, Ruckdeschel, Aisner and Eggleston8–Reference Ebi, Kubota, Nishiwaki, Hojo, Matsumoto and Kakinuma10
• Three patients with small cell carcinoma of the head and neck are presented
• Treatment was adapted from the Japanese Lung Cancer Treatment Guidelines for small cell lung carcinoma
• All patients underwent chemoradiotherapy; one case also had subsequent surgery
• Short-term results were equivalent to or better than usual outcomes for small cell lung carcinoma
The short-term results of the present study were equivalent to or better than the usual treatment outcomes for small cell lung carcinoma. Some questions remain to be answered, however, including: (1) whether better results might be obtained with accelerated hyperfractionation; (2) whether surgical intervention is indicated even for patients with stage II or III disease; and (3) whether starting both radiotherapy and chemotherapy on day 1 would ultimately yield better results. Finally, clinical trials are needed to identify optimal treatment strategies for small cell carcinoma of the head and neck.Reference Lee, Lee, Ryu, Chang, Kim and Kim23
Acknowledgements
The authors thank the Bioscience Medical Research Center, Second Department of Medicine, Department of Radiology, Department of Molecular Genetics, Division of Cellular and Molecular Pathology, and Division of Molecular and Diagnostic Pathology, at Niigata University.
