Primary small cell carcinoma of the parotid gland

Primary small cell carcinoma of the parotid gland ROBERTL. wffr, MD, FACS, Wilmington, Delaware

I ~ u r i n g the past several decades, small cell carcin o m a has b e e n recognized in extrapulmonary sites/ Previous reports in the literature have discussed epithelial and neuroendocrine subtypes of small cell carcinoma. These subtypes may have differential prognostic significance. In the past these epithelial and neuroendocrine subtypes have b e e n differentiated by electron microscopy, but recent advances in immunohistochemistry have also allowed such differentiation. Although it has b e e n reported that primary small cell cancer of the salivary gland has a better prognosis than bronchogenic small cell cancer, 2-4 surgical therapy alone is probably suboptimal, given the aggressive natural history of this t u m o r with the potential for rapid growth and distant metastasis. M a n a g e m e n t of this rare t u m o r has not b e e n clearly defined. Progress in the m a n a g e m e n t of small cell carcinoma of the lung has provided guidance in the m a n a g e m e n t of extrapulmonary small cell carcinoma. CASE REPORT

A 64-year-old man sought treatment for a left parotid mass 5 weeks before admission. He reported no cough, shortness of breath, or hemoptysis. The mass was nontender. His medical history was negative for prior malignancy and for smoking. Physical examination revealed two discrete masses in the left parotid gland and otherwise unremarkable upper respiratory tract and neck examinations. The remainder of the physical examination was also unremarkable. The chest radiograph was normal. A computed tomography (CT) scan revealed the two discrete parotid masses (Fig. 1). The patient underwent total left parotidectomy with a cable nerve graft to the marginal mandibularis 'branch of the facial nerve and a modified radical neck dissection. Pathologic examination of the re-

From the Department of Surgery, Medical Center of Delaware. Presented at the Annual Meeting of the Pennsylvania Academy of Otolaryngology-Head and Neck Surgery, Hershey, Pa., June 17-18, 1994. Received for publication Oct. 4, 1994; accepted Aug. 18, 1995. Reprint requests: Robert L. Witt, MD, 2401 Pennsylvania Ave., Suite 112, Wilmington, DE 19806. Otolaryngol Head Neck Surg 1996;114:826-9. Copyright © 1996 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/96/$5.00 + 0 23/4/68728 826

Fig. I. Preoperative CT scan demonstrating two discrete parotid masses {arrows).

sected parotid gland revealed undifferentiated small cell carcinoma (Fig. 2). Positive synaptophysin staining determined this carcinoma to be a neuroendocrine subtype. Positive keratin staining excluded lymphoma. Results of bronchoscopy and CT scans of the chest, abdomen, pelvis, and brain were negative. Results of a bone scan and bone marrow biopsy also were negative. After surgery, the patient underwent three cycles of chemotherapy with carboplatin (300 mg/m2intravenously on day 1) and VP-16 (Etoposide) (80 mg/m2 intravenously daily for 3 days). He tolerated the chemotherapy well, having some fatigue, but no fevers, sweats, cough, shortness of breath, nausea, vomiting, diarrhea, or headache. He had no alopecia, mucositis, low blood count, or concomitant infection. The patient subsequently received 5000 cGy of radiation therapy during a period of 5 weeks, after which he had mild mucositis. After several months, his lower face weakness improved. The patient remains free of disease after 2 years. DISCUSSICN

Small cell carcinoma of the lung is also known as oat cell, anaplastic, and undifferentiated carcinoma. Primary small cell carcinomas of the parotid gland

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Fig. 2. Histologic photomicrographs of small cell carcinoma of the parotid gland. [Hematoxylin and eosin stain; A, x l00; B, x4O0.}

are rare, and therefore optimal management strategies are not well defined. Only 4% of small cell carcinomas occur in extrapulmonary sites. 5 This tumor accounts for less than 1% of all parotid malignancies. L'6Parotid small cell carcinoma usually occurs in patients from 30 to 49 years of age as a painless mass/ The most common site for small cell carcinoma in the head and neck is the larynx. Laryngeal small cell carcinoma may cause hoarseness, shortness of breath, or dysphagia and is associated with lymph node metastasis in 70% of cases. 8 The 2- and 5-year survival estimates for these small cell carcinomas of the larynx are 16% and 5%, respectively.9In patients with major salivary gland small cell carcinoma, 2and 5-year survival rates have been reported to be 70% and 46%, respectively (Fig. 3). 9 Small cell carcinoma Of the parotid gland has a better prognosis than small cell carcinoma of the larynx, which has a

survival rate similar to that of small cell carcinoma of the lung. Other sites of small cell carcinoma in the head and neck have included the oral cavity, oropharynx, nose, and paranasal sinuses. Only 3.5% of minor salivary gland tumors are small cell carcinomas, 1 and these represent the majority of salivary gland small cell carcinomas. Differential diagnoses include adenoid cystic carcinoma, lymphoepithelioma, poorly differentiated adenocarcinoma or epidermoid carcinoma, lymphoma, and malignant melanoma. Small cell carcinoma is most closely mimicked by poorly differentiated adenoid cystic carcinoma. Small cell carcinoma has characteristic nuclear molding. 7 Lymphomas can be distinguished by their marked nuclear monomorphism and the predominance of single-lying cells and the absence of keratin on immunohistochemical staining.

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Time (Months) Fig. 3. Kaplan-Meier survival estimates for small cell c a r c i n o m a of the larynx a n d major salivary glands. (From G n e p p DR, et al. C a n c e r 1986;58:705-14; with permission.}

Table t. Response rates to single-agent chemotherapy in small cell lung cancer Drug

Response [%]*

Ifosfamide Procarbazine Vincristine Etoposide Cyclophosphamide Methotrexate Doxorubicin (Adriamycin) Vindesine Teniposide " Lomustine (CCNU) Cisplatin Mitozantrone

63 47 42 40 38 30 30 19 19 15 13 3

From Brewis RAL, et al., eds. Respiratory medicine. London: Balliere Tindall, 1990:859; with permission. *Response = 50% or greater reduction in tumor size measured in two perpendicular diameters.

Diagnosis of parotid small cell carcinoma is established by fine-needle aspiration biopsy or from tissue obtained by excision of the parotid gland. Metastatic disease from the lung, breast, kidney, gastrointestinal tract, and skin must be excluded. To exclude bronchogenic metastasis, bronchoscopy and a CT scan of the chest are important. To exclude bone metastasis, which is common with bronchogenic small cell carcinoma, a bone scan and bone marrow biopsy should be performed. In the past, it was necessary to use ultrastructural findings (electron microscopy) to differentiate the two distinct subtypes of small cell carcinoma. The more common is small cell epithelial carcinoma. Several cases of neuroendocrine carcinoma also

have been reported2 '4,6 Both types have been described as small cell ductal carcinoma arising from the cells of the salivary duct system.9 The use of immunohistochemical methods using antibodies to synaptophysin to differentiate subtypes of small cell carcinoma has not been reported in the otolaryngologic literature. This technology is more costeffective than electron microscopy. Synaptophysin is a major integral glycoprotein of the neuronal syn aptic vesicles found in mammalian endocrine cells. TM Antibodies directed against synaptophysin are a valuable tool for immunohistochemical quantitation of synapses, and synaptophysin is a reliable and specific marker molecule for normal and neoplastic neuroendocrine cells in the nervous system. Too few cases of the neuroendocrine subtype isolated to the salivary gland have been reported to definitively differentiate its biologic behavior; however, it has been suggested that neuroendocrine small cell cancer has a more aggressive behavior than that of epithelial origin.6 Therefore immunohistochemical analysis should be performed in all cases. Management of primary extrathoracic small cell carcinoma can be guided by what we know about bronchogenic small cell carcinoma. Bronchogenic small cell carcinoma characteristically grows rapidly, and extrathoracic metastasis is present in 70% of patients. Metastasis takes place through the lymphatic system and the bloodstream. In untreated patients with bronchogenic small cell carcinoma, the median survival is 8 weeks. In a study of unselected patients with small call cancer undergoing surgery, less than 1% were alive at 5 years." Although single-

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Table 2. Resultsof combination chemotherapy with three or four drugs in the treatment of small cell cancer of the lung

Disease

No. of patients

Complete response and partial response

Complete response {%)

Median survival [me)

Limited Extensive

246 990

81 67

52 26

5-14 4-14.5

Percentage 2-yr disease-free survival

From Brewis RAL, et al., eds. Respiratory medicine. London: Balliere Tinda[I, 1990:860; with permission.

agent therapy has had only a small influence on survival and only a moderate mean response rate (Table 1), 11 multiple-drug therapy has resulted in complete response rates of 20% to 50% (Table 2)21 Carboplatin, VP-16, cyclophosphamide, cisplatin, and do~:orubicin have been used frequently. Unfortunately, even with longer periods of survival with chemotherapy, the median length of survival for patients; with bronchogenic small cell carcinoma remains 10 to 15 months for limited disease and 6 to 12 months for extensive disease. The response rate (more than 50% reduction in tumor size) to radiation therapy is 80%, which is much higher than that for non-small cell bronchogenic carcinoma. This would suggest its possible use in extrathoracic small cell carcinoma. In a prospective randomized study of bronchogenic small cell cancer, it was found that at 1 year, patients treated with radiation and chemotherapy had an improvement in the control of recurrence and survival compared with patients who received single-modality treatment. 12 Surgery is believed to have a role in the treatment of the peripheral lesion, but the mainstay of treatment for bronchogenic small cell cancer is chemotherapy. Small cell cancer of the parotid gland is too rare to be considered for randomized prospective doubleblind studies. The evolution of treatment of small cell cancer of the lung lends itself to the management of extrathoracic small cell cancer. Because small cell carcinoma is an aggressive tumor with the potential for rapid growth and distant metastasis, it appears acceptable to consider multiple-modality treatment for parotid small call cancer, including surgery., chemotherapy, and radiation therapy (not necessarily in that order). CONCLUSIONS

Primary small cell cancer of the parotid gland is rare. Advances in immunohistochemical methods using synaptophysin have provided a more costeffective means of diagnosing the epithelial and neuroendocrine subtypes of extrapulmonary small cell cancer, which may have prognostic significance.

Management has been advanced by the progress in management of bronchogenic small cell cancer. Treatment options should include surgical excision, multiple-agent chemotherapy, and radiation therapy. I would like to thank Mark Mitchell, MD, Pathology Department, Medical Center of Delaware, Wilmington, Del., and Katrina Canard, MD, Pathology Department, Alfred I. duPont Institute, Wilmington, Del. I would also like to thank Karen McFadden, Department of Surgery, Medical Center of Delaware for her editorial assistance.

REFERENCES

1. Koss LG, Spiro RH, Hajdu S. Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 1972;30:737-41. 2. Leipzig B, Gonzales-Vitale JC. Small cell epidermoid carcinoma of the salivary glands. "Pseudo"-oat cell carcinoma. Arch Otolaryngol 1982;108:511-4. 3. Mair S, Phillips JI, Cohen R. Small cell undifferentiated carcinoma of the parotid gland. Cytologic, histologic, immunohistochemical and ultrastructural features of a neuroendocrine variant. Acta Cytol 1989;33:164-8. 4. Scher RL, Feldman PS, Levine PA. Small-cell carcinoma of the parotid gland with neuroendocrine features. Arch Otolaryngol Head Neck Surg 1988;114:319-21. 5. Levenson RM Jr, Ihde DC, Matthews MJ, et al. Small cell carcinoma presenting as an extrapulmonary neoplasm: sites of origin and response to chemotherapy. J Natl Cancer Inst 1981;67:607-12. 6. Kraemer BB, Mackay B, Batsakis JG. Small cell carcinomas of the parotid gland. A clinicopathologic study of three cases. Cancer 1983;52:2115-21. 7. Nagao K, Matsuzaki O, Saiga H, et al. Histopathologic studies of undifferentiated carcinoma of the parotid gland, Cancer 1982;50:1572-9. 8. Kimmelman CP, Hailer DG. Small cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 1983;91:708-12. 9. Gnepp DR, Corio RL, Brannon RB. Small cell carcinoma of the major salivary glands. Cancer 1986;58:705-14. 10. Redecker E Grube D. Synaptophysin in the nervous system and endocrine cells. Acta Histochem Suppl 1992;42:33-8. 11. Brewis RAL, Gibson GJ, Geddes DM, eds. Respiratory medicine. London: Balliere Tindall, 1990:859-66. 12. Radiotherapy alone or with chemotherapy in the treatment of small celt carcinoma of the lung: the results at 36 months. 2nd report to the Medical Research Council on the 2nd small-cell study. Br J Cancer 1981;44:611-7.