Basal cell carcinoma metastatic to the parotid: Report of a new case and review of the literature.

Abstract

Basal cell carcinoma is the most common of the cutaneous malignancies, accounting for 65 to 75% of all skin cancers. The natural history of this disease is one of chronic local invasion. Metastatic basal cell carcinoma is a rare clinical entity, with a reported incidence of only 0.0028 to 0.5%. Approximately 85% of all metastatic basal cell carcinomas arise in the head and neck region. We present a case of basal cell carcinoma that spread to the parotid gland in a man who had multiple lesions on his scalp and face. We also review the literature on metastatic basal cell carcinoma of the head and neck, and we discuss its epidemiology, etiology, histopathology, and treatment.

Introduction

Eighty-five percent of metastatic basal cell carcinomas arise in the head and neck region. [1] The natural history of this disease is one of chronic local invasion of surrounding tissue. However, in rare instances, these tumors do metastasize. The first reported case of metastatic basal cell carcinoma was published by Beadles in 1894. [2] Since then, approximately 200 cases have been documented in small series and case reports.

Three specific criteria for a diagnosis of metastatic basal cell carcinoma were developed in 1951 by Lattes and Kessler. [3] According to these criteria, the primary tumor must arise from the skin and not the mucosa; the histopathology of the primary tumor and that of the metastasis must be identical; and the metastasis must occur at a site distant from the primary tumor without evidence of direct extension. Unfortunately, we know that varying histologic patterns can occur within the same lesion, which makes it difficult to trace a metastasis to a specific primary tumor. This is especially difficult in a patient who has multiple primary lesions.

In this article, we describe the case of a patient who had multiple, recurrent basal cell carcinomas on the scalp and face that metastasized to the parotid gland and periparotid lymph node. We also review the literature on metastatic basal cell carcinoma of the head and neck, and we discuss its histopathology and therapeutic modalities.

Case report

Our patient was a 68-year-old white man who had a history of multiple basal cell carcinomas involving his scalp, face, trunk, and extremities. He was referred to our institution's Department of Dermatology by his dermatologist for Mohs' micrographic surgery on the recurrent basal cell carcinomas of the right temporal region and the right nasal alar crease. Histologic examination revealed that the carcinoma in the right temporal region was of the nodular subtype (figure 1) and the lesion in the alar crease was of the infiltrative subtype (figure 2). Prior to his referral to us, the patient had received numerous treatments for his temple and nasal lesions over a 10- to 12-year period. These treatments included local excision, curettage, and electrodesiccation, but no radiation therapy.

Mohs' surgery was first performed on a 0.8-cm recurrent basal cell carcinoma of the right temple in March 1992. A second Mohs' procedure was performed in that area in May 1993. At that time, the pathology showed a nodular pattern that did not extend to the level of muscle. In December 1994, a third Mohs' procedure was required in the same area. This time the pathology showed large tumor nests (a nodular pattern) with angulated margins. Tumor was found deep to muscle (figure 3). Clear margins were obtained. The right nasal alar lesion recurred in May 1993 and again in December 1998. On both occasions, the lesion was treated with Mobs' surgery. There was no evidence of recurrence at the time of this publication.

In May 1997, a palpable 2-cm mass in the region of the right tail of the parotid gland and a new 0.2-cm lesion on the left ear were noted by the patient's dermatologist. The patient was subsequently referred to our Otolaryngology--Head and Neck Surgery clinic for evaluation of the parotid mass. Cytology obtained by fine-needle aspiration of the parotid mass was consistent with metastatic basal cell carcinoma. On magnetic resonance imaging, the parotid lesion measured 1.3 x 0.9 cm. The patient subsequently underwent a right superficial parotidectomy with facial nerve dissection, a right selective neck dissection encompassing zones two and three, and a wide local excision of the ear lesion. Pathologic examination of the parotid revealed a metastatic basal cell carcinoma with prominent perineural invasion (figure 4). The histology again showed large tumor nests with angulated margins. Although no normal intraparotid lymph nodes were identified, metastasis to and obliteration of an intraparotid lymph node could not be excluded. The resection margins and all 19 lymph nodes were free of malignancy. The ear lesion was also documented to be an infiltrative basal cell carcinoma. A total of 6,000 cGy of external-beam radiation therapy was administered to the right parotid and 4,500 cGy to the right neck. The left ear lesion was widely excised at the time of the parotidectomy. The final pathology revealed a basal cell carcinoma with clear margins. At the time of this publication, there was no evidence of tumor recurrence.

It seems most likely that the metastatic disease to the parotid spread from the primary tumor that recurred on the temple in 1994. The primary tumor had an unusually deep infiltration, and its histology (figure 5) was very similar to that of the metastasis (figure 6).

Discussion

Incidence. Metastatic basal cell carcinoma is a rare phenomenon, with a reported incidence of only 0.0028 to 0.5%. [4,5] A review of 50,000 patients in Australia and New Zealand by Paver et al found an incidence of 0.0028%. [5] In another large review of 9,050 cases of basal cell carcinoma at Memorial Hospital in New York City, Contran found only nine cases of metastatic basal cell carcinoma, for an incidence of 0.l%. [6] Smaller studies have found similar or only slightly higher incidences. [7-11]

Sex, race, age, and duration. Men are more predisposed to metastatic basal cell carcinoma than women by a ratio of 2 to 1. [12] The most affected group are whites between the ages of 20 and 60 years. [13] There are only five reported cases of metastatic basal cell carcinoma in black patients, and not all of these cases involved the head and neck. [14-18] The median age of onset in patients with a primary tumor is 45 years, and the median interval between the appearance of the primary lesion and the onset of metastasis is 9 years; in one case, the interval was 45 years. [12] The median life expectancy after a metastasis is identified is only 8 months. [12]

Risk factors. There are several risk factors that appear to predispose patients to metastatic basal cell carcinoma. Often, there is a history of a persistent or recurrent tumor of many years' duration. The lesion is typically refractory to conventional forms of therapy, and a history of radiation therapy for a large primary or repeatedly recurrent tumor has been noted. The depth of tissue invasion and extension of the tumor into adjacent anatomic structures can also increase the risk of metastasis. [18,19]

The location and size of the primary tumor appear to play a role in the development of metastases. Blewitt reviewed 38 cases of metastatic basal cell carcinoma and noted that the primary tumor was usually located on the scalp or face. [20] He also found that large tumors were an outstanding feature of metastatic basal cell carcinoma. His finding was supported by a report of 12 cases of metastatic basal cell carcinoma by Lo et al, who noted that the size of the primary tumors in their series ranged from 3.6 x 3.0 cm to 20.0 x 7.0 cm. [7] Similarly, Snow et al reported that only about 9% of metastatic basal cell carcinomas originated in primary tumors that were smaller than 10 [cm.sup.2].[19] Finally, Sahl et al reported a 45% incidence of metastasis and/or death in patients whose primary tumors were larger than 10 cm in diameter. [21]

Primary tumor morphology and histopathology. The primary tumor is usually quite extensive, covering a large surface area with deep erosion into underlying tissue. Nevertheless, small primary tumors can also metastasize. [22] Approximately 85% of metastatic basal cell carcinomas originate in primary tumors of the head and neck. In an extensive review of 170 published cases of metastatic basal cell carcinoma, von Domarus and Stevens found that 67.6% of metastases originated in sites on the head and face, mostly on the midface. [12] Basal cell carcinomas in these regions have been noted to be more aggressive and destructive than lesions at other sites. [6,23] It has been postulated that the presence of embryonic fusion planes in the midface area results in more occult and distant spread, as well as more difficulty in surgical removal. [24]

In general, the histopathology of basal cell carcinoma features small, uniform basaloid cells with scant cytoplasm and large, round, or elongated nuclei. Another characteristic finding is the palisading of nuclei at the tumor periphery. Several histologic varieties of basal cell carcinoma have been described, and it is possible to see a mixture of histologic types in a single lesion. [25,26] The nodular subtype is the most common, and it usually remains localized to the primary site. It features the characteristic peripheral palisading and islands of tumor cells. Areas of central tumor nest necrosis or degeneration might be observed.

The second most common variety is the micronodular subtype, which consists of tumor islands in small, rounded nodules. The morphology of these nodules is similar to that of the larger nodular subtype. The keratotic variety is remarkable for its abrupt, central keratinization. The superficial subtype contains foci of tumor that extend from the epidermis adjacent to or into the papillary dermis. Peripheral palisading is well defined, and its contours are rounded and smooth. The morphen or sclerosing variant is an aggressive subtype, and local recurrences are common. This tumor consists of strands of closely arranged basaloid cells in dense, sclerotic stroma.

The infiltrative variety reveals tumor foci of varying sizes. These lesions have poorly defined peripheral palisading, with irregular, spiking contours. A higher incidence of incomplete excision and local recurrence has been seen in patients with this subtype, which is likely a result of the irregularity of the tumor. [26] Metatypical or basosquamous carcinoma is a subtype that is characterized by varying degrees of squamous differentiation. This subtype also tends to have a more aggressive biologic behavior, approaching that of a squamous cell carcinoma. A metastatic rate of up to 6% has been reported. [27]

Routes of metastasis. The primary routes of metastasis of basal cell carcinomas are the lymphatic and hematogenous channels. Metastasis to regional lymph nodes has been noted by some authors to occur in as many as 70% of cases. [28,29] Involvement of the parotid or submandibular glands as a result of metastasis to intra- or periglandular lymph nodes has been reported to occur in patients with metastatic basal cell carcinoma that spreads from the head and face. [4,6,13,30-32] This is the most likely explanation for the metastasis in our patient. Common sites of hematogenous dissemination include the lungs and pleura, liver, bone, and skin. [13] Other sites less frequently involved are the dura mater, pericardium, myocardium, kidney, adrenal gland, thyroid, diaphragm, pancreas, and brain. Lung involvement has also been reported as a result of aspiration of tumor cells from invasive basal cell carcinoma of the nasal and oral cavities. [33]

Perineural invasion by basal cell carcinomas is rare, and it has a poor prognosis. Von Domarus and Stevens [12] described three patients with metastatic basal cell carcinoma and perineural invasion, and Snow et al [19] reported seven. Hanke et al described 19 cases of perineural invasion with primary basal cell carcinoma in their review of the literature. [34] They reported that the preauricular and cheek regions appeared to be the most common sites of basal cell carcinoma and perineural invasion; involvement of the facial and trigeminal nerves usually occurred first. Perineural invasion was observed most often in recurrent lesions, and more than 50% of those patients had received previous radiation therapy. We now add an additional case of perineural involvement to those reports.

The underlying molecular mechanisms of tumor invasion and metastasis of basal cell carcinoma have yet to be elucidated. Farmer and Helwig have suggested that tumor metastasis is the result of immunologic alterations between the tumor and host. [35] Earlier experimental work has demonstrated the importance of the connective tissue stroma in the survival of tumor cells in human autotransplantation. [36] Recent studies have examined the role of cellular adhesion molecules in tumor metastasis, but no correlation was noted in the expression or distribution of various cellular adhesion molecules by the different histologic subtypes of basal cell carcinoma. [37,38] The pattern of integrins, a type of cellular adhesion molecule, expressed by basal cell carcinoma was similar to patterns expressed by the more aggressive malignant melanoma. [39] In contrast, striking differences were noted in the expression of integrins on both squamous and basal cell carcinomas. [40] It is difficult to draw definitive conclusions abou t the relationship between invasive potential and the differences in the expression of cellular adhesion molecules because of the phenotypical differences between tumor types.

Treatment. The therapeutic modalities used for metastatic basal cell carcinoma are surgery, radiation, chemotherapy, and a combination of the three. Treatment options are often dictated by the location and nature of the metastasis. Because of the paucity of cases, organized clinical trials to evaluate the efficacy of the various treatments are limited. Surgical management appears to provide the best long-term results; Farmer and Helwig reported that postoperative survival in their study was as long as 9 years. [35] In the head and neck region, metastases are typically found in the intraparotid, periparotid, and cervical lymph nodes. A superficial or total parotidectomy and/or a selective neck dissection is recommended, depending on the extent and location of the tumor.

Metastases to the bone, lung, and soft tissues that are not amenable to surgical resection can be treated with chemotherapy. Currently, experience with chemotherapy and metastatic basal cell carcinoma is limited to several case reports and small series. Pfeiffer et al have written an excellent review of the literature on systemic cytotoxic therapy and basal cell carcinoma. [41] Several agents have been reported to be successful, alone or in combination with each other; they include cis-platinum, methotrexate, cyclophosphamide, 5-fluorouracil, bleomycin, vincristine, and doxorubicin. [42] According to Pfeiffer et al, cis-platinum appears to be the most effective agent, as patients who received it had a median survival of 16 months, compared with only 8 months for patients who were treated with other regimens.

Radiation therapy is used alone or in combination with surgical resection to treat both primary and metastatic disease. It is often used for extensive or inoperable lesions. Although long-term survival is unlikely, symptomatic relief is often attained. The rationale for postoperative radiotherapy of metastatic basal cell carcinoma to the cervical and parotid regions parallels that of squamous cell carcinoma, but currently its role remains unclear.

Followup. Patients should be followed closely and undergo tumor surveillance with a thorough examination of the primary tumor site, as well as the regional lymphatic system. In addition, periodic chest x-rays, liver function tests, and measurements of alkaline phosphatase levels should be obtained to screen for distant metastases.

From the Division of Otolaryngology--Head and Neck Surgery (Dr. Malone and Dr. Fedok), the Department of Pathology (Dr. Belchis), and the Department of Dermatology (Dr. Maloney), The Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey.

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