Metastatic small cell carcinoma of the cervix to the oral cavity: A rare case report and an insight into pathogenesis of metastasis.

The oral cavity is an uncommon site for metastatic tumor cell colonization and is usually evidence of a widespread disease, with an incidence of about 1% of all oral cancers. The jawbones, particularly the mandible, are more frequently affected than the oral soft tissues (2:1). Small cell carcinoma (SCC) of the uterine cervix is a rare tumor characterized by a highly aggressive clinical course and poor prognosis. The purpose of this report is two-fold: To present a case of metastatic SCC of the uterine cervix to post extraction site in oral cavity, which is the first reported case in the literature, as per our knowledge and to analyze the possible mechanism of metastasis from the lower part of the abdomen to the post-extraction site and to gain additional knowledge in this phenomenon.

INTRODUCTION

Small cell carcinoma (SCC) of the uterine cervix was first described in 1957. It's an uncommon gynecological cancer comprising < 3% of all cervical cancers. It was considered to confer a poor prognosis because of their propensity to metastasize early to regional lymph nodes and distant sites.[1] Until date, only a few cases have been reported in head and neck region.[2] The most common sites of extra-pelvic metastasis in cervical carcinoma are lungs, bone and cervical lymph nodes.[3] We present a case of metastatic SCC of the uterine cervix to extraction site in the oral cavity, which is the first reported case in English literature, as per our knowledge.

CASE REPORT

A 35-year-old female patient came with a chief complaint of swelling in right lower back jaw region since 15 days accompanied by loss of sensation in the right lower lip with a history of extraction of permanent mandibular second molar (46) because of mobility, twenty days prior.

Medical history revealed hysterectomy due to SCC, 1-year back and was asymptomatic till date.

Intra-oral examination revealed a soft swelling in the extracted 46 region. The surface over the swelling was erythematous and was obliterating the vestibule [Figure 1]. OPG revealed ill-defined unilocular radiolucency with irregular margins measuring about 2 cm × 2 cm in the extraction site.

Figure 1

Soft tissue swelling in the mandibular right molar region with overlying erythematous reddish pink mucosa

Histopathological report of the lesion revealed parakeratinized stratified squamous epithelium with the underlying connective tissue consisting of round to oval, polygonal and spindle-shaped cells with large hyperchromatic nuclei and scanty indistinct cytoplasm. Tumor cells were arranged in alveolar pattern interspersed with thin fibrovascular septa [Figure 2a]. Correlating with the medical history, features were similar to that of the biopsy report of the primary SCC of uterine cervix [Figure 2b], whose slides were retrieved from the medical college, of the same institution. The tumor cells were also arranged in islands and sheets in both secondary metastatic tumor [Figure 3a] and primary tumor [Figure 3b]. Correlating with previous biopsy report, the present lesion was diagnosed as Metastatic SCC of the cervix.

Figure 2

Photomicrograph showing round to polygonal cells and spindle cells with hyperchromatic nuclei in alveolar pattern, (a) secondary lesion (H&E stain, ×100), (b) primary lesion (H&E stain, ×200)

Figure 3

Photomicrograph showing round to polygonal cells arranged in islands and sheets. (a) secondary lesion (H&E stain, ×50), (b) primary lesion (×50)

DISCUSSION

Metastatic tumors to the oral region are uncommon with an incidence of about 1% of all oral cancers. About 25% of oral metastases have been found to be the first sign of metastatic spread and in 23% it was the first indication of an undiscovered malignancy at a distant site.[4]

Few common tumors viz. tumors of breast, lungs, kidney, thyroid gland and the testis will metastasize to the oral cavity. Metastatic oral tumors reported from female genital tract are leiomyosarcoma, choriocarcinoma and germ cell tumor.[5]

The main presenting symptom of metastatic lesions of the jaws is a tender, soft tissue mass extruding from a recent extraction wound. It may be present in relation to the teeth because of which teeth may become painful and mobile.[6]

The most recent histologic typing of female genital tract tumors of World Health Organization recognizes only two types of neuroendocrine tumors, namely SCC and carcinoid tumor.[7] SCC of the uterine cervix is an uncommon gynecological cancer comprising < 3% of all cervical cancers. The median age at diagnosis is 45 years. The hallmark of this tumor is the aggressive malignant behavior with the propensity to metastasize. 33% of SCC had distant metastasis despite chemotherapy, brain was common site (66.6%), followed by bone and liver.[1]

The histopathological aspects of SCC include round to spindle-shaped small cells with hyperchromatic nuclei, inconspicuous nucleoli and sparse cytoplasm with high nucleus/cytoplasmic ratio. Nuclear shape varies from round to spindled. Nuclear molding is a characteristic feature. Local invasion, into the skeletal muscle, blood vessels and nerves, are commonly seen.[7]

Metastasis is a consequence of a complex biological cascade that begins with the detachment of the tumor cells from the primary tumor, spreading into the tissues, invading in to the lymphovascular structures followed by their survival in the circulation. Furthermore, tumor progression depends on angiogenesis and revascularization at the target site.[8]

Radiographically metastatic lesions show either radiolucent or radio-opaque lesion. Likewise, our case also showed a radiolucent lesion which may be the result of stimulation of osteoclastic activity by tumor cells through overexpression of parathyroid hormone related protein, interleukin (IL)-8 and IL-11.[8]

The oral cavity is an uncommon region for metastatic tumor colonization. In the oral cavity, jaw bones may harbor more metastatic lesions than oral soft tissues with a ratio of 2:1. Among jaw bones mandibular molar (82%) area is more frequently affected than any other sites.[4]

The common routes of metastases by distant tumors to the oral region and/or the jawbones are via lymphatic or by hematogenous spread. In case of carcinoma of the cervix, metastasis to the head and neck signals a grave prognosis for the patient. Although very uncommon, the spread of carcinoma from the uterine cervix to the supraclavicular region is best understood through a description of the lymphatic system. Carcinoma of the uterine cervix spreads through lymphatics from the pelvis up to the para-aortic nodes, into the mediastinum and then into the thoracic duct. The thoracic duct communicates with the central venous system in the neck at the junction of the left subclavian and internal jugular vein. A left-sided supraclavicular node represents the final common path of the body's infra-diaphragmatic lymphatic drainage. Small communications exist from the left side to right side of the neck.[9]

On reaching the lymph nodes, embolus of tumor cells begins to multiply and penetrates subcapsular space tissue leading to local spread. Blockage of the lymphatics leads to retrograde spread of the tumor. This would account for spread from left side to right side of the neck, even though there is no direct connection to the right side.[8] The most probable route of spread to the right mandible is from the right lymphatic duct into the subclavian vein. Subclavian vein enters internal jugular vein which is being drained into the submandibular lymph nodes which in turn drain to the right side of the mandible.[10]

Batson suggested “valveless vertebral venous plexus as a mechanism for bypassing filtration through the lungs; an increase in intra-thoracic pressure directs blood flow into this system from the caval and azygous venous system and accounts for increased distribution in axial skeleton and head and neck metastasis.”[4]

After entering the mandible, local factors in the extraction wound area may attract circulating tumor cells and they may be entrapped in a rich capillary network of granulation tissue formed in the extraction wound healing process. New proliferating capillaries have a fragmented basement membrane, making them more penetrable by tumor cells. Once tumor cells escape from the capillaries, they enter a favorable, loosened stroma of the wound. Tumor cells may adhere and further degrade the extracellular matrix elements by proteolytic enzymes. Additional growth and proliferation of the metastatic colony may be induced by tumor cells themselves and by cleavage products of matrix components, which have growth promoting, angiogenic and chemotactic activities. Thus, tooth extraction seems to serve as a promoting factor in the metastatic process.[6]

Any soft tissue growth in the post-extraction site may be confused with metastatic malignant melanoma and intra-osseous mucoepidermoid carcinoma (MEC). The presence of melanin and/or round to spindle shaped cell; and finding of mucous cells, intermediate cells and epidermoid cells will differentiate SCC of the cervix and MEC respectively, from these tumors.

A specialized radiographic technique such as chest X-ray, positron emission tomography scanning of breast, lungs and kidney has to be done to rule out primary lesion from these sites, since in females tumor from the above sites has the greatest tendency for metastasis. A detailed gynecological history of the patient will help in the diagnosis of the metastatic SCC of the cervix which is so in our presenting case.

Thus, if a clinician identifies any soft tissue growth in the extraction wound site accompanied by numbness of the lower lip, then metastatic tumors should be included in the provisional diagnosis.

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Conflicts of interest

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