Sebaceous carcinoma
Sebaceous carcinoma, also known as sebaceous gland carcinoma, sebaceous cell carcinoma, and mebomian gland carcinoma is an uncommon and aggressive malignant cutaneous tumor. Most are typically about 10 mm in size at presentation. This neoplasm is thought to arise from sebaceous glands in the skin and, therefore, may originate anywhere in the body where these glands are found. Sebaceous carcinoma can be divided into 2 types: ocular and extraocular. Because the periocular region is rich in this type of gland, this region is a common site of origin. The cause of these lesions are, in the vast majority of cases, unknown. Occasional cases may be associated with Muir-Torre syndrome. Due to the rarity of this tumor and variability in clinical and histological presentation, SGc is often misdiagnosed as an inflammatory condition or a more common type of tumor.
Currently the ocular SGc is commonly treated with wide surgical resection or Moh's micrographic surgery.
This type of cancer usually has a poor prognosis because of a high rate of metastasis.
Presentation
Sebaceous carcinoma is a skin cancer of the sebum producing glands. It is predominantly seen in the head and neck region, representing 25% of all reported lesions in this area. The periocular region, which includes the meibomian gland, caruncle, gland of Zeis and eyebrow, is one of the most common sites in which SC is observed. The meibomian gland is a type of sebaceous gland that lines the upper and lower eyelids, and does not contain a follicle. The glands of Zeis contain the individual eyelash. The upper eyelid contains more meibomian glands than the lower eyelid and consequently, SGc is 2-3 times more common in the upper eyelid.Patients diagnosed with SGc most commonly present with a painless subcutaneous nodule. Other presentations include an irregular mass, pedunculated lesion or diffuse skin thickening. SGc in the periocular region presents as a heterogeneous rapidly growing, pink or yellow colored painless papule.
Pathophysiology
The cell of origin is usually unknown. Sebaceous gland carcinoma clearly resembles normal sebaceous glands and is thought to arise from them. Ultraviolet and ionizing radiation are believed to play some role in the pathogenesis of these neoplasms. There is a strong association between Muir–Torre syndrome.There has been an association between the development of sebaceous carcinoma with the following: history of irradiation, immunosuppression, and genetic factors.
One possible hypothesis states that stem cells in the hair follicle bulge and suprabasilar layer respond to different environmental stimuli, such as radiation, that may lead to the development of cutaneous tumors. Immunosuppressed individuals and those undergoing radiotherapy are at an increased risk for SGc. There has been some association between SGc and HIV, HPV and mutations in tumor suppressor genes p53 and Rb. Rb mutations are responsible for retinoblastoma. Reports have also shown the onset of SGc within the field of irradiation for patients undergoing radiotherapy for retinoblastoma, eczema or cosmetic epilation.
In addition to external factors, genes also appear to play some role in the pathogenesis of this tumor. Extraocular SGc is closely associated with Muir Torre syndrome, with sebaceous tumors presenting in nearly 1/3 of patients with MTS.
MTS is an autosomal genodermatosis, described as a condition with 2 types of malignancies: one being a sebaceous gland tumor and the other an internal malignancy, a majority of which are colorectal and genitourinary. In 41% of patients with MTS skin lesions appeared either before or during the time of diagnosis of the primary malignancy.
Studies have shown that cancerous lesions in MTS develop as a result of mutations in DNA mismatch repair genes, which lead to a buildup of unstable microsatellite sequences and replications errors, predisposing one to different malignancies. Given that this is an autosomal dominant condition with multiorgan involvement, diagnosis requires a thorough medical history and physical in suspected cases of SGc in order to rule out potential visceral tumors.
A number of SGc associated mutated proteins have been shown to cause dysregulation in cell signaling. This dysregulation is responsible for the invasive growth and metastasis of SGc and identification of specific mutations could help determine patient prognosis and clinical outcomes.
Diagnosis
Due to the variable clinical and histological appearance of SGc, this condition is often misdiagnosed. The average delay in diagnosis has been reported to be 1 – 2.9 years from expected onset of the lesion.Patients with ocular sebaceous carcinomas present with nonhealing eyelid tumors that are often misdiagnosed for more common benign conditions such as chalazion or blepharoconjunctivitis. Extraocular SGc appears similarly to skin cancers such as basal cell carcinoma, squamous cell carcinoma and benign lesions such a molluscum contagiosum and pyogenic granuloma. Many tumors also share a histological presentation similar to SGC, such as sebaceous adenomas, basal cell carcinomas, squamous cell carcinomas and clear cell tumors. A high level of suspicion is extremely important to prevent treatment delay and increased mortality.
Given the aggressive growth and pagetoid spread of SGC, full thickness biopsy with microscopic examination is required for definitive diagnosis of sebaceous carcinomas. A full thickness biopsy of the eyelid includes the skin, tarsus, and palpebral conjunctiva. Map biopsies, taken from distinct areas of the conjunctiva, are recommended in cases exhibiting pagetoid spread in order to determine extent of disease. Different markers and stains help differentiate sebaceous carcinomas from other cancers. These markers include lipid stains such as oil red O stain and Sudan IV, and immunohistochemical stains.
Morphology
SGc is classified based on histopathological presentation, including cytoarchitecture, cytology, and pattern of growth. The lobular variant is the most common histological pattern followed by papillary, comedocarcinoma and mixed. Tumors may be also classified by differentiation, from poor to well differentiated. Well- and moderately differentiated sebaceous carcinoma tend to exhibit vacuolization within the cytoplasm of the tumor cells. This is known as sebocytic differentiation, where the vacuolization is caused by lipid containing cytoplasmic vacuoles that present as round clear areas in the cell. Periocular sebaceous gland carcinoma exhibits pagetoid spread, an upward growth of abnormal cells invading the epidermis, it is most often seen in the lid margin and/or conjunctiva. Periorbital SGC also presents with multicentric origins, in the upper and lower eyelids, increasing the risk of local recurrence.Immunohistochemistry
stains are also used when there are inadequate tissue samples or after microscopic examination, and are extremely useful in dermatopathology. Specific antigens such as epithelial membrane antigen, carcinoembryonic antigen, cytokeratin -7, Ber-EP4 and androgen receptor can be targeted in order to differentiate SGc from BCC or SCC.Tissue immunohistochemistry is also used is used to diagnose MTS. Expression of 4 DNA mismatch repair proteins along with medical history, followed by genetic evaluation for microsatellite instability and germline mutation testing is used to screen for MTS in patients diagnosed with sebaceous neoplasms.
Sentinel lymph node biopsy
Despite the risk of metastatic spread, there has been little research on the utility of sentinel lymph node biopsy. Since periocular tumor have a higher rate of regional metastasis, SLNB is suggested for all ocular SGc tumors greater than 10mm in diameter. Treatment for nodal metastasis confirmed via SLNB involves advanced imaging studies , followed by removal of the primary tumor and regional lymph nodes, with adjuvant radiotherapy. However, it is important to note there has been no evidence of decreased mortality in those who had SLNB identified lymph node involvement. In addition, subsequent risks associated with surgical and radiotherapy may increase morbidity.Staging
Sebaceous carcinomas are staged according to The American Joint Committee on Cancer Tumor, Node, Metastasis guidelines for nonmelanoma skin cancers. This classification system has different stages for ocular and extraocular tumors, given that periocular tumors have a higher risk for metastasis and recurrence.Treatment
This type of carcinoma is commonly managed by local resection, cryotherapy, topical chemotherapy, and radiotherapy. Multimodal therapy has been shown to improve both visual prognosis and survival.Surgical resection
Wide local excision, which has been replaced by Mohs micrographic surgery had been the primary treatment for both ocular and extraocular sebaceous carcinoma.Mohs micrographic surgery has become the gold standard of treatment for SGc. MMS allows for precise and accurate removal of the tumor and complete assessment of margins. Furthermore, MMS is associated with significantly lower local and distant recurrence rates in both periocular and extraocular SC, when compared to wide local excision. MMS also limits morbidity and is useful in cosmetically sensitive areas such as the face.
Chemotherapy
There is a limited amount of information on the effectiveness of chemotherapy or chemoradiation, and is not indicated for local tumors. Chemotherapy may be used in advanced tumors, to allow for local resection and in order to avoid exenteration . These treatments typically use 5-fluorouracil or cisplatin, also used in head and neck cancers. Few studies have shown that topical adjuvant chemotherapy is also effective in treating periocular SGC.Radiation therapy
Radiotherapy is associated with higher recurrence rates and mortality when compared to surgical excision. It is not recommended as a primary therapy and is only for patients who cannot undergo surgical excision. Potential adverse effects from radiation include keratitis, conjunctivitis, dry eyes, keratitis and loss of vision.Cryotherapy
Although uncommon, conjunctival cryotherapy used during surgical excision has also been reported, but the associated risks to one's vision and potential damage to the eye appear to outweigh its benefits.Mohs micrographic surgery has become the treatment of choice for this form of cancer. Mohs surgery allows for precise and accurate removal of the complete tumor and surrounding margins via frozen section. When used as the primary treatment modality for sebaceous carcinoma of the eyelid, Mohs surgery is associated with significantly lower local and distant recurrence rates.