We will consider specific clinical and histological features of the following tumors in this presentation:

Squamous cell carcinoma Sebaceous carcinoma Microcystic adnexal carcinoma

Selected references are given after each entity. An overall reference is: Schoelch SB, Barrett TL, and Greenway HG: Recognition and Management of High-Risk Cutaneous Tumors. Dermatologic Clinics 1999; 17: 93 - 111.

Squamous Cell Carcinoma
Squamous cell carcinoma is the second most common form of skin cancer in Caucasians (Johnson). Cutaneous SCCs are responsible for 2000 - 5000 deaths annually in the U.S. (Salasche). Most cutaneous SCCs are at low risk for recurrence or metastasis, however a subset occurs which may be very aggressive. The 5 year survival rate for metastatic SCC is only 25%. A primary goal therefore is to identify the patient at risk for metastasis.

Red Flags

Size greater than 2 cm Depth of invasion 4mm or greater Anatomic location: Ear or lip Rapid growth Immunosuppression Etiology: Chronic ulcer, sinus tract, radiation, and scar Aggressive histologic subtype: Poorly differentiated Perineural invasion Recurrence

Size and depth of invasion
Size and depth of invasion are the two most important prognostic factors. For all primary SCCs of the skin, the long term (> 5 year) metastatic rate is 5.2%. Lesions larger than 2 cm have double the local recurrence rate and three times the metastatic rate of lesions less than 2 cm (Johnson). Tumors greater than 4mm in depth have a higher metastatic and recurrence rate than those less than 4 mm. In one study, lesions with a depth of less than 4mm have a recurrence rate of 5.3% and a metastatic rate of 6.7% while tumors with a depth of greater than or equal to 4mm have a recurrence rate of 17.2% and a metastatic rate of 45.7% (Rowe). Additional studies may show depth to have similar significance in SCC as it does in melanoma.

Anatomic location
The ear and the lip are two sites consistently reported to have a higher risk of metastasis. Johnson sites a metastatic incidence of 11% for the ear and 13.7% for the lip. According to Salasche, the upper lip, the commissure and the pinna of the ear are especially dangerous locations. There are also reports that the dorsum of the hand is a high risk site, however, data on this appears conflicting.

Rapid growth
Tumors which enlarge visibly between diagnosis and treatment are especially dangerous. Rapidly growing lesions on the ear and eyelid have three times the metastatic rate of slower growing SCCs.

Immunosuppression
Immunosuppressed patients are at risk to develop more SCCs and, once developed, their SCCs are more aggressive. The usual SCC to BCC ratio changes from 1:4 to 1.2:1. According to Salasche, transplant patients usually develop tumors 5 - 10 years after transplantation and the lesions tend to be multiple, occurring in crops. The metastatic rate is 12.9% with a high percentage resulting in the death of the patient.

Etiology
There is often a latency of 20 - 30 years from development of the primary condition and the occurrence of an SCC. However, according to Johnson, SCCs which arise in chronic ulcers or sinus tracts have a metastatic rate of 18 - 31% while those arising in sites of radiation dermatitis have a 20 - 26% metastatic rate. SCC arising in a scar is also reported to behave aggressively.

Histology
Poorly differentiated histology is seen in only 19.1% of all cutaneous SCC but accounts for 51% of all metastasizing cutaneous SCCs (Johnson). These tumors have more than double the local recurrence rate and almost three times the metastatic rate of well and moderately differentiated SCCs. The most common SCC that we encounter in the skin is a SCC arising in an actinic keratosis. This tumor is usually small and well differentiated and has a good prognosis. SCC's with acantholytic (pseudoglandular) or cystic features are more aggressive than a typical SCC arising in an actinic keratosis.

Recurrence
Recurrent tumors have a 25 - 45% metastatic rate depending on the site (Johnson). The overall metastatic rate for recurrent SCC is 25%. When the recurrent site is the lip, the metastatic rate is 31.5% and when the recurrent site is the ear, the metastatic rate is 45%.

Perineural invasion
Evidence of perineural invasion on histologic examination has a severe prognosis. The incidence of perineural invasion by SCCs is about 4%. Recurrent tumors are more likely to demonstrate perineural invasion. Lesions with perineural invasion have a local recurrence rate of 47.2% and a metastatic rate of 47.3% overall. In one study of 187 SCCs of the lower lip, 60% of the lesions with perineural invasion metastasized. As with BCCs with perineural invasion, clearance of SCCs demonstrating perineural invasion may require much larger surgical defects than expected from the clinical appearance of the lesions. The peripheral branches of the trigeminal and facial nerves are particularly susceptible to invasion by neurotropic SCC and lesions occurring in these areas should carry a high index of suspicion. Direct intracranial extension may occur via these nerves. If perineural invasion is undetected during initial treatment it may be several years before symptoms occur. Symptoms of perineural invasion include pain, burning, anesthesia or paresthesia, and rarely facial paralysis. With perineural invasion, the local recurrence rate for standard excision followed by radiation is almost 50%. For perineural SCC treated with radiation therapy alone, one series reported an 80% recurrence rate. Mohs surgery followed by radiation appears to be the treatment of choice. Using Mohs followed by radiation therapy, a recurrence rate of 6% can be inferred from three studies involving a total of 32 patients. However, the cases in these series were followed for less than 3 years. Additional studies involving larger numbers of patients and longer follow-up periods are presently being conducted

Treatment
SCCs of low risk can be treated effectively by a number of modalities. Mohs surgery remains the treatment of choice for high risk SCCs with a recurrence rate of 3% compared to 13 % for non-Mohs modalities (Johnson). 75% of local recurrences and more than 80% of metastases occur within the first 2 years, therefore close followup of these patients is important. Adjuvant radiation therapy in high risk SCC without evidence of nodal spread has not been well defined. Radiation plus elective lymph node dissection is believed to be 95% effective in resolving occult disease in the neck, however, there have been no randomized trials that show improved survival (Johnson, Salasche). Salasche, in his review of high risk cutaneous SCCs of the head and neck without evidence of nodal spread, reported that elective treatment of the neck either by radiation alone or modified radical neck dissection or both should be considered in patients with SCC with poorly differentiated histology, perineural invasion, high risk location or immunocompromised status. A multidisciplinary approach is clearly indicated in these individuals. SCC which has spread beyond the regional lymph nodes has a particularly grim prognosis (Johnson).

Selected References

1. Barrett T, Greenway H, Massullo V, Carlson C: Treatment of Basal Cell Carcinoma and Squamous Carcinoma with Perineural Invasion. Advances in Dermatology, Vol 8, 1993, Mosby Yearbook Inc, St. Louis, MO.pp 277-305.
2. Berg D, Otley CC: Skin Cancer in Organ Transplant Recipients: Epidemiology, Patholgenesis and Management. JAAD 2002; 47: 1 - 17.
3. Cherpelis BS, Marcusen C, Lang PG: Prognostic Factors of Metastasis in Squamous Cell Carcinoma of the Skin. Derm Surg 2002; 28: 268 - 273.
4. Johnson TM, et al.: Squamous cell carcinoma of the skin (excluding the lip and oral mucosa). JAAD 1992, 26: 467 - 484.
5. Rowe DE, Carroll RJ, Day CL: Prognostic factors for local recurrence, metastasis and survival rates in SCC of the skin, ear and lip. JAAD 1992, 26: 976 - 990.
6. Salasche S, Cheney M, Varuares M: Recognition and management of the high - risk cutaneous squamous cell carcinoma. Curr Probl Dermatol 1993, 5: 141 - 192.

Sebaceous Carcinoma
Sebaceous carcinoma is an aggressive tumor derived from the adnexal epithelium of sebaceous glands. The tumor occurs most commonly in older adults and is slightly more common in women. The Meibomian glands of the upper eyelid are the most commonly affected site. The tumor may be difficult to diagnose and is often misdiagnosed as a chalazion or chronic conjunctivitis. The tumor may occur in extraocular sites where it has a more favorable prognosis than ocular sites. Mortality rates for ocular sites are 20 - 30 %(Dzubow), however the following features are associated with an even more unfavorable prognosis.

Red Flags

Size greater than 1 cm Anatomic location: Ocular Involvement of both upper and lower eyelids Histologic features: Multicentric origin Poor differentiation Pagetoid spread Infiltrative growth pattern Angiolymphatic invasion

Size
Tumors larger than 1 cm are reported to have a greater mortality than smaller lesions. Tumors present for greater than 6 months have a mortality of 38 % compared to 14 %.

Anatomic location
Origin from the Meibomian glands and glands of Zeis have the worst prognosis for gland of origin with a mortality rate of 58%. If both upper and lower lids are involved, the mortality rate is 83%. This is contrasted to a mortality rate of 28% for upper lid location only (Rao). Extraocular location has a significantly better prognosis. Bailet (see Nelson) reported a review of 92 patients with extraocular SC and found a recurrence rate of 29% and metastases in 21%.

Histologic features
Several features are associated with a more aggressive tumor. Rao found that tumors with poor sebaceous differentiation are associated with a high mortality (60%). He also reported that angiolymphatic invasion was associated with very aggressive behavior. A highly infiltrative growth pattern was associated with a history of multiple recurrences, orbital invasion, regional nodal metastasis and death. Pagetoid spread to the conjunctiva was seen in 59% of the fatal cases. EMA is a very useful immunoperoxidase stain to highlight sebaceous differentiation in poorly differentiated tumors.

Treatment
Evaluation of the patent with sebaceous carcinoma includes a complete skin exam, palpation of nodes and an ophthalmology referral. Patients must be evaluated for the Muir-Torre syndrome and family history reviewed for sebaceous neoplasms, keratoacanthomas, colorectal or genital malignancy. Treatment is primarily surgical (Nelson). Current recommendations call for 0.5 - 0.6 cm margins for primary tumors. Sebaceous carcinoma has a tendency for local recurrence due to the difficulties in obtaining clear margins. Mohs surgery has been difficult to utilize due to the multicentricity of some tumors, pagetoid spread and the difficulty in identifying malignant sebaceous cells on frozen section. Yount reported six cases where he utilized Mohs surgery with permanent sections. At an average follow-up of 56.8 months (range 34 - 84 months), one patient had recurrence with metastatic disease. Radiation therapy has been considered as adjunctive or palliative therapy but is generally not recommended as a primary treatment. The significance of the pagetoid spread and the best method of treatment remains controversial (Yount, Whitaker). Most authors recommend complete excision of all atypical cells. This may require exenteration of the eye . Lisman reported 6 patients with extensive residual pagetoid spread after primary excision treated with cryotherapy. The patients remained free of disease on follow-up biopsy at 6 - 50 months. Metastatic disease occurs in 14 - 25 % of cases. Most metastases occur in regional lymph nodes, followed by liver, lung, brain and bone. Regional lymph node metastases are treated with radical neck dissection. Treatment of metastatic disease includes surgery, radiation, chemotherapy or a combination of these modalities. Metastatic disease has a 50 - 67 % mortality (Nelson).

Selected References

1. Dzubow LM: Sebaceous carcinoma of the eyelid. Treatment with Mohs surgery. JDSO 1985, 11: 40 - 44.
2. Lisman RD, Jakobie FA, Small P: Sebaceous carcinoma of the eyelids: the role of adjuvant cryotherapy in the management of conjunctival Pagetoid spread. Ophthalmology 1989, 96: 1021 - 1026.
3. Nelson BR, et al.: Sebaceous carcinoma. JAAD 1995, 33: 1 - 15.
4. Rao NA, et al.: Sebaceous carcinoma of the ocular adnexa: A clinicopathologic study of 104 cases with 5 year follow-up data. Human Path 1982, 13: 113 - 122.
5. Whitaker DC: Sebaceous carcinoma of the eyelid, in: Surgical Dermatology and Advances in Current Practice. Mosby, 1993: 201 - 210.
6. Yount AB, Bylund D, Pratt SG, Greenway HT: Mohs micrographic excision of sebaceous carcinoma of the eyelids. JDSO 1994, 20: 523 - 529.

Microcystic Adnexal Carcinoma
Microcystic adnexal carcinoma (MAC) is a locally aggressive tumor arising, most commonly, on the central face of middle - aged patients. Clinically, the lesion presents as a pale yellow papule or plaque in the nasolabial region, particularly the upper and lower lip. These lesions are not impressive clinically and are ignored for years. The epidermis is usually normal. The lesions are highly neurotropic and the patients may complain of a "full" sensation in the involved area or paresthesia or pain. Originally believed to have features of both pilar and eccrine differentiation, the tumors are now believed by most to be of eccrine origin.

Red Flags

A lesion in the naso-labial area diagnosed as a desmoplastic trichoepithelioma or solitary syringoma The base of the lesion must be observed Look for perineural invasion

Histology
Histologically, the tumors are composed of strands of basaloid cells in a desmoplastic stroma. The tumor is characterized by areas with gland - like structures, ductal differentiation as well as small horn cysts. The cells are not pleomorphic and mitoses are uncommon. The tumors greatly resemble syringoma and desmoplastic trichoepithelioma. Perineural invasion is a characteristic feature and is very useful in making a correct diagnosis. Correct diagnosis requires a biopsy deep enough to see the base of the lesion. MAC infiltrates widely through tissue. The tumor can penetrate into muscle, perichondrium and periosteum. While recurrence rates after standard excision approach 47%, metastases have never been reported (Burns).

Treatment
Treatment is surgical. The literature is not clear about what constitutes adequate margins. Margins have ranged from a few millimeters to 3 - 5 cm. In one study, 40 patents treated with wide local excision had a recurrence rate of 59 % (Sebastien). Mohs would appear to be the treatment of choice, since this technique allows for visualization of all margins and perineural spread can be followed. However, studies using Mohs with long term follow-up of patients are not yet available.

Selected references

1. Burns MK, Cheen SP, Goldberg LH: Microcystic adnexal carcinoma: Ten cases treated by Mohs micrographic surgery. JDSO 1994, 20: 429 - 434.
2. Sebastien TS, et al.: Microcystic adnexal carcinoma. JAAD 1993, 29: 840 - 845.