Mohs Micrographic Surgery Evaluation and Treatment of Microcystic Adnexal Carcinoma

Etiology

Microcystic adnexal carcinoma is a tumor that most commonly occurs on the head and neck, especially on the central facial skin of middle-aged and older adults.[17] Risk factors include:

• Ultraviolet (UV) radiation.
• Prior radiation therapy.
• Immunosuppression or immunosuppressive medications.
• Genetic predisposition.

MAC has been noted to occur at increased incidence after therapeutic radiation in 19% to 50% of studied patients with Fitzpatrick skin types I and II (in whom ultraviolet skin damage may also be a contributing factor) after an average latent period of 30 to 40 years.[18] 

Although the association between immunosuppression and the risk of other skin cancers, such as squamous cell and basal cell carcinoma, has been well studied--the association between immunosuppression and the risk of the development of MAC is less clear.

Epidemiology

Microcystic adnexal carcinoma is a rare neoplasm most commonly seen in the fourth to sixth decade of life and occurs in near-equal distribution between sexes. However, a slight female preponderance has been noted in the literature.[13][19][14] Incidence is 1.6 to 6.5 per 10,000,000 individuals.[19] Between 1973 to 2004, a total of 223 cases of MAC were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.[19] 

Although it is most frequently reported in Caucasian patients, a few cases have also been reported in Japanese, Indian, and African-American patients.[19][13][20] History of prior radiation exposure has been reported in 10% of patients with MAC, with an average latency period of 30 years between exposure and development.[21] Ultraviolet radiation and immunosuppression are thought to be other predisposing factors.[22]

Pathophysiology

Clinically, microcystic adnexal carcinoma often presents as a slow-growing, firm, flesh-colored plaque, nodule, or cyst-like tumor on the head and neck of an elderly caucasian individual. It is most commonly confused clinically with basal cell carcinoma, which is often diagnosed with a simple shave biopsy. However, the definitive diagnostic pathology for MAC lies much deeper, and even a deep shave biopsy may be insufficient for adequate diagnosis. A deep punch or incisional biopsy should be considered if MAC is suspected or even in the differentia for diagnosis.

Histopathology

Microcystic adnexal carcinoma often presents as a firm plaque on the upper lip or medial cheek. Histologically, MAC has a "paisley-tie" cellular pattern with a dense red sclerotic stroma. It must be histologically differentiated from the other common paisley-tie-pattern lesions: syringoma, morpheaform basal cell carcinoma, and desmoplastic trichoepithelioma. The MAC tumor can have both eccrine and follicular differentiation.

Superficially, it is composed of keratin horn cysts (support a follicular origin) and islands of cells with basaloid and squamous epithelium with ductal differentiation (support an eccrine origin). The deeper component of the tumor consists of nests and strands of cells embedded in the hyalinized stroma. Perineural invasion is frequently noted. Perivascular lymphoid aggregates are common in tumor stroma. Minimal atypia and mitoses are noted. Due to all these features, this tumor is thought to be derived from a pluripotent adnexal keratinocyte which can have both eccrine and follicular differentiation.[23][24][25]

The histologic differential diagnosis includes:

• Trichoadenoma
• Syringoma
• Desmoplastic trichoepithelioma
• Morpheaform basal cell carcinoma

Superficially, MAC mimics syringoma, desmoplastic trichoepithelioma, or infiltrative BCC, making it challenging to diagnose MAC correctly without a good sample of the deep histologic architecture. And without a deeper biopsy enabling confirmation of the diagnosis early, MAC can progress and result in increased morbidity. 

Immunohistochemical staining can be somewhat unreliable, with conflicting staining patterns reported in the literature. 

• Carcinoembryonic antigen (CEA) has been reported in half the cases of MAC, which can help distinguish it from BCC and SCC. Numerous other stains have been investigated over the past decade--including Ki67, CK7, AE14, CK19, and CK20--in an attempt to accurately differentiate MAC from its histologic look likes, but none of these have so far been particularly reliable.[26][27][28]
• Epithelial membrane antigen and cytokeratin are noted in MAC, which can, in some cases, help make the diagnosis.

History and Physical

Clinically, microcystic adnexal carcinoma presents as a slow-growing, indurated white or pink nodule, plaque, or tumor located on the head and neck of a middle-aged to elderly Caucasian patient. In one retrospective analysis of MAC cases, 42 out of the 48 cases were reported to occur on the head and neck.[14] However, tumors on the trunk, axilla, and buttocks have also been reported.[29] 

Clinically, MAC is somewhat indolent, often appears benign, and is often present for many years by the time of diagnosis. The morphology on inspection is often of an ill-defined, skin-colored, or yellow lesion with overlying telangiectasia.[29][8] The surface of the tumor tends to be smooth and not ulcerated, though the overlying epidermis may be atrophic or fissured.[30][29] 

The average size MAC at presentation is about 2cm based on existing literature, though larger lesions have also been reported.[13] Lesions are often asymptomatic, though symptoms of pain, burning, and paraesthesia are sometimes reported.[7] Symptoms, if present, may be secondary to perineural invasion.[7][30]

Evaluation

MAC is often clinically indistinguishable from other flesh-colored tumors on the head and neck. In contrast to many other tumors, MAC can be profoundly infiltrative and has a predilection for significant perineural spread. Therefore, early and definitive diagnosis is key to allowing for early and complete treatment and prevention of morbidity.

Definitive early diagnosis is best established by providing the dermatopathologist with a biopsy sample of adequate tissue depth since a large part of the correct diagnosis depends upon visualization of tumor extension into the deeper dermis and possible observation of perineural invasion as well. A superficial biopsy can lead to an incorrect diagnosis, so an incisional or deep punch biopsy is greatly preferred if MAC is suspected. 

Skin Examination 

• If a biopsy diagnosis reveals a MAC, a full-body-skin examination should be performed.

Lymph Nodes 

• Although regional metastases are rare, a lymph node exam should be performed. 
• A Sentinal lymph node biopsy can be performed if lymph nodes are detected on examination. 

Imaging 

Imaging is not necessary in most cases of MAC. CT, MRI, or a fat-suppression MRI protocol could be considered if there is a concern for possible perineural spread or local invasion.[31] MRI can also sometimes be used to define tumor size and evaluate for metastasis. MAC is a fibrotic tumor with low cellularity. Hence, lesions have low T2 signal intensity on MRI.[32]

Dermoscopy 

Dermoscopic findings have been reported in a limited number of case reports, with one of the most characteristic findings being the presence of whitish "clods" of varying sizes. These white clods likely represent keratinous cysts.[33][34][35] As often described in basal cell carcinoma, arborizing vessels can also be present in MAC.[36]

Treatment / Management

MAC is treated surgically with wide excision or Mohs micrographic surgery. However, MAC frequently extends beyond the clinical margins. For this reason, Mohs micrographic surgery is the treatment of choice as it offers a higher cure rate and is the most tissue-sparing. Several case series in the literature have demonstrated that the tissue defects remaining after Mohs surgery were four times larger than the prior clinical estimate.[14] (B2)

This indicates that the preoperative estimate of margins is unreliable, and a complete histologic assessment of margins is recommended. Radiation is ineffective because the tumor is known to be radioresistant, and the literature suggests that surgical excision is the most effective and definitive treatment method. 

Wide Local Excision 

• Standard surgical margins should be more comprehensive than clinical margins because of the infiltrative growth of the tumor.

• With wide local excision, recurrence rates range from 40% to 60%.[14] The standard histologic method of margin assessment, based on bread-loaf sectioning of the specimen, examines only 0.2% of the margin and leaves much room for undetected tumors. 

• Significant soft tissue defects can be noted after tumor resection and may necessitate reconstruction with local flaps and skin grafts. Reconstruction after incomplete tumor excision, however, could require the later removal of a flap or graft, which has further obscured the area of tumor positivity. This can result in delayed detection of recurrence and significantly increased complexity of definitive treatment.

(B2)

MMS or Excision With Pathologic Margin Assessment 

• MMS uses horizontal en-face sections of the excised tissue, thereby examining 100% of the peripheral and deep margins. Several case series have been published showing much lower recurrence rates when MAC is treated with MMS. Tumors exhibiting PNI are regarded to be more aggressive and have higher morbidity and mortality. The infiltrative nature of MAC and associated PNI emphasize the importance of excision with margin control.

Lymph Node Sampling/Dissection 

• Nodal staging is not recommended initially for primary MAC.[31]

• Nodal metastasis in MAC is rare.

• Lymph node dissection of the draining nodal basin is rarely performed. Most of the rare cases of distal spread have been gleaned from the Surveillance, Epidemiology, and End Results (SEER) database and the medical oncology literature. 

(A1)

Radiotherapy 

The use of radiotherapy as monotherapy is not recommended. Although the role of radiation therapy is questionable, adjuvant radiotherapy has been used successfully and has sometimes been recommended if peripheral nerves are involved or if margins cannot be cleared surgically--based on recent evidence-based clinical practice guidelines. Despite this, chemoradiation with a carboplatin/paclitaxel combination has been used in patients who refused surgical treatment and those who remained tumor-free for six years.

Follow up 

The frequency of follow-up should be based on patient risk factors and the extent of local and systemic involvement. Education on photoprotection, periodic self-examination, post-operative care, and expectations regarding surgical scars and changes in sensation is advised.

Differential Diagnosis

The clinical differential diagnosis of MAC includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, metastatic adenocarcinoma, and syringoma.[37] A few characteristic histologic features of each of these tumors are listed below.

Morpheaform Basal Cell Carcinoma 

• Thin strands and nests of basaloid cells extending into the dermis
• Limited peripheral palisading
• Stroma is dense and sclerotic
• Perineural invasion can be seen

Syringoma histologic 

• The superficial proliferation of cells with pale pink cytoplasm forming nests and tubules of uniform size embedded in a sclerotic stroma
• The nests of syringoma vary in size and shape and may assume a comma or tadpole shape
• Tubular areas show ductal differentiation with central lumina lined by the eosinophilic cuticle
• Horn cysts and milia can be noted
• Lacks deep infiltration and pleomorphism
• They can be difficult to distinguish from sclerosing BCC, desmoplastic trichoepithelioma, MAC on superficial biopsies, and metastatic carcinomas

Metastatic Adenocarcinoma 

• Islands, clusters, or single files of large pleomorphic, atypical cells with or without ductal differentiation
• Pleomorphism and atypia are apparent on higher power
• Mitotic figures can be present

Desmoplastic Trichoepithelioma

• Histology on low power shows a dome-shaped papule with an infiltrative dermal basaloid proliferation, small tumor nests, cords, and fibrotic stroma
• Sweat ducts are not a part of the proliferation
• It tends not to invade the deep dermis and subcutaneous tissue

Surgical Oncology

• According to current evidence-based clinical practice guidelines, sentinel lymph node biopsy (SLNB) is not recommended for staging MAC.[31]

• Currently, no evidence supports neck dissection for detecting positive lymph nodes.

• The local disease should determine a treatment strategy for node-positive and metastatic disease.[38]

Radiation Oncology

As of now, radiation therapy is not known to be effective for microcystic adnexal carcinoma. Radiotherapy alone is not recommended. The latest evidence-based clinical practice guidelines for MAC state that adjuvant radiotherapy may be considered when MAC involves peripheral nerves, margins cannot be surgically cleared, or if the tumor is present at the margins.

A combination of carboplatin and paclitaxel has been used in chemoradiation to treat patients refusing surgical treatment, resulting in the possibility of a six-year tumor-free survival.[39] The current evidence does not support prophylactic radiotherapy of the sentinel node base.[31]

Prognosis

Microcystic adnexal carcinoma is a locally aggressive, deeply infiltrative tumor with a propensity for perineural invasion. Although metastasis is uncommon, it has been reported. There is a high propensity for recurrence in the setting of perineural invasion, especially when removed without full margin control.[40][41] 

Histologic margins often extend beyond the clinical margins, and MMS provides the highest cure rate for these tumors. Several cases in the literature have demonstrated that MAC is not only radioresistant, but that radiation may indeed induce conversion to a more aggressive tumor clinically and histologically. Long-term follow-up is recommended for patients with MAC, as cases of local recurrence have been reported decades after initial treatment.[21]

Untreated tumors are locally aggressive and result in local and regional invasion. Distant metastases and death have been reported, although this is rare. A few key statements that can be made based on prior literature are the following: 

1. Skin lesions suspicious for MAC require a deep biopsy that includes the deeper dermis and subcutis.

2. MAC is best treated by surgery that examines the surrounding and deep margins of the removed tissue.

3. The role of radiation therapy is debated. Use is limited to adjuvant therapy for MAC, cases of incomplete surgical treatment, or patients who are poor surgical candidates. 

4. Patients should be seen every 6 to 12 months for the first five years after treatment. 

5. Patient education on photoprotection, as well as periodic skin examinations, is advised.

Complications

The most common complication of untreated MAC tumors is locally aggressive invasion, sometimes with widespread perineural invasion. However, it may rarely result in distant metastasis and death. The involvement of vital structures is a further concern.