Merkel Cell Carcinoma and Rare Appendageal Tumors

Updated: Oct 07, 2019
  • Author: Guy J Petruzzelli, MD, PhD, MBA, FACS; Chief Editor: Gregory Gary Caputy, MD, PhD, FICS  more...
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Overview

Overview

Cutaneous tumors encompass a vast array of malignancies, ranging from neuroendocrine to lymphoid in origin. In addition to primary malignancies, the skin can also be a major site for metastatic disease. The diagnosis and treatment of these cutaneous tumors is constantly evolving, and the role of clinicians relies on accurate diagnosis and a thorough understanding of the clinical sequelae. [1, 2, 3]  This article focuses mainly on nonmelanoma skin cancers, with an emphasis on rare benign and malignant epithelial, dermal, and adnexal tumors.

As with all tumors, whether benign or malignant, identification of the cell or cell layer of origin is of the utmost importance. The origin of cutaneous tumors can be simplistically divided into three major categories: epidermal, dermal, and adnexal (see image below).

Layers of the Skin: A Schematic Depiction Layers of the Skin: A Schematic Depiction
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Tumors of the Epidermis

Pseudotumors

Keratoacanthoma

Keratoacanthomas (KAs) are benign cutaneous neoplasms that occur in elderly patients who are frequently exposed to the sun. Often presenting as solitary lesions, they have a predilection for the face. The spontaneous involution and eventual disappearance of these lesions, within months, characterizes the self-healing nature of KAs.

Keratoacanthoma Keratoacanthoma

Histologically, the fully formed domelike lesion reveals a mass of proliferating squamous epithelial cells, which created the central core of keratin. These proliferating cells exhibit no cytologic abnormalities and have a normal nuclear-to-cytoplasmic ratio. The surrounding normal epidermis is displaced upward with the lesion, providing the characteristic buttress appearance of KAs. [4]

KAs are well-contained lesions, but case reports have shown perineural and vascular invasion. [5]

Clinically, the lesion rapidly increases in size within 6-8 weeks, with the eventual formation of a central keratin plug. During the immunologically mediated regression phase, the central keratin plug is extruded, and only a flat scar remains.

KA lesions can easily be mistaken for squamous cell carcinoma (SCC). Sudden onset and rapid growth are the distinguishing features of KAs. SCCs display a more indolent growth rate. Nodular melanoma can also mimic KAs. [6]

In order to distinguish between KA and SCC, further histologic studies can be used, including proliferating-cell nuclear antigen immunostaining. [7]  In KAs, cells that stain positive with proliferating-cell nuclear antigen immunostaining are distributed only in the outer edges of the tumor, corresponding to the proliferating squamous epithelial cells. In contrast, cells within an SCC that stain positive with proliferating-cell nuclear antigen immunostaining are more diffusely distributed.

A class of drugs that treats melanoma with BRAF mutations by inhibiting BRAF has been noted to induce the formation of KAs. [8]

In treating KAs, several problems are often encountered:

  • Some umbilicated papules or plaques look like KAs but are actually SCCs. A biopsy is needed to differentiate between the two, and if the biopsy cannot firmly establish the diagnosis, excision is the preferred treatment option.
  • Hypertrophic lupus can histologically imitate SCC and KA. Specimens should be evaluated by a trained dermatopathologist. If the patient has lupus and a KA or SCC is suspected, a second opinion should be obtained.

  • KA involutes in most cases. However, the involution can lead to tissue destruction and scarring that permanently impairs function. Thus, on the sensitive eyelid, KAs should be treated promptly. Mohs surgery with reconstruction is the optimal treatment for KA on the eyelid.

  • Multiple KAs should raise suspicion of Muir-Torre syndrome, a genodermatosis with a defect in the  MSH mismatch repair gene that is associated with sebaceous neoplasms and gastrointestinal cancers. 

  • KAs have been noted in multiple reports to arise in tattoos. [9, 10]  Pseudoepitheliomatous hyperplasia must be distinguished from a squamous neoplasm.

  • Primary cutaneous CD30+ anaplastic large cell lymphomas mimicking KAs have been reported. [11]

Although these lesions are self-healing, several reports have advised a more aggressive approach for treatment. Beham and colleagues advocated surgical excision because of the difficulties in distinguishing between KAs and SCCs upon gross examination. [12]

Gray and colleagues proposed a more conservative approach, using topical 5-fluorouracil (5-FU) therapy to accelerate the regression phase of the keratoacanthoma without the need for diagnostic biopsy. [13]  With 5-FU treatment, the KAs in a limited number of patients had a partial response within 3 weeks and complete resolution within 8 weeks. On the other hand, SCC has a poor response to 5-FU treatment.

Studies have noted that topical Imiquimod demonstrates some efficacy against KAs.

Benign tumors of the epidermis

Clear cell acanthoma of Degos

One of the most common benign epithelial tumors is seborrheic keratosis/senile keratosis, a hereditary lesion that appears in individuals over age 30 years. On the other hand, clear cell acanthoma is a rare, benign epithelial cutaneous tumor. Typically, the clinical presentation of clear cell acanthoma is a solitary nodule of the lower extremities. It is usually pink or red-brown and described as glistening. [14]

Clear cell acanthomas usually range in size from 3-20 mm, and they tend to have a collarette of scale around the edges. Peeling this scale can elicit bleeding.

Upon histologic examination, the epidermis is abruptly interrupted with acanthotic epidermis, resembling psoriasis. The sharp demarcation of the borders of a clear cell acanthoma distinguishes it from psoriasis.

Cells of clear cell acanthoma are translucent because of the presence of glycogen, which can be demonstrated by a periodic acid-Schiff (PAS) stain. For this same reason, the cells within the acanthotic epidermis stain faintly; electron microscopy demonstrates that the defective keratinocytes also contain defects in mitochondria and nuclear structures. [15]

The acanthotic epidermis can also contain dendritic melanocytes, in which melanin granules are interspersed among the abnormal keratinocytes. This presence of melanin provides pigmentation to the benign tumor, and this occurrence has been termed pigmented clear cell acanthoma.  [16]

Clear cell acanthoma usually stains positive for epithelial membrane antigen and negative for carcinoembryonic antigen. With anti-keratin antibodies, the clear cell acanthomas stain for AE1 and AE3 but not for CAM5.2. In fact, clear cell acanthoma possesses a staining pattern similar to that of inflammatory dermatoses such as psoriasis vulgaris, lichen planus, and discoid lupus erythematosus and might actually be a localized form of inflammatory eruption rather than a true neoplasm.

Variants of the clear cell acanthoma have been noted and include polypoid, giant, multiple, and eruptive. It can be treated by surgical excision and cryotherapy, although spontaneous involution has been reported.

Premalignant lesions of the epidermis

Bowen disease (Bowen precancerous dermatosis) is a common cutaneous process that has invasive potential and can be considered SCC in situ. Patients with Bowen disease possess atypical cells throughout the entire thickness of the epidermis.

Actinic keratosis (solar keratosis), while possessing atypical cells that do not extend to the full thickness of the epidermis, are best considered a form of precancerous lesion, as only 2-5% will progress to become SCC or Bowen disease. Occurring predominantly on sun-exposed skin, actinic keratoses can present as solitary or multiple lesions and are often described as hyperkeratotic scaly macules or papules. Bowen disease predominantly arises in the lower limbs and is characterized by a slow-growing, scaly plaque that often resembles patches of dermatitis or psoriasis.

Premalignant fibroepithelial tumor of Pinkus

The fibroepithelial tumor of Pinkus is best considered a type of basal cell carcinoma (BCC). Originally identified by Herman Pinkus in the 1950s, the premalignant fibroepithelial tumor of Pinkus is a distinctive tumor that predominantly occurs on the lower trunk and thighs, often appearing as pedunculated lesions resembling fibromas. These tumors typically develop between the fourth and sixth decade of life.

Histologically, the tumor is composed of epithelial cells resembling basal cells surrounded by a fibrous stroma. [17]  With further cellular characterization, Heenen and colleagues demonstrated that these basal-like epithelial cells have different cell cycle characteristics in comparison with normal epithelial cells. [18]  It is suggested that this dysregulation of the cell cycle is a premalignant phenomenon and represents the potential progression into a transformed, cancerous cell. In rare cases, these faint-staining epithelial cells are replaced by more aggressive, smaller, dark-staining basaloid cells. These new basaloid cells eventually overtake the lesion, consequently, developing into an invasive basal cell epithelioma.

Malignant epithelial tumors

Basal cell carcinoma and squamous cell carcinoma

BCCs and SCCs make up the majority of nonmelanoma malignant skin cancers. BCCs are the most common malignant neoplasm. Although they are usually locally invasive, they have been observed to metastasize on rare occasions. The most common primary site of metastatic BCC is the scrotum, where the rate of metastatic disease is 12%. Primary lesions affecting the head and neck can also be a predisposing factor for metastasis, but this is less common.

SCCs are malignant neoplasms arising from transformed keratinocytes. They have rare metastatic potential, but in immunocompromised patients, SCCs are more aggressive and prone to metastasis.

Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy that is aggressive and often metastasizes to regional lymph nodes. The pathophysiology of this disease process appears to have an infectious etiology, as evidenced by Feng, who reported clonal integration of a polyomavirus in human MCC. [19] Merkel cell polyomavirus (MCPyV) is unique in the 10-member family of human polyomaviruses (HPyV) in that it causes cancer, particularly in the old and immunosuppressed patient. [20]  It is found in 60-80% of specimens of Merkel cell cancer. [21, 22]

The rarity of this malignancy is further emphasized by data obtained from the Surveillance, Epidemiology, and End Results program, through which Miller and Rabkin determined that the age-adjusted prevalence of MCC is 0.23 cases/100,000 persons and 0.01 cases/100,000 persons for individuals who identify as white or black, respectively. [23]

The average age of onset for MCC is between the late sixth and early seventh decade of life. As with BCC and SCC, MCC has a higher prevalence in patients who are immunosuppressed, with a median age within the fifth decade in this population. [24, 25]  Interestingly, Friedlaender and colleagues observed that in organ transplant patients, the discontinuation of the immunosuppressant cyclosporine caused temporary regression of MCC metastases. [26]

A 2009 study based on 1980-2004 data from a population-based cancer registry showed increases in standardized incidence rates for rare skin tumors, including MCC. [27]  A 2007 report by Bichakjian noted that the incidence of MCC had tripled in the previous 20 years, which was likely attributable to increasing lifespans. [28]

Clinical Presentation

The physical appearance of MCC is often that of a solitary nodule or plaque with a red, violaceous hue. Considering the similarity in appearance to BCC, clinicians must ensure proper diagnosis and respective treatment of these lesions. MCC often occurs in sun-exposed skin, with approximately 50% developing on the head and neck and 33% developing on the extremities. [29]  It can also occur on the breast. [30]

Regardless of the treatment, more than 50% of the patients develop regional lymph node metastasis. In approximately 36% of cases, distant metastasis is seen. [31]  The most common sites for distant metastases include the brain, bone, liver, and skin. One report noted MCC metastasis to the pancreas.  [32]

Pathology

While MCPyV appears to play a role in the pathophysiology of this disease process, the etiology of MCC still requires further exploration. Merkel cells are accessory cells that secrete nerve growth factors to enable cutaneous nerves to develop into nerve endings. The embryologic origin of Merkel cells is also controversial; initially, Merkel cells were hypothesized to have arisen from neural crest cells. However, subsequent evidence suggested that fetal Merkel cells are derived from epidermal keratinocytes. [33]  Others postulate that the cancerous cells in MCC arise from stem cells that develop neuroendocrine properties similar to the wild-type Merkel cells. [34]

Identifying MCC with conventional histologic examinations is problematic, as it resembles other poorly differentiated neoplasms such as cutaneous large cell lymphoma, amelanotic melanoma, small cell carcinoma, and Ewing sarcoma. For a definitive diagnosis, electron microscopy and immunohistochemistry studies are necessary. [35, 36]

Similar to normal Merkel cells, electron microscopy reveals that the cells in MCC contain perinuclear intermediate filaments and electron-dense cytoplasmic secretory granules. In one study, investigators used immunohistochemistry findings to distinguish MCC cells from pulmonary small cell carcinoma. Chan and colleagues identified that the critical difference was the constitutive expression of cytokeratin-20 in Merkel cells and cells from MCC. [37]  In contrast, pulmonary small cell carcinomas, which grossly appear similar to MCC, lacked expression of cytokeratin-20.

Molecular Basis

As mentioned, MCPyV undoubtedly plays a role in the molecular basis of MCC. However, karyotypic abnormalities have also been identified in chromosomes 1, 11, and 13. [38] Further, molecular characterization has implicated two tumor suppressor genes involved in the molecular pathogenesis of MCC: (1) P73, a member of the TP53 family of tumor suppressors localized on chromosome 1 and (2) SDHD (succinate-ubiquinone oxidoreductase subunit D), localized on chromosome 11. [39, 40]

Programmed cell death of ligand 1, which has been shown to be important in SCCs and melanomas, seems to play a similar role in the propagation of MCC. This presents as a  future target for chemotherapy. [41]

A study by Behr et al indicated that a strong association exists between the existence of tertiary lymphoid structures in the MCC's microenvironment and recurrence-free survival. [42]

Treatment

The clinical workup of a patient with MCC should include chest radiographs and computed tomography (CT) scanning of the chest and abdomen. These are utilized to help differentiate a primary MCC with metastasis from a primary lung cell carcinoma with skin metastases. The abdominal CT scan is critical for staging, because MCC preferentially metastasizes to the liver.

Yiengpruksawan and colleagues at Memorial Sloan Kettering Cancer Center developed the staging system for MCC, as follows [39] :

  • Stage Ia - Primary tumor ≤2 cm
  • Stage Ib - Primary tumor >2 cm
  • Stage II - Regional lymph node metastasis
  • Stage III - Distant metastases

Due to the rarity of MCCs, clinical treatment protocols have not undergone extensive comparative trials. Furthermore, no consensus on postsurgical treatment, such as adjuvant chemotherapy versus adjuvant radiation therapy, has been reached in the medical literature.  

Lyhne suggested that treatment and staging for MCC with curative intent should involve (1) CT or positron emission tomography (PET) imaging of the thorax and abdomen, (2) excision of the primary MCC with wide margins, (3) sentinel lymph node biopsy, (4) surgical bed adjuvant radiotherapy, and (5) systemic palliative chemotherapy for patients with advanced-staged metastatic MCC. [43]

Excision of MCC with negative margins is the foundation of surgical treatment. [44]  Surgical resection of the primary tumor entails wide excision with 1-3 cm margins. [39, 45]  Tai and colleagues comprehensively reviewed previously published cases of MCC and concluded that complete excision significantly improved overall survival. [29] In addition, tumor size and location greatly impacted the outcome of surgical excision. A worse prognosis has been associated with primary tumors larger than 2 cm and located in the perianal and vulvar regions.

The high rate of local recurrence even after surgical excision, approximately 50% in some reports, argues strongly for regional lymphadenectomy. [31] In a limited number of cases, Smith and colleagues demonstrated that patients with local and regional control (excision of primary tumor and regional lymphadenectomy) had 50% lower recurrence and mortality rates. [46] However, in one retrospective study, locoregional control did not significantly improve disease-free survival when compared with local control for MCC localized in the neck. [29]  Sentinel node biopsy, which is often used to stage melanoma, does not seem to be useful for staging MCC or for predicting survival. [47]

After surgical excision, adjuvant therapy for MCC is recommended to prevent local recurrence, either via radiation therapy, chemotherapy, or a combination of the two. A 17-patient series supported the use of adjuvant radiotherapy for MCC. [48]

As MCC is radiosensitive, radiation therapy has been shown to decrease the local recurrence rate. [49]  Neck dissection and adjuvant radiotherapy are the foundation for treatment of MCC with positive nodes, while high-risk MCC without positive nodes should also receive adjuvant radiotherapy. [44]  In one retrospective study, Kokoska and colleagues demonstrated that aggressive treatment of MCC with locoregional control (surgical excision and regional lymphadenectomy) in combination with radiation therapy significantly improved survival rates when compared with local excision alone. [50]  A retrospective study by Tai et al demonstrated that the ideal overall radiation dose is 41-50 Gy in MCC therapy. [29]

The role of chemotherapy as adjuvant therapy is not well established in the literature. The basis of chemotherapy is for palliative treatment and advanced-stage MCC. [44]  The chemotherapy regimens used most often for treating MCC are etoposide and cisplatin; cyclophosphamide, doxorubicin, and vincristine; and cyclophosphamide, methotrexate, and 5-fluouracil. In one study, Boyle and colleagues demonstrated carboplatin and etoposide as effective treatment to reduce regional nodal disease in 8 (40%) of 20 patients. However, chemotherapy was less effective than radiation therapy. [51]  In contrast, a small retrospective study by Kokoska et al demonstrated that chemotherapy had no survival benefit. [50]  In another retrospective study, Tai and colleagues obtained similar findings. Chemotherapy was associated with a poorer outcome. These results are confounded by the fact that these patients had more advanced stages of disease. [52]

For metastatic disease, chemotherapy is rarely curative and serves only as palliative treatment. In the literature, no consensus has been reached regarding the ideal chemotherapy regimen. In a retrospective study by Tai and colleagues, the temporary response rate to chemotherapy for distant disease was higher than 50%. However, the disease soon relapses, and the prognosis is poor. Studies have shown no difference in prognosis among the different chemotherapy agents. Furthermore, the response to chemotherapy is usually temporary. [53, 54]

The combination of radiation and chemotherapy seems to be effective for advanced stages of MCC with local and regional involvement. [55]  In a retrospective study of 40 patients, Fenig and colleagues showed that chemotherapy alone was only effective short-term in a regional (lymph node) response, with a 69% partial or complete response. [56]  The addition of radiation significantly improved the efficacy, with a 91% partial or complete response.

Avelumab (Bavencio), an anti–programmed death ligand-1 (anti-PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody, was approved by the US Food and Drug Administration (FDA) in March 2017 for metastatic MCC in adults and pediatric patients aged 12 years or older.

Approval of Avelumab was based on the JAVELIN Merkel 200 open-label, single-arm, multicenter study made up of 88 patients with histologically confirmed metastatic MCC, with progressive disease on or after administration of chemotherapy for distant metastatic disease. The overall response rate reached 33% (29 patients), with partial response in 22% and complete response in 11% of subjects. 86% of subjects with tumor responses had lasting effects for at least 6 months (25 patients), and 45% lasted at least 12 months (13 patients). Response duration lasted from 2.8 to over 23.3 months. [57]

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Tumorlike Lesions of Fibrous or Elastic Tissue

The next set of localized abnormalities includes lesions that can emulate tumors. These benign lesions arise from either elastic tissue or dermal collagen. Often appearing to develop from the fascia, with extension into dermal and subcutaneous fat, these benign fibrotic nodules must be distinguished from fibrosarcomas.

Palmar fibromatosis (Dupuytren contracture)

Clinical presentation

Palmar fibromatosis (PF) is a relatively common contracture of the palmar fascia, extending into the fingers, usually affecting the fourth and fifth digits. [58]  Contracture upon flexion of the fingers at the metacarpophalangeal and proximal interphalangeal joints characterize Dupuytren contracture (DC). PF usually appears after the fifth decade of life, affecting more men than women. It is predominantly found in patients of northern European descent and is often informally termed "Viking Disease." 

Pathogenesis

PF is a polyclonal process and thus, a type of non-neoplastic fibroblastic proliferation. Although PF seems to have a dominant inheritance pattern, the molecular etiology of the lesion remains elusive. [59, 60]  Smoking, alcoholism, and diabetes mellitus have been associated with PF, but no definitive causal link has been made.

PF is a disease that involves two distinct fibrotic elements, a nodule and a cord. The actual pathogenesis of Dupuytren contracture remains unclear. The nodules begin as outgrowths from the fascia, and, based on electron microscopy findings, may contain myofibroblasts. As the lesions mature, the nodules become more collagenous and fibrous, with less cellular content. The resulting cord develops in the fascia, producing the familiar contracture and flexion of the fingers. Moyer and colleagues have reproduced this change from the nodule to the cord in vitro, demonstrating that serial passage of nodule fibroblasts eventually develops into cord fibroblasts. [61]  

In rare instances, these types of nodules may develop in the plantar fascia. In plantar fibromatosis, the nodules often grow more rapidly and larger. [62]  However, these nodules have less collagen deposition compared with palmar fibromatosis, and the contracture of the toes is less severe.

Because this disease has a dominant inheritance pattern, many investigators have attempted to identify molecular lesions that predispose patients to PF. The genes involved in the transforming growth factor (TGF) pathways are known to mediate proliferation in fibroblasts and are obvious molecular candidates that could be involved. However, studies have demonstrated no association between TGF genes and Dupuytren contracture. [60, 59]

Children can also present with palmar-plantar fibromatosis. In some such cases reported by Fetsch, the patient had a history of trauma, occasionally involving a foreign body. [63]

Palmar fasciitis and polyarthritis syndrome (PFPAS) is an uncommon paraneoplastic syndrome that is associated with several malignant neoplasms. In particular, it is associated with ovarian carcinoma.

Treatment

Collagenase Clostridium histolyticum (CCH) is an injectable treatment for PF that was approved by the FDA in February of 2010 and in the European Union (EU) in 2011. In a 3-year study of 1080 CCH-treated joints, 35% of the joints experienced recurrence. Of these recurrences, an additional intervention was required in 7% of patients.​ [64]  In the 1080 CCH-treated joints, partial correction of 301 joints occurred in the original study. In these, 50% experienced nondurable responses. While treatment failures occurred, adverse effects were rare. In most successfully treated joints, a contracture remained well beneath the threshold for surgical intervention 3 years posttreatment. Recurrence rates in effectively treated joints appeared lower compared with nondurable response rates in partially corrected joints.

A study by Nordenskjöld et al indicated that in collagenase injection treatment for Dupuytren contracture, recurrence is more likely to result following treatment of the proximal interphalangeal joint of the small finger, as well as in the presence of more severe pretreatment contracture and if fasciectomy was previously carried out on the treated finger. [65]

A study by Nayar et al of patients with Dupuytren contracture who were treated with collagenase Clostridium histolyticum (CCH) injection found that contracture in 95% of metacarpophalangeal joints immediately improved from 50° to 1.5°, while in 42% of the proximal interphalangeal joints, improvement from 44° contracture to 16° was seen. At 2-year follow-up, contractures of 17° and 35.5° were observed in the metacarpophalangeal and proximal interphalangeal joints, respectively. [66]

If the decision is made to treat PF, then surgery is the treatment of choice. Mild or moderate disease, it seems, should just be monitored. Patients with a mild Dupuytren contracture and some disability can be monitored for several years without surgical intervention. The criteria for surgical intervention include a metacarpophalangeal joint contracture of greater than 30º or any proximal interphalangeal joint contracture. The surgery entails a fasciectomy.

Nodular fasciitis (pseudosarcomatous)

Nodular fasciitis, or pseudosarcomatous, lesions are benign proliferations that are often idiopathic or develop in response to trauma. [67] These lesions are often mistaken for fibrosarcomas or liposarcomas.

Clinical Presentation

Nodular fasciitis lesions may appear in persons of any age, with the peak incidence between the second and fourth decades of life. Sex distribution appears to be equal.

The most common site is the volar portion of the forearm, but nodular fasciitis can appear anywhere. The chest and back are other common sites for nodular fasciitis lesions. Nodular fasciitis lesions usually appear as rapidly growing solitary nodules that are often tender and typically develop over a 2- to 3-week period. [68]  Most cases are idiopathic; however, 10-15% are associated with previous trauma.

Another variant, called dermal nodular fasciitis, can involve the external ear region, cheeks, and scalp. [69]

Pathogenesis

Nodular fasciitis lesions arise in the deep dermis and consist of a haphazard arrangement of immature, spindle-shaped or triangular mesenchymal cells in a feathery pattern within the context of myxoid stroma.

Based on immunohistochemistry studies, the cells in nodular fasciitis lesions stain with smooth muscle–specific actin and desmin, suggesting a myofibroblastic origin of these mesenchymal cells. [68] On the periphery of these lesions, capillary proliferation is abundant and contributes to the extravasated red blood cells that are often intermixed in the stroma. The cells have prominent nucleoli, and mitotic activity is high, corresponding to the rapid growth rate of nodular fasciitis lesions. Because of the immature appearance of the cells and the high mitotic activity, nodular fasciitis lesions can easily be confused with sarcomas. Therefore, proper diagnosis is critical in order to exclude malignancy. [70, 71]

Treatment

Because of the resemblance to malignant lesions, the clinical management of nodular fasciitis lesions necessitates proper diagnosis.

In a limited number of patients, Stanley and colleagues reported that fine needle aspiration is an effective method for diagnosing nodular fasciitis lesions. [72] All 11 of their patients had spontaneous resolution of lesions within 11 months and did not require surgical excision.

In contrast, others have reported difficulty with utilizing cytology to distinguish nodular fasciitis lesions from malignant low-grade sarcomas. [73, 71] Despite this limitation, fine needle aspiration and cytology results can help differentiate metastatic carcinoma, lymphoma, high-grade sarcoma, and infectious processes.

In the context of the clinical history, nodular fasciitis lesions can usually be identified properly with fine-needle aspiration. [68] For lesions with equivocal fine needle aspiration results, surgical excision and subsequent histologic studies can be used for proper diagnosis.

Even with positive margins on the biopsy specimen, nodular fasciitis lesions do not reappear. [74, 68, 75] If the lesion recurs, then a different diagnosis must be considered. For larger lesions for which complete surgical excision may be difficult, Graham and colleagues used corticosteroid injections to reduce the size of the lesion. [76]

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Tumors of Histocytic Origin

Dermatofibroma

Dermatofibromas (DFs) are common benign cutaneous tumors. Of unknown etiology, DFs usually occur as solitary lesions on the extremities; however, they may appear as multiple nodules. The presence of multiple nodules (>15) can be indicative of lupus or human immunodeficiency virus (HIV). Evidence found of clonal growth within the lesion suggests that DFs are true neoplastic growths rather than the result of reactive processes. [77]  

DF can be diagnosed clinically with the Fitzpatrick sign, also called the dimple sign, in which lateral pressure against the tumor produces a depression. The presence of factor XIIIa within cells is thought to indicate a DF rather than a dermatofibrosarcoma protuberans (DFSP). The presence of CD34, on the other hand, is positive in DFSP and not DF. However, these immunostains are not infallible. 

Dermatofibrosarcoma protuberans

Clinical Presentation

Dermatofibrosarcoma protuberans (DFSP) is a slow-growing neoplasm in the dermis that appears as a firm, indurated plaque, usually either red or blue in hue. [78]  DFSP typically appears on the trunk and extremities; however, case reports have shown that DFSP can also occur on the scalp or the face. [79] As the lesion develops, multiple protuberant nodules form within the indurated plaque.

Local recurrence is common because the tumor has microscopic extensions beyond the visible lesion. Therefore, wide excision is recommended for treatment. Mohs surgery has been endorsed as the preferred treatment. DFSP rarely metastasizes. Radiation therapy is not recommended, as it can often elicit more aggressive behavior within the tumor. 

Pathogenesis

Upon histologic examination, DFSP involves the dermis and often the subcutaneous fat. The lesion consists of plump spindle cells, which radiate from a fibrous center to form the characteristic cartwheel or storiform pattern. This characteristic storiform pattern does not occur in DFs. Corresponding clinically to an indolent growth rate, the lesion contains infrequent mitotic figures. The lesion is not as well defined at the margins, with increased collagen deposition that blends in with the normal dermis. Fingerlike projections of this lesion extend into normal tissue, thereby establishing territory in seemingly normal tissue. This extension often creates difficulties in excising the lesion and is the basis for its frequent recurrence.

The cell origin of DFSP remains controversial. Through tissue culture studies, Shindo and colleagues have concluded that the DFSP cells are of histocytic origin. [80] Through electron microscopic studies, other investigators have concluded DFSP cells have characteristics that are more in line with fibroblasts or myofibroblasts. [81, 82]

Although the characteristic cartwheel pattern can be used to distinguish DFSP from DF, cellular DF can appear similar to DFSP, making histologic diagnosis difficult. With the exclusive expression of the hematopoietic progenitor antigen CD-34 in cells from DFSP, immunohistochemistry studies have been used to differentiate DFSP from DF and cellular DF. [83, 84, 85]

In the era of cytogenetics and molecular biology, a characteristic reciprocal translocation, t(17;22)(q22;q13), has been identified for DFSP, [86, 87] creating the fusion of collagen type I alpha 1 (COL1A1) to platelet-derived growth factor beta (PDGFB). [88] This rearrangement fuses the COL1A1 to the PDGFB chain. However, this fusion product may not necessarily be the oncogenic factor responsible for DFSP. This translocation deletes exon 1 of PDGFB, resulting in the elimination of the normal regulation of the PDGFB gene. In addition, the resulting COL1A1/PDGF-B fusion protein is processed and dimerized to become PDGF-BB, which can then act as a ligand to the PDGFB receptor. [89] The combination of dysregulation of the PDGFB gene at the chromosomal locus and at the posttranslational step presumably results in the constitutive activation of the PDGFB receptor, providing autocrine signals for the cells to proliferate.

For diagnostic purposes, Nishio and colleagues used comparative genomic hybridization as a method to distinguish between DF and DFSP, focusing on chromosomes 17 and 22 as critical determinants. [90] However, comparative genomic hybridization is a cumbersome, time-consuming technique and is currently impractical as a clinical diagnostic tool. On a more practical level, other investigators have used reverse transcriptase polymerase chain reaction to amplify and identify the COL1A1-PDGFB fusion product. [88, 91, 92]

Treatment

DFSP is a difficult lesion to treat because of the high rate of recurrences. Surgical excision requires both proper diagnosis at presentation and effective treatment.

DFSP on the face can be removed successfully with wide surgical excision and closure with rotational flaps. [93]

DFSP lesions smaller than 2 cm in diameter are often mistakenly identified as DFs or keloids. [94] D'Andrea and colleagues further argue for aggressive surgical treatment with excision of 5 cm of surrounding tissue in order to prevent local recurrences.

In a small retrospective study, Sun and colleagues concluded that radiation as adjuvant therapy helps reduce the rate of local recurrences. [95]

Originally effective for inhibiting the BCR/ABL fusion product in patients with chronic myelogenous leukemia (CML), the drug STI571 (Gleevac) has also been used to inhibit other tyrosine kinases, including c-kit and the platelet-derived growth factor receptors. Because the translocation in DFSP is associated with constitutive activation of the platelet-derived growth factor receptor, several labs have used tissue culture and animal models to demonstrate that Gleevac is able to inhibit proliferation of cells derived from DFSP or cells that express the COL1A1-PDGFB fusion product. [96, 97] These results are encouraging and may lead to the future use of Gleevac as either neoadjuvant or adjuvant therapy for DFSP.

Reports have also supported the use of imatinib mesylate. [98]

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Tumors of Adipose Origin

Lipomas

The most common tumor of adipose origin is the lipoma. Lipomas appear as painless, round, mobile masses that are well-circumscribed and often pseudo-encapsulated. [99] These benign lesions are often located in the subcutaneous tissues of the head, neck, shoulders, and back. The average age at presentation is between the fourth and sixth decades of life. Histologic examination reveals mature adipose tissue, often encapsulated by fibrous layers. Focal points of necrosis or calcification can also be seen.

Most lipomas can be managed conservatively. If the lipoma becomes painful or begins to grow rapidly, then surgical excision is definitive treatment. Infiltration of lipomas into muscle has been described. The removal of such infiltration leads to bleeding and postoperative hematomas. Therefore, larger and deeper lipomas should be removed under controlled conditions by a skilled surgeon to ensure proper dissection. 

Variants of lipomas include angiolipomas, spindle cell lipomas, and pleomorphic lipomas. All lipomas must be distinguished from liposarcomas. Therefore, tissue should be sent for histopathologic examination. Angiolipomas tend to be more painful than lipomas. They also tend to occur more often in younger individuals. Consisting of painful, well-circumscribed, subcutaneous nodules with a marked capillary component, these lesions usually affect the upper extremities and trunk.

Spindle cell lipomas [100] and pleomorphic lipomas [101] are two variants of lipomas that are easily confused with liposarcomas upon histologic examination. Both of these benign tumors have well-demarcated margins and usually occur on the back or on the posterior surface of the neck and shoulders. Histologically, these lesions contain mature lipocytes within a mucinous background. In spindle cell lipomas, the lesion also contains fibroblast-like spindle cells that are associated with bundles of collagen. In contrast, pleomorphic lipomas contain multi-nucleated giant cells associated with the bundles of collagen.

Liposarcoma

Clinical presentation

Liposarcomas usually manifest in the fifth to seventh decades of life. However, case reports have been published that describe liposarcomas in the pediatric population. [102]

These tumors manifest clinically on the proximal upper and lower extremities or within the retroperitoneum. Liposarcomas often grow very large and can exhibit a variety of histologic variants, including well-differentiated, myxoid, round cell, and pleomorphic. The well-differentiated subtype contains lipocytes and appears histologically similar to lipomas. The other subtypes contain cells (lipoblasts) that have a more primitive differentiation, resembling fetal fat cells with characteristic lipid-containing vacuoles that abut the nucleus. The most common variant is the myxoid subtype, which is histologically characterized by the presence of stellate mesenchymal cells with a sparse amount of lipoblasts. Clinically, the round cell and pleomorphic variants are more aggressive than the well-differentiated and myxoid subtypes; therefore, they are associated with a worse prognosis and have a tendency to recur after surgical excision.

Pathogenesis

Of all the subtypes, the best-characterized is the myxoid variant. Crozat and colleagues identified a characteristic balanced chromosomal translocation creating the TLS-CHOP fusion protein. [103] The exact function and role of this fusion protein in actual tumorigenesis remains a mystery. 

Treatment

The surgical treatment for liposarcoma entails excision and, if possible, resection with wide margins, depending on anatomic constraints. [104, 105]

Radiation therapy and chemotherapy as adjuvant treatments have been proposed and attempted on individual patients, but they have not been studied rigorously in clinical trials. [106, 107]  Radiotherapy for liposarcoma of the vulva was reported effective by Yokouchi in 2000. [108] Randomized trials need to be performed to define the specific role of radiation.

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Adnexal Tumors

Although often classified together as sweat glands, the apocrine and eccrine glands are two distinct types of glands, differing in embryologic origin and function. Apocrine glands are derived from the pilosebaceous follicles, which also include the hair follicles and the sebaceous glands. In contrast, the eccrine glands are considered the true sweat glands. This section focuses on tumors of the sebaceous, apocrine, and eccrine glands.

Sebaceous gland tumors

Sebaceous gland tumors can vary from the benign (hyperplasia of the sebaceous gland) to the malignant (sebaceous carcinoma). Hyperplasia of the sebaceous gland often manifests in elderly persons and can be clinically mistaken for BCC.

Sebaceous hyperplasia

Sebaceous hyperplasia is a very common finding in Caucasians over age 50 years, particularly in those who have rosacea. It appears as yellow papules. Sebaceous hyperplasia can resemble BCC, fibrous papules, milia, and closed comedones. Treatment can be effected with trichloroacetic acid 20-30% or with curette and light electrodesiccation.

Benign sebaceous adenoma

Benign sebaceous adenomas are rare benign tumors. [109] Histologically, these lesions resemble sebaceous glands, and they must be distinguished from sebaceous hyperplasia. In contrast to the normal sebaceous gland, sebaceous adenomas contain lobular patterns that are irregular (see image below). In addition, the adenomas contain dark-staining basaloid cells, which surround lipid-containing cells that are smaller than the cells in the normal sebaceous gland. Surgical excision without wide margins is curative, and recurrence is extraordinarily rare.

Sebaceous Adenoma Sebaceous Adenoma

Sebaceoma

Troy and Ackerman defined the term sebaceoma as a benign neoplasm of basaloid cells with varying numbers of mature sebocytes. [110]

Carcinoma of the sebaceous gland

Clinical presentation and pathogenesis

Carcinomas of the sebaceous gland are rare malignant tumors that usually occur in the sebaceous glands of the eyelids, but they can also arise elsewhere on the head and neck. [111, 112] Case reports have described sebaceous carcinomas on the vulva. [113, 114]

This lesion is composed of lipid-containing cells that appear foamy and pale. Sudan IV staining confirms the presence of lipids in these foamy cells. The nuclei are pleomorphic and hyperchromatic. If the tumor is well differentiated, the lesion may contain a peripheral layer of dark-staining basaloid cells, resembling BCCs. The tumor typically spreads by direct extension.

Treatment

To minimize local recurrence, Snow and colleagues advocate Mohs surgery, especially in persons with evidence of intraepithelial spread. [115]

In addition, Cook and colleagues recommend conjunctival map biopsies, to assess whether or not the lesion has extended into the conjunctiva. [116]

The metastatic potential for sebaceous carcinoma is greatest when it occurs on the eyelids. The existence of sebaceous adenoma or carcinoma should raise the possibility of Muir-Torre syndrome, which can also be related to tumors of the intestines.

Local radiation treatment may be an alternative treatment, especially for patients who do not want surgery. [117]

Apocrine gland tumors

Hidradenoma papilliferum

Hidradenoma papilliferum is a benign adenoma of the apocrine gland that occurs in the vulva and perineum of adult women. This lesion is a benign papillary tumor with cystic characteristics. Although considered a skin lesion of the anogenital region in women, case reports have described these adenomas outside the anogenital region in both sexes. The nonanogenital growths have been termed ectopic hidradenoma papilliferums and occur frequently (60%) in the head and neck region. [118] Simple surgical excision is definitive treatment. [118, 119]

Apocrine adenocarcinoma (extramammary Paget disease)

Clinical presentation

Paget disease commonly refers to the malignant infiltration of breast cancer (typically ductal carcinoma) into the apocrine glands of the areola of the nipple. Extramammary Paget disease is a rare tumor that occurs in the anogenital region that is often, but not necessarily always, associated with adenocarcinoma of the apocrine gland. [120] Cases have been reported that demonstrate Paget disease arising from transitional cell carcinoma of the bladder, adenocarcinoma of the rectum, and squamous carcinoma of the cervix.

Histologically, the thickened epidermis is infiltrated by Paget cells, which are large pale cells with clear cytoplasm. If the cells are derived from mucin-secreting epithelium, then staining with Alcian blue dye can reveal the deposition of mucin within the cytoplasm. This presence of mucin is diagnostically important. In contrast, in extramammary Paget disease from SCC, mucin is absent and is not a distinguishing factor. Therefore, diagnostic difficulties arise because of the complexity in distinguishing atypical melanocytic hyperplasia from squamous carcinoma in situ. [121, 122] Definitive diagnosis requires immunohistochemical staining of the biopsy sample.

Treatment

For minimally invasive extramammary Paget disease, treatment options include surgical excision with clear margins or Mohs microscopy surgery. [123, 120]  Vigilance is needed after removal of the lesion due to high rates of recurrence.

Eccrine gland tumors

The nomenclature used to describe and distinguish between apocrine and eccrine tumors is confusing. Fortunately, histologic examination reveals the distinctive feature of sweat duct (eccrine) tumors: the double layer of epithelium. [121] Benign eccrine gland tumors include syringoma and eccrine poroma.

Syringoma

Syringomas occur around the eyes, axilla, or anogenital region. This distribution pattern is similar to apocrine tumors. [124] This tumor is a benign hamartomatous lesion. The presence of succinic dehydrogenases and phosphorylases provides evidence that this lesion is of eccrine origin. Syringomas can occur as solitary or multiple lesions. [125] Removal of these lesions has had variable results. [126] In a case report, Belardi and colleagues used cryotherapy as a successful treatment to remove multiple, painful syringomas. [124] Syringomas are associated with Down syndrome.

Eccrine poroma

Eccrine poroma is a benign tumor that typically occurs on the palms and soles. [127] This lesion is superficial and arises within the epidermis, with sharply demarcated borders. As the lesion develops, the tumor grows into the dermis layer. Upon histologic examination, the lesion contains small, pale cells with oval-shaped, centrally-located nuclei. The pale-staining aspect of these cells distinguishes them from the dark-staining cells of BCC. Other evidence suggests that some of these lesions may actually be derived from the apocrine gland rather than the eccrine gland. [128] The preferred treatment is surgical excision. [129] Although extraordinarily rare, the malignant variant (eccrine porocarcinoma) does occur. The eccrine poroma is sometimes friable and resembles a pyogenic granuloma.

Eccrine carcinomas

Primary eccrine carcinomas are rare malignant tumors with variable histologic forms, including eccrine porocarcinoma, clear cell carcinoma, and mucinous carcinoma. [130] All these tumors have the capacity to metastasize to skin and regional lymph nodes.

Eccrine porocarcinoma is the malignant variant of eccrine poroma. [131] The lesion is characterized histologically by intradermal islands of anaplastic cells bordered by acanthotic epidermis. As the tumor progresses, these anaplastic cells invade the dermal layer. The traditional treatment for eccrine porocarcinoma is wide local excision. Alternatively, Wittenberg and colleagues have demonstrated that Mohs micrographic surgery is effective, with no local recurrence in a limited number of patients. [132] For metastatic lesions, Barzi and colleagues used the combination of isotretinoin and interferon alfa as a chemotherapy regimen, with moderate success. [133]

Clear cell eccrine carcinomas consist of cells with clear cytoplasm and prominent round or oval hyperchromatic nuclei. [134] The abundance of glycogen contributes to the distinctive cytoplasm. Case reports demonstrate difficulties in treating clear cell eccrine carcinomas because of frequent local recurrences. [135] In addition, chemotherapy has been ineffective against metastatic disease.

Mucinous carcinoma typically develops on the eyelids. [136, 137] The tumor contains clusters of small, dark basophilic cells with eosinophilic cytoplasm surrounded by pools of mucin. This lesion often appears as a poorly-differentiated infiltrating tumor with similarities to anaplastic squamous carcinoma. Traditional treatment is excisional biopsy, but definitive treatment is difficult and is complicated by the high rate of local recurrence. [138, 139]

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Pilomatrical Neoplasms

Pilomatricoma and pilomatrical carcinoma

The classic features of a benign pilomatricoma—pleomorphic basaloid cells accompanied by central areas with keratotic material, shadow or ghost cells, and zones of necrosis with surrounding stromal desmoplasia—suggest a carcinoma rather than a benign neoplasm. 

Features of pilomatrical carcinoma, which are more fulminant and exuberant than those of pilomatricoma, include asymmetry, poor circumscription, large and variably-shaped aggregations of pleomorphic basaloid cells, basaloid cells with vesicular nuclei and prominent nucleoli, atypical mitotic figures, extensive areas of necrosis, ulceration, and infiltrative growth patterns. No single feature is diagnostic of pilomatrical carcinoma and immunohistochemistry does not distinguish benign from malignant pilomatrical neoplasias. 

Pilomatricomal carcinoma has most often been treated with wide surgical excision, although Mohs micrographic surgery has reportedly been effective. Radiation therapy may have a role in the palliation of metastatic pilomatrical carcinoma, which is usually fatal. [140]  (Text reproduced with permission from the Dermatology Online Journal.)

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