Merkel Cell Carcinoma and Rare Appendageal Tumors

Updated: Mar 28, 2017
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Gregory Gary Caputy, MD, PhD, FICS  more...
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Overview

Overview

Cutaneous tumors encompass a vast array of malignancies, from neuroendocrine to lymphoid. In addition to primary malignancies, the skin can also be a major site for metastases of internal cancers. The treatment and diagnosis of many cutaneous tumors is continually changing, and the role of clinicians (eg, primary care physicians, dermatologists, plastic surgeons, pathologists) focuses on an 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, the paradigm of comprehension depends on identifying the cell or cell layer of origin. The origin of cutaneous tumors can be simplistically divided into 3 major categories: epidermal, dermal, and adnexal (see image below).

Skin malignancies, Merkel cell carcinoma and rare Skin malignancies, Merkel cell carcinoma and rare appendageal tumors. Schematic depiction of layers of the skin.

See Nonmelanoma Skin Cancers You Need to Know, a Critical Images slideshow, to help correctly identify these lesions.

Fields et al reviewed 500 patients with Merkel cell carcinoma in a single-institution study. The median age at diagnosis was 71 years. The 5-year overall survival rate was 56%, with about half dying from other causes. The disease-specific death rate was 30%. [4]

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Tumors of the Epidermis

Benign Tumors of the Epidermis

Clear cell acanthoma of Degos

One of the most common benign epithelial tumors is seborrheic keratosis/senile keratosis, which is a hereditary lesion that appears in persons aged more than 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 in the lower extremities. It is usually pink or red-brown and is described as glistening. [5]

Clear cell acanthomas usually range in size from 3-20 mm, and they tend to have a little moat or collarette of scale (also called a wafer-like crusty scale) around the edges. Peeling this scale can elicit droplets of blood. Scheinfeld noted that clear cell acanthomas can be brown. [6]

Case reports in the literature report clear cell acanthomas with multiple lesions, (ie, polypoid clear cell acanthoma). [7, 8] Upon histologic examination, the epidermis is abruptly interrupted with acanthotic epidermis. In fact, histologically, it resembles psoriasis. The sharp demarcation of the borders of a clear cell acanthoma distinguishes clear cell acanthoma from psoriasis.

The cells within the acanthotic epidermis stain faintly because of the overload of glycogen content in the keratinocytes. Electron microscopic studies demonstrate that these defective keratinocytes also contain defects in mitochondria and nuclear structures. [7]

Their cells are translucent because of the presence of glycogen, which can be demonstrated by a periodic acid-Schiff (PAS) stain (and eliminated with diastase) or electron microscopy.

The acanthotic epidermis can also contain dendritic melanocytes, which contain melanin granules 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. [9]

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

Pseudotumors

Keratoacanthoma

Clinical presentation

Keratoacanthomas (KAs; ie, self-healing squamous cell carcinoma [SCC]) are benign cutaneous neoplasms, usually solitary, that occur in elderly patients who are frequently exposed to the sun; they often manifest on the face (see image below). The spontaneous involution and eventual disappearance of this lesion within months characterizes the self-healing nature of keratoacanthomas. A study by Wagner et al indicated that KA of the lip arises from the outer root sheath cells of hair follicles, especially the cells associated with the upper outer root sheath. [10]

Keratoacanthoma. Keratoacanthoma.

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.

Nodular melanoma can mimic KAs. [11]

Keratoacanthoma lesions can easily be mistaken for SCC. Clinically, the sudden onset and rapid growth are the distinguishing features of keratoacanthoma. SCCs display a more indolent growth rate.

In treating KAs, surgeons face several problems, as follows:

  • Some umbilicated papules or plaques look like KAs but are actually SCCs. A biopsy is needed to define the process and, if the biopsy cannot firmly establish that the process is a KA, an excision is perhaps the preferred treatment option.
  • Hypertrophic lupus can histologically imitate SCC and, sometimes, KAs. Specimens should be read 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, KA should be treated very promptly. Mohs surgery with plastic 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 cancer.
  • KAs have been noted in multiple reports to arise in tattoos. [12, 13] Pseudoepitheliomatous hyperplasia must be distinguished from a squamous neoplasm.
  • Primary cutaneous CD30+ anaplastic large-cell lymphomas mimicking keratoacanthomas have been reported. [14]

Pathogenesis

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 keratoacanthoma. [15]

Keratoacanthomas are well-contained lesions, but case reports have shown perineural and vascular invasion. [16]

In order to distinguish between keratoacanthoma and SCC, further histologic studies can be used, including proliferating-cell nuclear antigen immunostaining. [17] In keratoacanthoma, 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, in SCC, the cells 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. [18]

Treatment

Although these lesions are self-healing, several reports have advocated a more aggressive approach for treatment.

Beham and colleagues have advocated surgical excision because of the difficulties in distinguishing between keratoacanthomas and SCCs upon gross examination. [19]

Gray and colleagues have proposed a more conservative approach, using topical 5-fluorouracil therapy to accelerate the regression phase of the keratoacanthoma without the need for diagnostic biopsy. [20] With 5-fluorouracil treatment, the keratoacanthomas 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-fluorouracil treatment.

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

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 epidermitis.

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

Premalignant fibroepithelial tumor of Pinkus

The fibroepithelial tumor of Pinkus is best considered a type of BCC. However, the distinguished dermatopathologist Leboit thinks it might be a fenestrated trichoblastoma. [21] 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. These tumors typically develop between the fourth and sixth decade of life. This tumor often appears pedunculated, resembling a fibroma.

Histologically, the tumor is composed of epithelial cells resembling basal cells surrounded with a fibrous stroma. [22] With further cellular characterization, Heenen and colleagues have demonstrated that these basallike epithelial cells have different cell cycle characteristics in comparison to normal epithelial cells. [23] This observation suggests 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, these tumors develop into an invasive basal cell epithelioma.

Malignant epithelial tumors

Basal cell carcinoma and squamous cell carcinoma

Basal cell carcinoma (BCC) and SCC comprise the majority of nonmelanoma malignant skin cancers. BCC is the most common malignant neoplasm. BCC is typically locally invasive, but it can metastasize on rare occasions. The most common primary site of metastatic BCC is the scrotum, where the rate of metastatic disease is 12%. Occurrence on the head and neck can also set the stage for the spread of BCC, but this is less common.

SCC is a malignant neoplasm arising from transformed keratinocytes. SCC has rare metastatic potential, but in patients who are immunocompromised (ie, by immunological disease or immunosuppressant medication), SCC is more aggressive and more 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. Feng reported clonal integration of a polyomavirus in human MCC, suggesting that this virus might be important in the development of this cancer. [24] Sentinel node biopsy, which is often used to stage melanoma, does not seem to be useful for staging MCC or for predicting survival. [25]

An epidemiology study from Finland of 181 cases bears out the fact that MCC is rare. [26]

Merkel cell polyomavirus (MCPyV) is unique in the 10-member family of human polyomavirus (HPyV) in that it causes cancer, in particular in the old and in the extensively immunosuppressed patient. [27]  It is found in 60-80% of specimens of Merkel cell cancer. [28, 29]

Through the Surveillance, Epidemiology, and End Results program, Miller and Rabkin have determined that the age-adjusted prevalence of MCC is 0.23 cases and 0.01 cases per 100,000 persons for white persons and black persons, respectively. [30]

The average age of onset for MCC is between the late sixth decade and early seventh decade of life. As with BCC and SCC, MCC has a higher prevalence in patients who are immunosuppressed because of organ transplants or those with HIV infection, with the median age within the fifth decade in one study. [31, 32]

Friedlaender and colleagues have observed that in organ transplant patients, the discontinuation of the immunosuppressant cyclosporine caused temporary regression of MCC metastases. [33]

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, Paget disease, adnexal carcinoma, and sarcoma. [34]

Bichakjian has noted that the incidence of MCC has tripled in the last 20 years. [35] He attributes it to increasing duration of life and has set forth guidelines for multidisciplinary management.

Clinical presentation

The physical appearance of MCC is often that of a solitary nodule or plaque with a red, violaceous color. This tumor may have an appearance similar to BCC; therefore, clinicians must ensure the 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. [36]  It can also occur on the breast. [37]

Regardless of the treatment, more than 50% of the patients develop regional lymph node metastasis; in approximately 36%, metastases are distant. [38] The most common sites for distant metastases are the brain, bone, liver, and skin. One report noted MCC metastasizing to the pancreas. [39]

Pathology

While MCPyV is the proximate cause, the etiology of MCC still requires further definition. Merkel cells are accessory cells that secrete nerve growth factors to enable cutaneous nerves to develop into nerve endings. [40] The embryological origin of Merkel cells is also controversial; initially, Merkel cells were believed to have arisen from neural crest cells. However, more recent evidence suggests that fetal Merkel cells are derived from epidermal keratinocytes. [40] Others hypothesize that the cancerous cells in MCC arise from stem cells that develop neuroendocrine properties similar to the wild-type Merkel cells. [41]

Identifying MCC with conventional histologic examinations is difficult because MCC resembles other poorly differentiated neoplasms (eg, cutaneous large cell lymphoma, amelanotic melanoma, small cell carcinoma, Ewing sarcoma). For a definitive diagnosis, electron microscopy and immunohistochemistry studies are required. [42, 43]

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. [44] In contrast, pulmonary small cell carcinomas, which grossly appear similar to MCC, lacked expression of cytokeratin-20.

Molecular basis

In MCC, karyotypic abnormalities have been identified in chromosomes 1, 11, and 13. [45] Further molecular characterization has implicated 2 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. [46, 47]

The virus MCPyV is certainly an important part of the molecular basis of MCC.

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 and thus might be a future target for chemotherapy combined with surgery. [48]

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. [49]

Treatment

The clinical workup of a patient with MCC should include chest radiographs and CT scans of the abdomen and chest. Both the chest x-ray films and the CT scans are needed to distinguish a primary MCC with metastases from a primary lung cell carcinoma with skin metastases. The abdominal CT scan is critical for staging investigations because MCC preferentially metastasizes to the liver.

Yiengpruksawan and colleagues at Memorial Sloan-Kettering Cancer Center developed the staging system for MCC. [46] Stage Ia is primary tumor only, 2 cm in size. Stage Ib is primary tumor only, larger than 2 cm. Stage II is regional node disease. Stage III is distant disease.

Because of the rarity of MCC, clinical treatment protocols for MCC have not been scrutinized and studied in randomized clinical trials. Also, no consensus on postsurgical resection treatment, ie, adjuvant chemotherapy versus adjuvant radiation therapy, has been reached in the medical literature.  

Surgical excision of MCC with negative margins is the foundation of surgical treatment. [50]  Surgical resection of the primary tumor entails wide excision with 1-3 cm of margin. [46, 51] Tai and colleagues comprehensively reviewed previously published cases of MCC and concluded that complete excision significantly improved overall survival. [36] 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 (~50%) argues strongly for regional lymphadenectomy. [38] 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. [52] 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. [36]

After surgical excision, adjuvant therapy for MCC is recommended to prevent local recurrence. The three methods of adjuvant therapy are radiation therapy, chemotherapy, and combination therapy with radiation and chemotherapy. A 17-patient series published in 2013 supported the use adjuvant radiotherapy for MCC. [53]

Because MCC is radiosensitive, radiation therapy has been shown to decrease the local recurrence rate. [54] 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. [50]  In one retrospective study, Kokoska and colleagues demonstrated that aggressive treatment of MCC with locoregional control (ie, surgical excision and regional lymphadenectomy) in combination with radiation therapy significantly improved survival rates when compared with local excision. [55] In a larger retrospective study, Tai and colleagues demonstrated that radiation therapy improved survival only when used as adjuvant therapy and not as a single, initial treatment. [36] This same study demonstrated that the ideal overall radiation dose is 41-50 Gy. Although a trial has investigated adjuvant prophylactic regional radiotherapy compared with observation in MCC stage I and radiation seems to confer benefits, this question requires further study. [56]

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. [50]  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. [57] In contrast, a small retrospective study by Kokoska et al demonstrated that chemotherapy had no survival benefit. [55] In another retrospective study, Tai and colleagues obtained similar findings. Chemotherapy was associated with a poorer outcome; however, these results are confounded by the fact that the patients had more advanced stages of disease. [58]

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 is 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. [59, 60]

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 in 88 patients in whom metastatic MCC had been histologically confirmed and in whom the disease had progressed on or after administration of chemotherapy for distant metastatic disease. The overall response rate reached 33% (29 patients), partial response was 22%, and complete response was 11%. Eight-six percent of tumor responses lasted 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. [61]

The combination of radiation and chemotherapy seems to be effective for advanced stages of MCC with local and regional involvement. [62, 63] 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. [63] The addition of radiation significantly improved the effectiveness, with a 91% partial or complete response.

Half forehead reconstruction with a single rotational scalp flap for dermatofibrosarcoma protuberans treatment.

Lyhne suggested that treatment and staging for MCC with curative intent should involve (1) excision of the primary MCC with wide margins, (2) use of the sentinel node biopsy procedure, (3) thorax and abdomen CT scanning or positron emission tomography (PET) scanning, (4) surgical bed adjuvant radiotherapy with (5) for metastatic MCC advanced disease, use of systemic palliative chemotherapy. [64]

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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 start from the fascia and extend 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 the fourth and fifth digits. [65] Contracture and flexion of the fingers at the metacarpophalangeal and proximal interphalangeal joints characterize Dupuytren contracture. PF is a polyclonal process and, thus, must be deemed to be a type of non-neoplasmic fibroblastic proliferation.

The lesion usually appears after the fifth decade of life, affecting more men than women. Dupuytren contracture (DC) is predominantly found in patients of northern European descent and is often informally termed Vikings disease. Although Dupuytren contracture seems to have a dominant inheritance pattern, the molecular etiology of the lesion remains elusive. [66, 67] Although smoking, alcoholism, and diabetes have been associated with Dupuytren contracture, no definitive causal link has been made.

Pathogenesis

PF is a disease that involves 2 distinct fibrotic elements, a nodule and a cord. The actual pathogenesis of Dupuytren contractures 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. [68] In rare instances, these types of nodules may develop in the plantar fascia.

In plantar fibromatosis, the nodules often grow more rapidly and larger. [69] However, these nodules have less collagen deposition compared with PF 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 Dupuytren contracture. The genes involved in the transforming growth factor pathways are known to mediate proliferation in fibroblasts and are obvious molecular candidates that could be involved. However, recent studies have demonstrated no association between the transforming growth factor genes and Dupuytren contracture. [67, 66]

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. [70]

The knuckle pad is a manifestation of PF. PF can occur in children in its many forms.

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 a treatment for injection into DC that was approved by the FDA in February of 2010 and in the EU in 2011. In a 3-year study of 1,080 CCH-treated joints reported in 2013, [71] 35% recurred; of these recurrences, doctors performed an intervention in 7% of patients. In the 1,080 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 joints successfully treated, a contracture remained well beneath the threshold for surgical intervention 3 years post treatment. Recurrence rates in effectively treated joints appeared lower compared with nondurable response rates in partially corrected joints.

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. For a more detailed discussion, see Dupuytren Contracture.

Nodular fasciitis (pseudosarcomatous)

Nodular fasciitis or pseudosarcomatous lesions are benign proliferations that are often idiopathic or develop in response to trauma. [72] 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 is 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. [73]

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. [74]

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. [73] 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. [75, 76]

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. [77] All 11 of their patients had spontaneous resolution of lesions within 11 months and did not require surgical excisions.

In contrast, others have reported difficulty with the capability of cytology findings to distinguish nodular fasciitis lesions from malignant low-grade sarcomas. [78, 76] 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, the proper diagnosis of nodular fasciitis lesions can usually be identified properly with fine-needle aspiration. [73] 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, the nodular fasciitis lesions do not reappear. [79, 73, 80] 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. [81]

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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. Multiple nodules (>15) can be a sign of lupus or human immunodeficiency virus (HIV). Recent evidence of clonal growth within the lesion suggests that DFs are true neoplastic growths rather than the result of reactive processes. [82] One of the variants of DF is cellular DF, which has been reported have a local recurrence rate of 26%. [83]

DF can be diagnosed clinically because, when squeezed, they display the dimple sign. The presence of factor XIIIa in cells is thought to indicate a DF rather than a dermatofibrosarcoma protuberans (DFSP). The presence of CD34, on the other hand, is positive for DFSP and not DF. However, these immuno stains are not always foolproof.

Dermatofibrosarcoma protuberans

See the list below:

  • Clinical presentation
    • DFSP is usually a slow-growing neoplasm in the dermis that appears as a firm, indurated plaque, which can be either red or blue. [84] The DFSP typically appears on the trunk and extremities; however, case reports have shown that DFSP can occur on the scalp or the face. [85] 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. Some have stated that Mohs surgery is preferred as a treatment. DFSP rarely metastasizes.
    • DFSP should not be treated with radiation, as this can cause the neoplasm to exhibit more aggressive behavior.
  • 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 origin of the cell of DFSP remains controversial. Through tissue culture studies, Shindo and colleagues have concluded that the DFSP cells are of histocytic origin. [86] Through electron microscopic studies, other investigators have concluded DFSP cells have characteristics that resemble fibroblasts or myofibroblasts. [87, 88]
    • Although the characteristic cartwheel pattern can be used to distinguish DF from DFSP, 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. [89, 90, 91]
    • In the era of cytogenetics and molecular biology, a characteristic reciprocal translocation, t(17;22)(q22;q13), has been identified for DFSP, [92, 93] creating the fusion of collagen type I alpha 1 (COL1A1) to platelet-derived growth factor beta (PDGFB). [94] 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. [95] 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. [96] 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. [94, 97, 98]
  • 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. [99]
    • DFSP lesions smaller than 2 cm in diameter are often mistakenly identified as DFs or keloids. [100] 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. [101]
    • Originally effective for inhibiting the BCR/ABL fusion product in persons with chronic myelogenous leukemia, 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 the drug STI571 is able to inhibit proliferation of cells derived from DFSP or cells that express the COL1A1-PDGFB fusion product. [102, 103] These results are encouraging and may lead to the future use of STI571 as either neoadjuvant or adjuvant therapy for DFSP.
    • Recent reports have supported the use of imatinib mesylate. [104]
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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. [105] 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. Note that lipoma can infiltrate into muscles. The removal of such infiltration leads to bleeding and can lead to postoperative hematomas. Therefore, larger and deeper lipomas should be removed under controlled conditions by a skilled surgeon so proper surgical dissection can occur.

Variants of lipomas include angiolipomas, spindle cell lipomas, and pleomorphic lipomas. Angiolipomas tend to be more painful than lipomas. All lipomas must be distinguished from liposarcomas. Therefore, tissue should be sent for histopathological examination. In contrast to surgical excision, lipomas may be treated with liposuction.

In contrast to lipomas, angiolipomas usually occur in much younger persons, eg, adolescents. These lesions consist of painful, well-circumscribed subcutaneous nodules with a marked capillary component. They are often located along the upper extremities and trunk.

Spindle cell lipomas [106] and pleomorphic lipomas [107] are 2 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, both of these tumors contain mature lipocytes within a mucinous background. In spindle cell lipoma, the lesion also contains fibroblastlike spindle cells that are associated with bundles of collagen. In contrast, the pleomorphic lipomas contain multinucleated giant cells associated with the bundles of collagen.

Liposarcoma

See the list below:

  • Clinical presentation
    • Liposarcomas usually manifest in the fifth to seventh decade of life. However, case reports have been published that describe liposarcomas in the pediatric population. [108]
    • These tumors manifest clinically on the proximal lower and upper extremities or within the retroperitoneum. Liposarcomas often grow very large.
    • Liposarcomas 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 myxoid and well-differentiated 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 subtype is the myxoid variant.
    • Crozat and colleagues identified a characteristic balanced chromosomal translocation, creating the TLS-CHOP fusion protein. [109] 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. [110, 111]
    • 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. [112, 113]
    • Radiotherapy for liposarcoma of the vulva was reported effective by Yokouchi in 2000. [114] Randomized trials need to be performed to define the role of radiation.
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Adnexal Tumors

Anatomy

Although often classified together as sweat glands, the apocrine and eccrine glands are 2 distinctive types of glands, differing in embryological 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 white persons aged more than 50 years, particularly in those who have rosacea. It appears as yellow papules. Sebaceous hyperplasia can resemble basal cell carcinoma, 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. [115] Histologically, these lesions resemble sebaceous glands, and they must be distinguished from sebaceous gland hyperplasia, especially with limited tissue specimens from small biopsy samples. 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. [116] Steffen and Ackerman illustrated many examples of sebaceoma. [117]

Carcinoma of the sebaceous gland

See the list below:

  • Clinical presentation
    • Carcinomas of the sebaceous gland are rare malignant tumors that usually occur in the sebaceous glands of the eyelids, but they can also occur in the head and neck. [118, 119] Case reports have described sebaceous carcinomas located in the vulva. [120, 121]
    • 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
    • Snow and colleagues advocate Mohs microscopy surgery. [122] To minimize local recurrence, this study suggests the removal of an additional layer via Mohs surgery, especially in persons with evidence of intraepithelial spread.
    • Cook and colleagues also recommend conjunctival map biopsies to assess whether or not the lesion has extended into the conjunctiva. [123]
    • 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. [124]

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 lesions outside the anogenital region in both sexes. These nonanogenital hidradenoma papilliferum have been termed ectopic hidradenoma papilliferum and occur frequently (60%) in the head and neck region. [125] Simple surgical excision is definitive treatment. [125, 126]

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. [127] 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. [128, 129] 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. [130, 127]
    • Vigilance is needed after removal of the lesion because it has a high rate of recurrence.

Eccrine Gland Tumors

The terminology and 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. [128] 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. [131] 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. [132] Removal of these lesions has had variable results. [133] In a case report, Belardi and colleagues used cryotherapy as a successful treatment to remove multiple, painful syringomas. [131] Syringomas are associated with Down syndrome.

Eccrine poroma

Eccrine poroma is a benign tumor that typically occurs on the palms and soles. [134] 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. [135] The preferred treatment is surgical excision. [136] Although extraordinarily rare, the malignant variant (eccrine porocarcinoma) does occur. The eccrine poroma is sometimes friable and resembles a pyogenic granuloma.

Eccrine carcinoma

Primary eccrine carcinomas are rare malignant tumors with variable histologic forms, including eccrine porocarcinoma, clear cell carcinoma, and mucinous carcinoma. [137] All these tumors have the capacity to metastasize to skin and regional lymph nodes.

Eccrine porocarcinoma is the malignant variant of eccrine poroma. [138] 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. [139] For metastatic lesions, Barzi and colleagues used the combination of isotretinoin and interferon-alfa as a chemotherapy regimen, with moderate success. [140]

Clear cell eccrine carcinomas consist of cells with clear cytoplasm and prominent round or oval hyperchromatic nuclei. [141] The abundance of glycogen contributes to the distinctive cytoplasm. Case reports demonstrate difficulties in treating clear cell eccrine carcinomas because of frequent local recurrences. [142] In addition, chemotherapy has been ineffective against metastatic disease.

Mucinous carcinoma typically develops on the eyelids. [143, 144] 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. [145, 146]

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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. Perforating pilomatricoma manifesting as an ulcer on the external ear's helix was noted in a 2014 report. [147]

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, very extensive areas of necrosis en masse, ulceration, and infiltrative growth patterns. No single feature is diagnostic of pilomatrical carcinoma and immunohistochemistry does not distinguish benign from malignant pilomatrical neoplasia.

Pilomatricomal carcinoma has been most often treated with wide surgical excision, although Mohs micrographic surgery has been reported effective. Radiation therapy may have a role in the palliation of metastatic pilomatrical carcinoma, which is usually fatal. [148] (Text reproduced with permission from the Dermatology Online Journal.)

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