MERKEL CELL CARCINOMA
MCC is a rare, aggressive, malignant solid tumor known by many other names, including trabecular cell carcinoma, neuroendocrine or primary small cell carcinoma of the skin, and anaplastic cancer of the skin. Classic clinical presentation of MCC is identical to that of numerous other benign and malignant neoplasms. Establishing a high index of suspicion is difficult because MCC is uncommon and lacks unique clinical features. Its aggressive nature makes prompt diagnosis and adequate treatment essential.
The etiology of MCC is unknown, but it is thought to be derived from the Merkel cell, a specialized, nonkeratizing epithelial cell found in the basal cell layer of the epidermis and dermis and around hair follicles.
MCC has a predilection for sun-exposed areas (e.g., head, neck, extremities), suggesting that chronic UVR exposure plays a role in etiology. MCC has been described in patients treated with PUVA and UVB phototherapy. MCC can present in unexposed areas (e.g., penis, vulva), indicating that other etiologic factors are involved. No predisposing conditions have been consistently identified; however, the incidence is higher among immunosuppressed patients. Numerous cases of spontaneous remission have been reported, presumably immune-mediated, illustrating the importance of the immune system in the development, prognosis, and treatment of MCC.
MCC tumors can be solitary or multiple and have high rates of local recurrence (25%) and regional lymph node metastases (25%–50%) (Wolff et al., 2005). MCC tumors frequently disseminate to the viscera and central nervous system, and distant metastasis occurs in 33% of cases (Wolff et al.). MCC mortality rates exceed those of melanoma (Wolff et al.).
MCC accounts for far less than 1% of all cutaneous malignancies in the United States. Each year, approximately 1,200 new cases of MCC are diagnosed, compared with 60,000 new melanoma cases and the more than 1 million new NMSC cases. The incidence of MCC tripled between 1986 and 2001.
The average age at diagnosis is 69 years; 5% of cases are diagnosed in people younger than age 50. Most MCCs occur in Caucasians; however, cases have been reported in Japanese people, but very few blacks have been diagnosed with MCC. Extensive sun exposure is a risk factor, and older white men (65 years or older) and immunosuppressed patients are at higher risk.
The prognosis is poor. Overall, 50%–75% of patients survive two years after diagnosis, and only 30%–64% survive to five years after diagnosis (Rigel et al., 2005; Wolff et al., 2005).
Pathogenesis and Etiology
The histogenesis of MCC is controversial. MCC initially was thought to arise from epidermal Merkel cells. However, most tumors arise intradermally, rarely involving the epidermis. Several cells of origin are possible, including epidermal Merkel cells, dermal Merkel cells, neural crest-derived cells, and residual epidermal stem cells. Merkel cells have been found free in the dermis and in association with terminal axons, where they probably function as slowly adapting mechanoreceptors.
The etiologic role of UVR is presumed to be caused by the higher incidence of MCC among Caucasians and the predominance of tumors on sites of maximal sun exposure. Other risk factors are immunosuppression, erythema ab igne, irradiation, congenital ectodermal dysplasia, and Cowden disease (Rigel et al., 2005).
The most common symptom of any skin cancer is a change in an existing lesion; this also is true of MCC. MCC typically presents as a solitary, firm, painless, smooth, shiny, telangiectatic, nonulcerated, fixed intracutaneous nodule that may resemble a cyst. It can be skin-colored, bluish-red, or violaceous. MCC usually is found on sun-damaged skin of the head, neck, and extremities of Caucasians older than age 50 (see Table 2-3).
MCC can resemble BCC and can appear as a cutaneous plaque. Generally, overlying skin is intact; however, superficial ulceration in larger lesions may be present. The median size of a primary MCC is 2 cm. Satellite lesions may occur; rarely, they are multifocal or disseminated (see Figure 2-17).
MCC begins as a slow-growing tumor that undergoes a period of rapid growth, prompting the patient to seek medical attention. MCC has a predilection for the periorbital area and has been reported on unexposed areas, such as the trunk and nasal and oral mucosa.
At initial diagnosis, most patients have localized disease; 76%–89% of patients have one primary skin lesion, 10%–18% of patients have nodal disease, and 1%–2% of patients have distant disease. 50%–70% of patients develop regional lymph node metastases; 30%–50% develop distant metastases. The most common sites of distant metastases are distant lymph nodes, liver, bones, brain, lungs, and skin. The site of distant metastases does not correlate with primary tumor location. About 2% of patients present with nodal or distant disease with no apparent primary skin lesion (Rigel et al., 2005; Wolff et al., 2005).
Patient Evaluation, Diagnosis, and Differential Diagnosis
The nonspecific characteristics of MCC create a lengthy differential diagnosis, including SCC, KA, amelanotic melanoma, epidermal cyst, pyogenic granuloma, adnexal tumor, and lymphoma. Diagnosis rarely is made before histopathologic evaluation. Histologic diagnosis can be difficult because MCC resembles many other widely recognized small blue cell tumors. The most challenging differentiation is between primary MCC and metastatic small cell lung cancer (SCLC). If histology confirms a diagnosis of MCC, a chest x-ray must be performed to rule out SCLC; additional studies are performed as clinically indicated.
Natural development of MCC proceeds in stepwise fashion, beginning with local disease, then regional metastasis to the lymph nodes, and finally distant metastases. MCC staging is important for determining prognosis and treatment options.
The most consistently reported adverse prognostic features are the tumor stage and tumor size. Several staging systems exist, including those created by the Memorial Sloan-Kettering Cancer Center (MSKCC, 2007); the Seattle Cancer Care Alliance (2004a); and Yiengpruksawan, Coit, Thaler, Urmacher, and Knapper (1991). See Table 2-4, 2-5, and 2-6 for system details. MSKCC staging recently changed, and both new and old stages are listed, with two- and five-year survival rates.
The staging workup should include palpation of lymph nodes, liver, and spleen; liver function tests; chest radiograph; and MRI or CT of the chest, abdomen, and pelvis to assess for dissemination to lymph nodes and viscera. Routine head CT is controversial in asymptomatic patients. Chest imaging is important because SCLC can metastasize to the skin.
Fine needle aspiration is used to assess and to confirm metastatic spread. Octreotide scans help to evaluate visceral metastases. Immunohistochemical analysis of sentinel lymph nodes (SLNs) increases sensitivity of detecting clinically occult lymph node metastases, suggesting that SLN mapping and biopsy may be useful in staging and management of MCC (Rigel et al., 2005).
MCC usually arises from the dermis, extends into the subcutis, and rarely involves the epidermis. Diagnosis by light microscopy is difficult because of the similarity between MCC and many other poorly differentiated small cell neoplasms, including SCLC, cutaneous large cell lymphoma, neuroblastoma, metastatic carcinoid, amelanotic melanoma, sweat gland carcinoma, Langerhans cell histiocytosis, and Ewing sarcoma. Sixty percent of MCCs are misdiagnosed using light microscopy alone. Ancillary techniques, such as electron microscopy and immunohistochemistry, usually are needed to make a definitive diagnosis (Rigel et al., 2005).
On light microscopy, MCC is composed of aggregates of small, closely packed cells with little cytoplasm and a high nuclear-cytoplasmic ratio throughout the dermis. It is characterized by a triad of features: a high mitotic index, apoptosis, and vesicular nuclei with inconspicuous nucleoli (Rigel et al., 2005). The epidermis usually is spared; a Grenz zone, an uninvolved area of dermis, separates the tumor from the epidermis. Commonly, lymphocytes infiltrate around the periphery. MCC tumors are classified into three cellular patterns: trabecular, intermediate, and small cell type (Rigel et al.) (see Table 2-7).
MCC exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity of intermediate filaments, including cytokeratins, distinguishes MCC from other undifferentiated tumors. Immunohistochemical detection of intermediate filaments, thyroid transcription factor-1, and neuroendocrine markers differentiate MCC from metastatic small cell cancer (Rigel et al., 2005). Definitive diagnosis requires negative reactivity for S100 (a calcium-binding protein and a marker for the immunohistochemical identification of malignant melanoma), leukocyte common antigen, and high molecular weight cytokeratins (e.g., cytokeratin 20) to rule out malignant melanoma and cutaneous lymphoma. Perinuclear dot-like staining pattern for cytokeratin 20 is specific for MCC and distinguishes it from small oat cell carcinoma (Rigel et al.).
Electron microscopy helps to confirm the diagnosis and may be essential if tumor identity is uncertain. Characteristic features that are not found in any other primary cutaneous neoplasms and are seen on electron microscopy include membrane-bound, dense-core granules 75–200 nm wide and perinuclear whorls of intermediate filaments 7–10 nm wide. These findings confirm the diagnosis of MCC (Rigel et al., 2005).
Many chromosomal abnormalities (e.g., gains, losses, rearrangements) have been detected in MCC (Rigel et al., 2005). The relationship of these genetic changes to pathogenesis is not clear. Most frequently, chromosomes 1, 11, and 13 are affected. Similar chromosome gains and losses are seen in SCLC. Structural abnormalities of chromosome 1p are seen in up to 40% of MCC cases. Suppressor gene mutations may be associated with MCC, including the loss of heterozygosity in chromosome 3p21, a region affected in many SCLCs (Rigel et al.).
Limited information is available in the literature addressing the best management of MCC. Therapy primarily is based on the presence or absence of metastases. Surgery is the primary treatment modality, with little consensus for postsurgical adjuvant treatment with RT or chemotherapy (Rigel et al., 2005). According to Garneski and Nghiem (2007), the role of adjuvant RT “is increasingly supported by observational data” (p. 166). Following excision with clear margins, adjuvant RT decreases rates of local recurrence and is associated with improved survival. Conversely, Garneski and Nghiem believe that adjuvant chemotherapy has not been shown to decrease rates of local recurrence or to increase overall survival and is associated with “significant treatment-related mortality” (p. 168). Finally, they acknowledge that the immune system plays an important role in controlling MCC, which behaves more aggressively in patients who are immunocompromised.
Most treatment guidelines recommend wide excision of the primary tumor with or without adjuvant RT. A 1–3 cm margin of surrounding normal-appearing skin should be taken and confirmed by frozen section. MMS yields more favorable results in terms of local recurrence and tissue sparing compared to wide excision (Rigel et al., 2005).
SLNB is important in the staging and treatment of MCC. Excision followed by locoregional RT or elective lymph node dissection (ELND) with wide local excision is associated with longer time to recurrence, decreased incidence of local recurrence, and possibly improved survival (Rigel et al., 2005). ELND and prophylactic RT are controversial (Tai, Yu, Tonita, & Gilchrist, 2000). Approximately 50% of patients eventually develop locoregional recurrence after resection of tumor alone (Tai et al.). ELND often is used for patients with stage I MCC. No data exist to determine if ELND prolongs survival. Some researchers suggest that ELND be used only for patients with head and neck primary sites, for tumors larger than 1.5 cm, or when histologic evidence exists of lymphatic or vascular invasion (Tai et al.).
Patients with clinically or radiographically diagnosed nodal disease should undergo therapeutic regional lymphadenectomy (Rigel et al., 2005; Tai et al., 2000). Seattle Cancer Care Alliance (2004b) recommends that all patients with stage I MCC should undergo SLNB and that regional lymphadenectomy be considered for all patients with stage II MCC. No reliable factors to determine relative risk for regional recurrence exist; all MCC patients should be considered high-risk (Rigel et al.; Tai, 2007; Tai et al.).
Sentinel Lymph Node Mapping and Selective Lymphadenectomy
Intraoperative SLN mapping and selective lymphadenectomy commonly are used for patients with melanoma (Rigel et al., 2005; Tai, 2007) and may benefit patients with MCC. This procedure has less inherent morbidity than total lymphadenectomy. The technique involves preoperative injection of radioactive sulfur colloid and radiolymphoscintigraphic localization and/or intraoperative SLN localization with vital blue dye injection (Rigel et al.). If the SLN is histologically negative, the likelihood of other residual nodal disease is low (Tai et al., 2000). If the SLN is histologically positive, a formal lymphadenectomy is required (Tai). Positive SLN is associated with higher rates of recurrence (Rigel et al.; Tai et al.). Seattle Cancer Care Alliance (2004b) recommends SLNB at the time of wide excision for all patients.
MCC is radiosensitive (Rigel et al., 2005; Tai, 2007). According to the National Comprehensive Cancer Network (NCCN, 2008), if SLNB is not performed following local excision of the primary MCC tumor, postoperative RT to the primary site, in-transit lymphatics, and draining nodal basins are recommended. If SLNB is negative, postoperative RT to the primary site only is indicated (NCCN). If SLNB is positive, postoperative RT to primary tumor site, in-transit lymphatics, and draining nodal basins, with or without therapeutic lymph node dissection, are advised (NCCN). In cases of positive SLN by immunohistochemical methods only, RT may be considered. When lymph nodes are clinically positive, in the absence of distant metastatic disease, treatment mirrors that of patients with positive SLNB.
RT to the primary tumor site after local excision is used as adjunctive therapy (Tai, 2007). RT has been advocated to decrease locoregional recurrence rates, to prolong time to progression, and to improve length of survival. RT is recommended in cases of local recurrence and regional node involvement. Postexcision RT is associated with lower rates of local or regional recurrence. Adjuvant RT is associated with a significantly higher two-year disease-free interval and fewer local recurrences at 18 months. However, adjuvant RT has not been shown to have a significant effect on overall survival (Rigel et al., 2005).
NCCN 2008 guidelines recommend using adjuvant nodal RT when SLN biopsy is not performed or when regional lymph nodes are clinically positive. Dosing schedules are similar to those used for SCC (Rigel et al., 2005; Tai 2007). For tumors with positive margins, doses should be increased. The surgical bed and the draining regional lymphatics should be irradiated, if technically possible. All regional lymphatics must be irradiated to avoid geographic misses. Research has shown that a median wait of 24 days for RT is associated with increased risk of disease progression (Tai).
RT is recommended for patients with high-risk features including tumor size larger than 2 cm, positive resection margins or tumors closely approximating the margins, angiolymphatic invasion, positive regional lymph nodes and in cases when regional lymph nodes were not pathologically staged, and immunocompromised status (e.g., HIV/AIDS, transplant recipients) (Tai, 2007).
Postoperative (Adjuvant) Chemotherapy
MCC is a chemotherapy-sensitive tumor, yet adjuvant chemotherapy for MCC has not been extensively studied. Adjuvant chemotherapy is associated with significantly worse outcomes because the patients who received it had high-risk or recurrent tumors (Tai, 2007). Whether adjuvant chemotherapy is beneficial for more advanced locoregional disease is controversial (Tai).
Chemotherapy for MCC is based on success in treating neuroendocrine carcinomas in other sites (Rigel et al., 2005). No specific MCC regimen exists; a number of chemotherapy regimens are used. Chemotherapy for recurrent and metastatic MCC is complicated in older adult patients, who tend to tolerate aggressive treatment poorly (Rigel et al.).
Most clinicians and institutions use chemotherapy with or without surgery only in cases of distant metastatic disease (Tai, 2007). The benefits of adjuvant chemotherapy have not been demonstrated in clinical trials. Generally, patients are treated according to SCLC chemotherapy regimens, most commonly with cyclophosphamide/doxorubicin/vincristine (CAV) or carboplatin/etoposide/vincristine (CEV) (Tai). No overall difference exists between CAV and CEV; both produce an overall response rate of 76% and a complete response rate of 35% (Tai). The two- and five-year survival rates after treatment with CAV/CEV are 36% and 17%, respectively (Tai). Use of etoposide with carboplatin or cisplatin may be preferable for patients with cardiac disease (Tai).
Chemotherapy with RT may provide better palliation than chemotherapy alone for patients with advanced disease (Tai, 2007). For patients with recurrent or locally advanced MCC, local excision with combined chemotherapy and RT is the treatment of choice (Tai).
Despite the conclusion of several studies that no association exists between use of adjuvant chemotherapy and survival in patients with node-positive MCC, adjuvant chemotherapy should be considered for high-risk disease (Tai, 2007). Adjuvant chemotherapy is not recommended for patients with node-negative disease. Reporting treatment results is important to help to identify optimal chemotherapy regimens (Rigel et al., 2005; Tai).
Course and Prognosis
MCC can have a variable course. Some patients with localized primary tumors have long-term control following treatment with local excision only (Tai, 2007). Most MCCs are aggressive, behaving like thick or ulcerated melanomas in their propensity for locoregional recurrence and early lymph node metastases (Rigel et al., 2005). Survival rates for MCC with nodal or systemic disease are similar to those of malignant melanoma (Tai).
Significantly favorable prognostic factors for overall survival include initial localized disease, tumor on an extremity, being female, being younger than age 65 at time of diagnosis, and absence of comorbid conditions (Rigel et al., 2005). Presence of nodal disease is the most powerful predictor of survival and distant metastasis: Median survival is 13 months with regional nodal involvement, versus 40 months without it (Tai, 2007).
Primary tumor site directly affects prognosis; truncal lesions, especially those in the vulvar or perianal areas, have the worst prognosis, possibly related to late detection (Rigel et al., 2005; Tai, 2007). MCCs on the legs have high recurrence rates because of poor blood supply and poor tolerance of high-dose irradiation in this area (Rigel et al.; Tai).
Following initial treatment, local recurrence occurs in 29%–43% of patients at a median of four months post-treatment and usually within one year of initial therapy (Tai, 2007). Following margin-negative excision, the local recurrence rate is reduced to 8% (Tai). Nodal disease and distant disease each occur in 33% of cases (Rigel et al., 2005). Patients with an initial nodal recurrence are at higher risk for developing other distant metastases than patients without nodal recurrence (Tai) (see Table 2-8).
Median overall survival is 31 months. When recurrence happens and is treated, median overall survival is 27 months (Tai, 2007). Combination therapy (i.e., surgery, RT, chemotherapy) for recurrence provides the best survival potential (Rigel et al., 2005; Tai).
After primary tumor resection, the median time to develop clinically detectable nodal recurrence is seven to eight months. 11% to 66% of patients with nodal involvement at presentation or local recurrence die of MCC within five years (Tai, 2007). Combination therapy is associated with the best outcomes following nodal recurrence (Tai).
Systemic disease is associated with particularly poor prognosis (Rigel et al., 2005; Tai, 2007). Systemic metastases develop after a mean time of 18 months after initial diagnosis. Almost half of all patients followed for two years develop systemic recurrence, and 65%–75% die from MCC (Tai).
Most recurrences and deaths from MCC occur within the first three years. Different clinicians and institutions have varying recommendations for patient follow-up. The general recommendation is that patients should have regular skin and lymph node examinations every three to six months for the first three years and then annually thereafter. Annual chest radiograph is indicated; CT scans of the chest, abdomen, or head may be needed for symptomatic patients (Tai, 2007). If recurrence is detected, a full staging workup should be performed (Tai). For patients with highrisk MCC, CT scans may be performed every six months for up to five years.
Second Primary Cancers
MCC is associated with high incidences of other skin tumors and hematologic malignancies. As many as 25% of patients with MCC had a second neoplasm, half of which are SCCs. Patients who develop second neoplasms usually have higher MCC-specific mortality rates.
Whether the medical community will gain a better understanding of MCC in the future is unclear. Despite advances in diagnosis, overall prognosis for patients with MCC is poor. Optimal treatment modalities remain poorly defined because of the lack of randomized controlled studies and the rarity of MCC (Rigel et al., 2005). Currently, wide local excision of the primary lesion remains the standard treatment for MCC (Rigel et al.). Whether SLN mapping versus ELND will improve overall patient survival remains unclear (Rigel et al.).
DFSP is a relatively uncommon soft tissue neoplasm. These tumors, referred to as cutaneous sarcomas, are nonepithelial growths that are quite invasive locally and aggressive but rarely metastasize even after recurrence.
The incidence of DFSP is very low, with only a few cases per million per year diagnosed, but it is the most common cutaneous sarcoma, accounting for about 6% of tumors in this class. DFSP most often arises in adults in their third to fifth decade and is slightly more common in males. Generally, it is regarded as a rare tumor in children; however, McKee and Fletcher (1991) reported eight cases, two of which were thought to be congenital.
A pigmented variation called the Bednar tumor is distinguished by the presence of melanin-containing cells in an otherwise typical DFSP. The pigmented variation is even less common and represents only 5% of all DFSPs (McKee & Fletcher, 1991).
Early DFSP presents as a plaque-like area of cutaneous thickening that frequently is red or violaceous at the margins. Rarely, DFSP occurs within a scar, as in the case reported by Elgart, Hanly, Busso, and Spencer (1999), where the lesion presented within the site of immunization. Appearance within a melanocytic congenital nevus also has been noted, although this is very rare. As the tumor enlarges, it becomes raised, firm, and nodular, and the surrounding skin may be telangiectatic. The nodule is fixed to the skin but moves freely over underlying structures. Later in the course of the disease, the nodule may become fixed to deeper structures. If left untreated, DFSP can achieve significant size and produce the large “protuberant nodules for which they are named” (Mendenhall & Scarborough, 2006).
Most DFSPs have an indolent growth pattern, but accelerated growth is reported during pregnancy (Parlette, Smith, Germaine, Rolfe, & Skelton, 1999) (see Figure 2-18).
These sarcomas raise additional considerations when they appear in children. In the early stages, DFSP can resemble vascular malformations; therefore, histologic confirmation is essential. The differential diagnosis of DFSP includes dermatofibroma, epidermal inclusion cyst, keloid and hypertrophic scar, malignant melanoma, and metastatic carcinoma of the skin. The most common location for DFSP is the trunk, followed by lower extremities, upper extremities, and head and neck. Often, the rarity of the condition, its slow progression, and variation in clinical appearance can lead to a delay in diagnosis.
Definitive diagnosis is made with full-thickness incisional biopsy. Identification of monomorphic benign-appearing spindle cells arranged in an irregular whorled pattern is characteristic. The mitotic rate is usually low. The early lesions may have a narrow tumor-free zone between the tumor and the epidermis. In most cases, histology is sufficient for accurate diagnosis; however, when the diagnosis is questionable, immunohistochemical staining may be needed. CD34 stains will help to differentiate DFSP from other soft tissue tumors because almost 80% of DFSP are CD34 positive. Studies suggest that staining for hyaluronate and CD44 may be useful because DFSP is strongly positive for hyaluronate but CD44 is diminished or absent (Calikoglu, Augsburger, Chavaz, Saurat, & Kaya, 2003; Haycox, Odland, Olbricht, & Piepkorn, 1997).
Because DFSP and other soft tissue sarcomas display unique chromosomal changes, polymerase chain reaction (PCR) may be used to identify the fusion transcripts of the chimeric genes. MRI may be useful in determining the depth of involvement, especially in recurrent or very large tumors, and can be useful for planning surgery or radiation therapy. Routine chest x-rays are recommended preoperatively because pulmonary metastases can occur. Chest CT scans are preferred if the tumor is advanced or of prolonged duration.
As previously stated, DFSP tumors rarely metastasize. Lymphatic or hematogenous spread is uncommon; therefore, an initial staging workup usually is unnecessary, and lymph nodes generally are assessed by palpation.
The preferred initial treatment is excision with pathologically negative margins. Even with MRI evaluation, the extent of deep invasion and extension can be difficult to appreciate clinically, which often leads to inadequate resection. The risk of recurrence is as high as 50% with simple excision. Wide local excision, although preferred, results in a recurrence rate up to 12%. As the width of optimal margins is controversial, most surgeons recommend that a 3 cm margin of uninvolved skin be taken, up to and including fascia, which can be difficult depending on the size and location of the tumor.
MMS is the treatment of choice when a skilled surgeon is available. Mapping with MMS has revealed a tentacle-like tumor beyond the 3 cm margin, leading some to recommend 5 cm margins (D’Andrea, Vozza, Brongo, Di Girolamo, & Vozza, 2001). Because the MMS is microscopically controlled, the removal of the tumor is maximized, whereas the destruction of normal skin is minimized. The benefit of MMS is supported by a study by Parker and Zitelli (1995). RT is rarely recommended for primary treatment. However, it is recommended in conjunction with surgical resection when surgical margins are close or positive and further surgery is not feasible. In these situations, RT can result in reduced recurrence rates.
Lymph node metastasis is rare; prophylactic lymph node dissection or lymph node irradiation is not necessary.
Molecularly targeted therapy with imatinib mesylate (Gleevec®, Novartis Pharmaceuticals) is a new approach to treatment (Micromedex, 2007b). This is a potent inhibitor of several tyrosine kinases including the platelet-derived growth factor receptors (McArthur et al., 2005). Imatinib is a proteintyrosine kinase inhibitor, which inhibits the Bcr-Abl tyrosine kinase. “Imatinib mesylate was one of the first selective protein kinase inhibitors developed for the treatment of chronic myelogenous leukemia” (Strebhardt & Ullrich, 2006, p. 2481).
More than 90% of DFSPs are associated with a chromosomal translocation involving the COL1A1 gene on chromosome 17 and the platelet-derived growth factor B gene on chromosome 22. Recent data show that inhibiting platelet-derived growth factor receptors can be achieved with imatinib and results in high rates of clinical response (Labropoulos, Fletcher, Oliveira, Papadopoulos, & Razis, 2005; McArthur et al., 2005; Mizutani et al., 2004). The FDA has approved imatinib for treatment of unresectable DFSP and for rare patients with advanced DFSP in whom further surgery would greatly impair function. In these cases, imatinib induces tumor regression.
Most local recurrences become evident within three years of surgery, but 25%–30% develop after five years; therefore, follow-up must be lifelong. More frequent follow-ups are recommended during the first three years after diagnosis.
KS was first described in 1872 by Hungarian dermatologist Moritz Kaposi. KS originates in the cells that normally develop into blood vessels and usually appears first in the skin. It was uncommon in the United States before the 1980s when it began to appear in HIV-infected patients. KS carries a variable clinical course ranging from minimal mucocutaneous disease to extensive organ involvement (Dezube & Groopman, 2007).
KS is linked to the presence of human herpes virus 8 (HHV-8) and not UV exposure. HHV-8 is the etiologic agent in the pathogenesis of KS, and genomic sequences have been identified by PCR in more than 90% of all types of KS lesions, suggesting a causative role. Other factors involved include aberrant cytokine expression, production of multiple angiogenic peptides, and immune dysregulation, although the specific mechanism by which HHV-8 participates in the oncogenic process is unclear (Jimenez-Acosta & Poblet, 2003).
AIDS-related KS, unlike other forms of KS, tends to have an aggressive clinical course. In patients with highly active antiretroviral therapy, the disease often has a more indolent clinical course or may regress spontaneously (Rose, Fishman, & Sparano, 2004).
The most common causes of morbidity include cosmetically disfiguring cutaneous lesions, lymphedema, and gastrointestinal involvement. Pulmonary involvement is a common cause of mortality and may be difficult to distinguish from opportunistic infections (Wolff et al., 2005).
Classification and Clinical Variants
The following are the four epidemiologic forms of KS (Wolff et al., 2005).
- Classic KS is an indolent, cutaneous, proliferative disease affecting mainly the lower extremities of older adult men of Mediterranean and Jewish origin (see Figure 2-19).
- Endemic or African KS is found in all parts of equatorial Africa and is not typically associated with immune deficiency. It presents with four clinical patterns.
Iatrogenic/organ transplant–associated KS occurs after solid organ transplantation and affects mainly patients receiving chronic immunosuppressive therapy, such as azathioprine, cyclosporine, or corticosteroids to prevent organ rejection.
AIDS-related or epidemic KS is the most common tumor arising in individuals who are HIV-positive and is considered an AIDS-defining illness by the CDC. In the United States, KS is more than 20,000 times more common in people with AIDS than in the general population and more than 300 times more common in those with AIDS than in other immunosuppressed patients (e.g., renal transplant recipients) (Casper & Corey, 2007).
- Nodular type has a fairly benign course, with a mean duration of five to eight years, and resembles classic KS.
- Florid or vegetating type has a more aggressive biologic behavior. It also is nodular but may extend deeply into the subcutaneous tissue, muscle, and bone.
- Infiltrative type has a more aggressive course with florid mucocutaneous and visceral involvement.
- Lymphadenopathic type mostly affects children and young adults. It frequently is confined to lymph nodes and viscera but also may involve the skin and mucous membranes.
KS cells are likely derived from the endothelium of the blood/lymphatic microvasculature. It is not a true malignancy but rather a widespread reactive cellular proliferation in response to angiogenic substances. KS lesions produce factors that promote their own growth as well as the growth of other cells (Wolff et al., 2005). KS is linked to the presence of HHV-8 and not UV exposure.
Natural Disease Course
Mucocutaneous lesions are usually asymptomatic and at times may ulcerate and bleed easily. Large lesions on palms or soles may impede function. Lesions on the lower extremities that are tumorous, ulcerated, or associated with significant edema may be moderately or severely painful.
Urethral or anal canal lesions can be associated with obstruction. Gastrointestinal involvement rarely causes symptoms and can occur anywhere in the gastrointestinal tract. Pulmonary KS can cause bronchospasms, intractable coughing, progressive respiratory failure, and shortness of breath (Wolff et al., 2005).
KS often begins as an ecchymotic-like macula that evolves into papules, plaques, nodules, and tumors that are violaceous, red, pink, or tan and become purple-brownish with a greenish hemosiderin halo as they age. Nearly all lesions are palpable and nonpruritic. The lesions initially may occur at sites of trauma and typically are concentrated on the lower extremities and head and neck region. Lesions may range in size from several millimeters to several centimeters in diameter. Mucous membrane involvement is common (e.g., hard and soft palate, gingiva, tongue), but conjunctival lesions are less commonly seen. Ulcerated or bulky tumor involvement may interfere with speech or mastication (Rose, Fishman, & Sparano, 2004; Wolff et al., 2005).
Lymphedema usually occurs on the lower extremities and results from confluent lesions of the lymphatics and lymph nodes. Distal edema initially may be unilateral but later becomes symmetric and involves not only the lower legs but also the genitalia and the face.
The distribution of lesions may be widespread or localized, discrete or confluent. Lesions most often are seen on the nose, penis, and extremities and appear in a linear symmetric distribution along skin tension lines. HIV-associated KS presents with early involvement of the face and widespread distribution on the trunk (Wolff et al., 2005).
The diagnosis of KS is made by clinical suspicion and histologic confirmation. A punch biopsy of the skin may be sufficient, and the findings typically include proliferation of spindle cells, prominent slit-like vascular spaces, and extravasated red blood cells (Rose et al., 2004). Other diagnostic tests may be needed to determine the extent of the disease and may include CD4 lymphocyte counts and plasma HIV viral-load studies for patients with HIV infection. Bronchoscopy may be performed to determine pulmonary involvement, and colonoscopy frequently demonstrates gastrointestinal lesions.
The goal of therapy for KS is to control the symptoms of the disease and to shrink tumors to alleviate edema, organ compromise, and psychological stress and to prevent disease progression. The choice of treatment may be influenced by the severity of the underlying HIV infection and by the presence of other complications. Local and systemic therapies are used (Habif, 2004).
Cryotherapy involves freezing the lesion with liquid nitrogen, which causes the lesion to blister, scab, and slough off. This treatment usually leaves minimal marks on fair-skinned people but may cause loss of pigmentation on darker-skinned individuals. Laser surgery may be used to treat specific lesions.
RT may be used when the lesions are large and bulky or cause pain. It is used more commonly to treat KS of the skin and oral cavity than KS of the internal organs.
Intralesional chemotherapy with anticancer drugs such as vinblastine may be used to treat individual lesions.
Topical alitretinoin (a derivative of vitamin A) was approved by the FDA in 1999 for direct application to KS lesions (MSKCC, 2007).
Systemic Chemotherapy and Biologic Therapy
If the lesions of KS involve extensive areas or internal organs or cause lymphedema, IV chemotherapy may be administered. The most commonly used drugs are liposomal doxorubicin, liposomal daunorubicin, and paclitaxel. IFN alfa may be used to inhibit some of the growth factors associated with KS and to inhibit HIV, as well.
Because the formation of new blood vessels (angiogenesis) plays an important role in the growth of many cancers, researchers are studying natural and synthetic angiogenesis inhibitors in the treatment of AIDS-associated KS. Thalidomide, which was approved by the FDA in 1998 for use in patients with leprosy and for newly diagnosed cases of multiple myeloma, is an example of one angiogenesis inhibitor being studied in this disease (MSKCC, 2007).
Course and Prognosis
Classic KS has an average length of survival of 10–15 years, and death usually occurs from unrelated causes. Secondary malignancies arise in more than 35% of cases. The mean survival in young adults with African-endemic KS is five to eight years; in young children, two to three years. Iatrogenic immunosuppression-associated KS may have a chronic or rapidly progressive course, but the KS lesions usually resolve after immunosuppressive drugs are discontinued (Wolff et al., 2005).
In HIV-associated KS, individuals with high CD4+ T-cell counts can have stable or slowly progressive disease for many years. Patients with only a few lesions, without history of opportunistic infections, and with CD4+ T-cell counts greater than 200 tend to respond better to therapy and have a better overall prognosis (Wolff et al., 2005).
Clearly, many of the risk factors for NMSC are the result of a complex combination of circumstances and are unavoidable. However, UV exposure is the simplest factor to modify and should be minimized, especially if other genetic and biologic factors exist. Educating people, especially children, to protect themselves from the carcinogenic effects of the sun, as well as artificial sources such as tanning booths, will go a long way in decreasing the number of new NMSCs in the future. As stated by Schroeder (2003), “Prevention is better than treatment.”
Fortunately, many options exist today for protecting against overexposure to the sun. Improved research and manufacturing techniques have led to significant advances in the quality of sunscreens. Several products with enhanced delivery systems and improved cosmetic elegance that physically and chemically block the penetration of the sun’s rays are available in multiple forms such as creams, lotions, and sprays.
Until recently, sunscreens primarily targeted UVB rays, but newer products, “broad-spectrum” sunscreens, protect against UVA and UVB and are the current recommendation. The American Academy of Dermatology (AAD, 2007) recommends that everyone use a sunscreen with a sun protection factor (SPF) of at least 15, regardless of racial background, skin color, tanning ability, or age. Organ transplant recipients should wear SPF 30 or greater. This number SPF reflects the protection from UVB rays only; therefore, the consumer must be aware of other components in the preparation that will protect from UVA rays such as avobenzone or titanium dioxide. Choosing the broad-spectrum product is a smarter and easier option and will ensure that adequate coverage is achieved. To help to identify quality sun protective products, the Skin Cancer Foundation established a Seal of Recommendation program in 1979 and is a respected standard for ensuring the safety and efficacy of these products.
A broad-spectrum sunscreen with SPF 15 actually absorbs 93% of the UVR, and one with SPF 30 absorbs 97% of UVR, but only if applied properly. This raises many questions about the proper use and application of these products (AAD, 2007).
Sunscreens should be applied at least 30 minutes before sun exposure and must be reapplied every two hours during exposure to maintain the same level of protection, especially when swimming. To cover an entire adult body requires one to two fluid ounces, which should be applied to all exposed surfaces, including lips, ears, back of the neck, and back of the legs. At least two coats also are recommended, and no sunscreen is “rub-proof,” so reapplication is necessary should one towel off after a swim (ACS, 2007).
Using less than the recommended amount of sunscreen affords less protection. Because most people do not apply enough sunscreen in the f irst place, the true SPF is not achieved, and, in fact, they are only receiving about 50% of the stated SPF on the package (Bech-Thomsen & Wulf, 1992).
A general rule to keep in mind and teach children is “short shadow, seek shade.” When the sun is high in the sky, directly over our heads, it casts a short shadow, demonstrating the need for protection. As the sun sets, our shadow lengthens, and the strength of the sun’s rays decreases. Leith Holloway, meteorologist and astronomer, is credited with devising this rule, which is based on a number of complicated calculations and measurements (Zerbe, 1990). This phrase is a simple tool for teaching children when the risk of burning is greatest and is especially useful for children who do not tell time. It works independently of daylight savings time, is not affected by time zones, and adjusts automatically for seasons.
Sun Protective Clothing
Clothing offers some protection from UV rays, but many factors influence its effectiveness. In general, lightweight, light-colored, and loosely woven fabrics do not offer much protection. Darker colors are slightly more protective. A plain white cotton T-shirt offers an average SPF of 7. A dark green T-shirt has an SPF closer to 10, but all clothes lose their protective ability over time.
Special fabrics containing UV absorbers are now available. They are appropriate for use by all people, not just those who have been diagnosed with skin cancer. The new standard for sun protective clothing, UPF, is similar to SPF but actually measures the protection from UVA and UVB and is a great option for people with a high risk for skin cancer. Clothes with a rating of 15–50 may be labeled as sun protective. In the case of a UPF 15, only 1/15th of the sun’s rays will penetrate that fabric. As with other clothing, these fabrics may be less effective if they become or wet or are repeatedly washed and worn. Wide-brimmed hats and hats with protective neck flaps also are available. Popular brands include Coolibar®, Sun Precautions®, and Sunday Afternoons®.
Research has shown that wearing UV protective sunglasses prevents sun damage to the eyes. Sunglasses should block 99%–100% of UVA and UVB rays. This is best accomplished by wearing sunglasses with wraparound protection. The UV absorption often is listed and should read “UV absorption up to 400 nm” which means 100% protection. Other labels may say, “Meets ANSI requirements,” which is equal to 99% protection (Schroeder, 2003). Darker lenses are not necessarily more protective as the UV protection actually comes from an invisible chemical that is applied to the lens. Ideally, all eye-wear including prescription glasses and contact lenses should protect against the entire UV spectrum (ACS, 2007).
As sunscreens improve and protection from UV light is enhanced, questions and concerns regarding the effects of sunscreen on the production of vitamin D have emerged. Many people also believe that UV light is protective against some nonskin cancers, such as prostate, colon, and breast cancers, and use this belief as an argument against the use of sunscreens. The risk of getting skin cancer is now weighed against the need for adequate amounts of vitamin D. Vitamin D is produced in the skin after UVB exposure and is necessary for calcium homeostasis and healthy bones.
The most definitive work to date on vitamin D is a recently published article by Wolpowitz and Gilchrest (2006), who looked at all aspects of this controversy. Their conclusions are based in part on the well-published data linking skin cancer with overexposure to UV light. Wolpowitz and Gilchrest stated that because “the UV action spectra for DNA damage leading to skin cancer and for vitamin D photosynthesis are virtually identical, the harmful and beneficial effects of UV irradiation are inseparable” (p. 301). However, the authors concluded that the benefits of having adequate levels of vitamin D are achievable through dietary supplementation and do not require UV exposure. Additionally, the authors call into question some of the protective qualities previously ascribed to the sun.
An aging population contributes to the increased incidence of skin cancer. Many older adult patients are unable to obtain enough sun exposure to satisfy their daily requirement of vitamin D. This is compounded by the lack of foods available to this population that are good natural sources of vitamin D.
Wolpowitz and Gilchrest (2006) concluded that 5–10 minutes of UV exposure on unprotected skin in very limited areas such as the face, neck, and hands two to three times per week is adequate to sustain sufficient levels of vitamin D for most people. For individuals with dark skin, more sun exposure may be necessary. Even when a sunscreen is used, some UV rays reach the skin. Greater skin exposure does not add to vitamin D stores but greatly increases the risk for photo aging and skin cancer.
For those older adults or homebound individuals who have limited opportunities to be outdoors, Wolpowitz and Gilchrest (2006) further recommended daily intake of two 8 oz. glasses of fortified milk or orange juice or daily supplementation of vitamin D (200–1,000 IU), which is easy to accomplish and without risk. A balance between protection from the carcinogenic effects of the sun and maintenance of necessary levels of vitamin D by the use of noncarcinogenic supplements offers a reasonable and harmless solution.
Heliocare® (Aero Pharmaceuticals), Polypodium leucotomos, a botanical from the fern family that is native to Central America, has demonstrated antioxidant and photoprotective properties. In one clinical trial, Caccialanza, Percivalle, Piccinno, and Brambilla (2007) found that Polypodium leucotomos proved to be an effective and safe method of protecting the skin from UV radiation and thus could be beneficial to the treatment of solar urticaria and polymorphous light eruption.
Reduction in Immunosuppression
Immunosuppression for solid organ transplant recipients results in a 20-fold increase in the rate of NMSC. The level of immunosuppression varies with the organ involved. Cardiac transplants require the greatest immunosuppression because of the risk of death from organ rejection. However, the overall level of immunosuppression is related directly to the formation of some premalignant lesions, such as AK and NMSC. Reducing the dosage of immunosuppressive agents may be helpful but may increase the risk of rejection of the transplanted organ. Supplementation of an oral vitamin A derivative such as acitretin has been shown to significantly reduce the formation of new NMSCs in cardiac transplant recipients (McNamara, Muir, & Galbraith, 2002). The drug often is discontinued, however, because of side effects. The skin lesions tend to reappear rapidly after discontinuation (McNamara et al.).
Individuals who are at high risk for NMSC should see their dermatologist at least once a year for a complete skin examination. In addition, careful self-examination of the skin is recommended regularly for all patients regardless of history. Early detection of most skin cancers, even melanoma, can lead to a very high cure rate with less invasive treatment and better cosmetic results (see Figure 2-20).
Although not as deadly as malignant melanoma, NMSC affects more lives annually, and the incidence is increasing in epidemic proportions. Certain subgroups of people, such as organ transplant recipients or patients with inherited conditions such as BCNS or XP, are at risk for developing large numbers of NMSCs. NMSC that develops in inherited conditions is related to DNA damage and the inability to repair that damage. Much research is being conducted in that area, including a trial of a topical preparation, TN45 liposome lotion (Dimericine®, AGI Dermatics). This lotion contains an enzyme derived from bacteria that will repair damage to DNA. The medication allows for the replacement of proteins in the cells, enabling researchers to see if it alters the cells’ repair characteristics. A study of patients with XP using TN45 liposome lotion found a decrease in the frequency of precancerous and cancerous lesions (Schroeder, 2003). The gene therapy field is continuously looking at ways to identify those people at increased risk because of defects in DNA repair genes or normal variations in gene sequence.
The use of isotretinoin, a vitamin A derivative, has been studied as an agent to help to prevent skin cancer in patients with XP. Kraemer, DiGiovanna, Moshell, Tarone, and Peck (1988) found that isotretinoin significantly reduced the number of new NMSC occurrences. Isotretinoin has many long-term side effects, as previously described. Patients with XP would have to take this medication continuously; therefore, at present, isotretinoin is not a practical treatment (Schroeder, 2003). Many other drugs are in the retinoid family, but the hope is that an equally effective, less-toxic substitute for isotretinoin will be found in the future.
The study of antioxidants to prevent damage to DNA is ongoing. A recent study by Rees et al. (2007) looked at black and green tea consumption and its effect on development of NMSC. Despite the presence of some confounding risk factors, the study supports the existence of an inverse association between tea consumption and skin cancer.
Targeted therapies represent a new approach to the treatment of cancer and can be applied in limited situations to treat skin cancers. Targeted cancer therapies interfere with cancer cell growth while preserving the normal cells in different ways and at various points during the development, growth, and spread of the cancer. Some of these drugs block the signals that tell the cells to grow and divide; others cause the cells to undergo apoptosis (cell death); and some block specific enzymes and growth factor receptors. Researchers hope that these therapies will allow for more individualized treatments that will harm fewer normal cells, reduce side effects, and improve quality of life (NCI, 2006). McArthur et al. (2005) currently are investigating the use of imatinib mesylate in the treatment of DFSP.
This chapter has been designed as an overview of the most common types of skin cancer and is by no means an exhaustive review.
Once viewed as a condition of the older adult population, the presence of skin cancer now is recognized as universal and is frequently presented to primary care providers, oncology practitioners, and other specialists. Therefore, this increased incidence challenges every provider to recognize the presence of early lesions and to refer or to treat accordingly.
The many advances in the field of dermatology have led to greater understanding of the biology of these tumors. With the development of dermoscopy, digital photography, and confocal microscopy, healthcare professionals now are able to detect and treat skin cancers at an earlier stage, which results in greater cure rates and increased longevity for many. Advances in sun protection and identification of the deleterious effects of sunbathing and tanning booth exposure should have a significant effect on the younger generation who need not suffer the severe effects that long-term sun exposure had on their parents and grandparents. Continued research into the use of chemoprevention for patients at high risk for developing numerous lesions is promising.
It is the authors’ hope that the readers will incorporate some of the elements of this chapter into their everyday practice and that they will question and not ignore the presence of certain lesions. It is imperative that all providers have a high index of suspicion and a good framework for diagnosis. The authors hope that the readers now are better prepared to address the challenge that skin lesions present to everyone and that this chapter will be a useful reference to daily practice.
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