Malignant Growths

Adnexal Carcinoma

Adnexal carcinomas are a diverse group of malignant skin tumors that are derived from the various components of the skin appendageal structures. These tumors are extremely rare and comprise well less than 1% of all skin cancers diagnosed annually. They are difficult to diagnosis clinically because they can all mimic the more common types of skin cancer, particularly basal cell carcinoma and squamous cell carcinoma. They can be diagnosed with certainty only after histological examination. These tumors are believed to be derived from hair follicle, sebaceous gland, apocrine gland, or eccrine gland epithelium. They are thought to arise de novo and can also arise from a preexisting benign precursor. An example is an eccrine porocarcinoma developing within an eccrine poroma.

Clinical Findings: These tumors are very rare, and one is unlikely to consider them in the differential diagnosis when evaluating an individual with an undiagnosed skin growth. There are few clues to their origin, which makes diagnosis of these cancerous tumors almost impossible based on clinical findings alone. Most manifest as a solitary papule, plaque, or dermal nodule. Most are asymptomatic, but pruritus, bleeding, and pain may be present.

The diagnosis of these tumors requires tissue sampling. A punch or excisional biopsy is the best method to biopsy these lesions, because it allows the pathologist to get a large enough piece of tissue to evaluate. A punch biopsy is especially important to help differentiate microcystic adnexal carcinoma from a benign syringoma. The latter is very superficial in nature, whereas the microcystic adnexal carcinoma displays a deep infiltrative growth pattern that will not be appreciated with a superficial shave biopsy.

Pathogenesis: The pathogenesis of these tumors is poorly understood. In contrast to basal and squamous cell carcinomas, they are unlikely to be caused by ultraviolet light exposure. The rarity of the tumors makes them difficult to study. There appears to be no genetic inheritance to these malignant tumors, with the lone exception of the sebaceous carcinoma. Sebaceous carcinoma can be seen in the Muir-Torre syndrome, which is inherited in an autosomal dominant pattern.

Histology: Each tumor is unique histologically. The tumors can be subdivided according to the type of epithelium from which they are derived: sebaceous, hair follicle, eccrine, or apocrine. The pathologist is able to differentiate these tumors based on certain criteria. The tumors show varying amounts of cellular atypia and an invasive growth pattern. They are usually poorly circumscribed with varying amounts of mitotic figures, necrosis, and abnormal-appearing cells. Various gland-like structures can be seen in some tumors, which can be helpful in making the diagnosis. Often, special immunohistochemical stains are used to help differentiate the subtypes of these tumors.

Treatment: These tumors should all be surgically excised with clear surgical margins. The Mohs surgical technique has been used successfully to treat these tumors, as has a standard wide local excision. Sentinel node removal and evaluation is not routinely performed, but some clinicians advocate its use, especially in some of the more aggressive subtypes such as the eccrine porocarcinoma. Sentinel node removal and evaluation has not shown any survival benefit to date. Mohs surgery may lead to a decrease in recurrence rate and is tissue sparing. Because of the rare nature of these tumors and the lack of prospective randomized studies, it is difficult to determine the best removal method. For the same reasons, the ultimate prognosis and the recurrence rate of these tumors are unknown. After diagnosis and removal of these tumors, the patient should have long-term follow-up to evaluate for recurrence.

Adnexal tumors that have metastasized are treated with chemotherapy with or without radiotherapy. The prognosis is poor for patients who develop metastatic adnexal carcinoma.

Angiosarcoma

Angiosarcoma is a rare, aggressive, malignant tumor of vascular or lymphatic vessels. These tumors can be seen as a solitary finding or secondary to long-standing lymphedema, such as after radiation therapy or an axillary or inguinal lymph node dissection. This latter form tends to occur years after the radiation or surgical procedure. Soft tissue sarcomas are very rare and make up a small percentage of all malignancies reported.

Clinical Findings: Angiosarcomas are most common in the older male population. They have no race predilection. The tumors most commonly arise in the head and neck region and can manifest in many fashions. They often appear as a red to purple plaque with ill-defined borders. They can often look like a bruise, and the diagnosis can be delayed. The tumor continues to expand, forms satellite foci of involvement, and eventually ulcerates and bleeds. For some reason, the scalp and face of older men are most commonly involved. The tumor has a propensity to involve sun-exposed areas of the face and scalp. The tumors typically show an aggressive growth pattern and have a tendency to metastasize early in the course of disease.

Angiosarcomas can also arise in regions of previous long-standing lymphedema caused by radiation exposure or surgical procedures. Any procedure that can result in abnormal lymphatic drainage can lead to chronic lymphedema. It is believed that long-standing lymphedema can result in the development of angiosarcoma. Common surgical procedures that cause chronic lymphedema are radical mastectomies and lymph node dissections of the axilla or groin after a diagnosis of lymph node involvement by breast cancer or melanoma. Angiosarcomas arising in areas of chronic lymphedema were first described by Stewart and Treves and have been given the eponym Stewart-Treves syndrome . This type of angiosarcoma is highly aggressive and portends a poor outcome. The Stewart-Treves type of angiosarcoma has been reported most commonly in women who have undergone radical mastectomy or lymph node dissection for treatment of breast cancer. After years of chronic lymphedema in the ipsilateral limb, the patient may develop a reddish, bruise-like area on the limb. This area slowly enlarges and develops plaque-like areas or nodules within the affected region. At this point, the diagnosis is often entertained, and the diagnosis is made with a skin biopsy. These tumors tend to be large at diagnosis, which most likely accounts for the poor prognosis.

Radiation-induced angiosarcomas may occur at the site of the radiation therapy or as a result of long-standing chronic lymphedema if the radiation therapy interrupts the lymphatic drainage. These tumors also tend to be diagnosed after they have become quite large, and this portends a poor prognosis. These tumors tend to occur 4 to 10 years after the initial radiation therapy.

Pathogenesis: Angiosarcomas are soft tissue tumors that are derived from the endothelial lining of small blood or lymphatic vessels. Some tumors are found to have elevated levels of vascular endothelial growth factor (VEGF), which is critical in the regulation of vessel growth. Other potential players in the pathogenesis of this tumor are mast cells, which cause an increase in stem cell factor; Fas and Fas ligand expression; and lack of the vascular endothelial cadherin protein. All of these factors may interact in an unknown way to induce tumorigenesis. The exact mechanism of formation of angiosarcoma is unknown. Radiation-induced angiosarcoma may result from a direct mutagenic effect of the radiation on the endothelial DNA. No relation with human herpesvirus-8 infection has been proven.

Histology: All angiosarcomas share the same pathological features. The tumor lobules are poorly circumscribed and have an infiltrative growth pattern. They contain large amounts of vascular tissue in a disorganized arrangement. The lining of the vascular spaces contains atypical-appearing endothelial cells. Mitoses are frequently encountered, as are intracytoplasmic lumina. The same tumor can contain well and poorly differentiated regions.

Treatment: The standard treatment is wide local excision with the goal of obtaining clear margins. This is usually followed by postoperative radiation therapy. The 5-year survival rate is low (15%-20%). Tumors that are metastatic or nonoperable can be treated palliatively with various chemotherapeutic regimens. The median survival time in these cases is 3 to 6 months.

Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common malignancy in humans. Its true incidence is unknown, but the number of BCCs diagnosed each year easily surpasses the number of all other malignancies combined. It is estimated to affect approximately 25% to 33% of the U.S. Caucasian population over their lifetimes. The yearly number of BCCs diagnosed is quickly approaching 1 million. BCC rarely metastasizes or causes mortality. The real crisis it presents is in the significant morbidity and cost to the health care system. The vast majority of these lesions are located on the head and neck region and are of considerable cosmetic concern. The major morbidity involved is the significant disfigurement that these locally invading tumors can inflict.

Clinical Findings: The prototypical BCC is described as a pearly red papule with telangiectasias that has a rolled border and a central dell or ulceration. They occur with highest frequency in sun-exposed areas of the skin. Most BCCs start as a small red macule or papule and slowly enlarge over months to years. Once this occurs, the tumor may be friable and may bleed easily with superficial trauma. The tumors most commonly range in size from 1 mm to 1 cm. However, neglected tumors can be enormous and have been reported to cover areas up to 60 cm ² or more. They affect males and females with equal frequency. BCCs are more common in individuals with Fitzpatrick type I skin and decrease in frequency as one moves across the skin type spectrum. Fitzpatrick type VI skin has the lowest incidence of BCC, but these individuals still can develop these tumors. BCCs occur with an increasing frequency with age. They are uncommon in childhood, with the exception of the association of childhood BCCs with the nevoid BCC syndrome (also called basal cell nevus syndrome or Gorlin's syndrome).

The tumors are most likely to occur (>80%) on the head and neck region. The trunk is the next most common area. The vermilion border, the palms and soles, and the glans theoretically should not develop BCCs because these areas are devoid of hair; however, they can be affected by direct extension from a neighboring tumor. These tumors rarely metastasize, and those that do are most often neglected large tumors or tumors in immunosuppressed patients. BCC most commonly metastasizes to regional lymph nodes and the lung.

Many clinical variants of BCC exist, including superficial, pigmented, nodular, and sclerotic or morpheaform variants. There are many other histological variants. Clinically, a superficial BCC manifests as a very slowly enlarging, pink or red patch without elevation or ulceration. If left alone for a long enough period, it will develop areas of nodularity or ulceration. Nodular BCCs are probably the most common variant; they manifest as the classic pearly papule with telangiectasias and central ulceration. The pigmented variant can mimic melanoma and is often described as a brown or black papule or plaque with or without ulceration. Early on, these types of BCCs can appear as pearly papules or plaques with minute flecks of brown or black pigmentation. Patients with the sclerotic or morpheaform version often have larger tumors at presentation because of their slow, inconspicuous growth pattern. These slow-growing tumors are almost skin colored and have ill-defined borders. They tend not to ulcerate until they have become large, and this often delays the seeking of medical advice. These tumors can mimic the appearance of scar tissue, which can also hinder making the diagnosis. Eventually, the tumor enlarges enough to cause ulceration or superficial erosions, and the diagnosis is made. The sclerotic BCC is often much larger than the other variant types at the time of diagnosis.

The most important genetic syndrome associated with the development of BCCs is the nevoid BCC syndrome. This syndrome is inherited in an autosomal dominant fashion and is caused by a defect in the patched 1 gene, PTCH1 . This gene is located on chromosome 9q22. It encodes a tumor suppressor protein that plays a role in inhibition of the sonic hedgehog signaling pathway. A defect in the patched protein allows for uncontrolled signaling of the smoothened protein and an increase in various cell signaling pathways, ultimately culminating in the development of BCCs. Patients with nevoid BCC syndrome also may have odontogenic cysts of the jaw, palmar and plantar pitting, various bony abnormalities, and calcification of the falx cerebri. Frontal bossing, mental delay, and ovarian fibromas are only a few of the associated findings that can be seen in this syndrome.

Other rare syndromes in which BCCs can be seen include xeroderma pigmentosa, Bazek's syndrome, and Rombo syndrome.

Pathogenesis: Risk factors associated with the development of BCC include cumulative exposure to ultraviolet radiation and ionizing radiation. In the past, arsenic exposure was a well-recognized cause of BCCs, and arsenic pollution is still a concern in some areas of the world. Since the advent of organ transplantation, there has been an increase in the development of skin cancers in immunosuppressed organ recipients. The incidences of BCC, squamous cell carcinoma, and melanoma are all increased in these chronically immunosuppressed patients. Mutations of various genes have also been implicated in the pathogenesis of BCCs, including PTCH1, p53 (TP53), sonic hedgehog (SHH), smoothened (SMO), and the glioma-associated oncogene homolog 1 (GLI1) . However, it is still believed that most BCCs are sporadic in nature.

The greatest amount of information is known about the pathogenesis of BCC in the nevoid BCC syndrome. The genetic defect in the PTCH1 gene allows for uncontrolled signaling of the smoothened signaling pathway. This pathway initiates uncontrolled signaling of the GLI1 transcription factors, which ultimately leads to uncontrolled cell proliferation.

Histology: Many histological subtypes have been described, and a tumor can show evidence of more than one subtype. The most common subtypes are the nodular and superficial types. These tumors arise from the basaloid cells of the follicular epithelium. The tumor always shows an attachment to the overlying epidermis. The tumor extends off the epidermis as tumor lobules. These lobules are basophilic in nature and show clefting between the basophilic cells and the surrounding stroma. The cells have a characteristic peripheral palisading appearance. The cells in the center of the tumor lobules are disorganized. The ratio of nuclear to cytoplasmic volume in the tumor cells is greatly increased. Mitoses are present, and larger tumors usually have some evidence of overlying epidermal ulceration. The tumor is contiguous and does not show skip areas. The nodular form of this tumor extends into the dermis to varying degrees, and its depth of penetration is dependent on the length of time it has been present.

The superficial type is also quite common. The tumor does not extend into the underlying dermis but appears to be hanging off the bottom edge of the epidermis. It has not yet penetrated the dermal-epidermal barrier. There are numerous other histological subtypes of BCC including micronodular, adenoid, cystic, pigmented, infiltrative, and sclerosing varieties.

Treatment: Various surgical and medical options are available, and the therapy should be based on the location and size of the tumor and the wishes of the patient. Tumors on the face are most often treated with Mohs micrographic surgery. This surgical technique allows for the highest cure rate and is tissue sparing, resulting in the smallest possible scar. It is more labor intensive than a routine elliptical excision. Most BCCs can be treated with an elliptical excision or electrodessication and curettage.

Medical therapy with imiquimod or 5-fluorouracil has also been shown to be useful in selected BCCs, usually the small, superficial type. One of the newest treatments is photodynamic therapy. It is performed by applying aminolevulinic acid to the skin tumor and then exposing the area to visible blue light. An oral inhibitor of the smoothened protein, called GDC-0449, has shown excellent results in patients with the nevoid BCC syndrome.

Bowen's Disease

Bowen's disease is a variant of cutaneous squamous cell carcinoma (SCC) in situ that occurs on non–sun-exposed regions of the body. That strict definition is not always followed, and the term Bowen's disease is often used interchangeably with squamous cell carcinoma in situ . SCC in situ is often derived from its precursor lesion, the actinic keratosis. Actinic keratosis is differentiated from SCC in situ and Bowen's disease by its lack of full-thickness keratinocyte atypia, which is the hallmark of Bowen's disease and SCC in situ.

Clinical Findings: Bowen's disease can occur on hair-bearing and non–hair-bearing skin, and the clinical appearance in various locations can be entirely different. Bowen's disease on hair-bearing skin often starts as a pink to red, well-demarcated patch with adherent scale. Women are most commonly affected, and it occurs later in life. Multiple lesions can occur, but it is far more common to see this as a solitary finding. Erythroplasia of Queyrat is a regional variant of Bowen's disease that occurs on the glans penis. These lesions tend to be glistening red with crusting. The area is often well circumscribed. The diagnosis is often delayed because the lesion is easily confused with dermatitis, psoriasis, and cutaneous fungal infections. A biopsy should be performed on any nonhealing lesion or rash in the genital region. It has been estimated that up to 5% of untreated Bowen's disease lesions will eventually develop an invasive component.

The relationship between Bowen's disease and internal malignancy has come under scrutiny; if it exists at all, it is likely a consequence of the use of arsenic in the past. Patients with a history of arsenic ingestion are at a higher risk of developing Bowen's disease and internal malignancy. Now that arsenic exposure is limited in most developed countries, the association between Bowen's disease and internal malignancy is thought to be unlikely.

Most SCCs in situ are found on sun-exposed areas of the skin and develop directly from an adjacent actinic keratosis. Some SCCs in situ eventually develop into an invasive form of SCC. This is clinically evident by increased thickness, bleeding, and pain associated with the lesion.

Pathogenesis: Exposure to arsenic and other carcinogens has been implicated in the development of Bowen's disease. Certainly, ultraviolet radiation and other forms of radiation play a role in the its pathogenesis. Human papillomavirus (HPV) has been implicated in causing many forms of SCC. The oncogenic viral types 16, 18, 31, and 33 are notorious for causing mutagenesis and malignancy in cervical and some other genital SCCs. HPV vaccines may decrease the incidence of these tumors dramatically in the future. HPV can cause cellular transformations to occur and is directly responsible for tumorigenesis.

Histology: Bowen's disease shows full-thickness atypia of the keratinocytes within the epidermis. No dermal invasion is present. The underlying dermis may show a lymphocytic perivascular infiltrate. The atypia of the keratinocytes extends down to involve the hair follicle epithelium, and care must be taken when evaluating these lesions histologically not to mistake this finding for dermal invasion. Various amounts of cellular atypia are present.

Treatment: Treatments can be divided into surgical and nonsurgical forms. The choice depends on various factors, most importantly the location and size of the lesion. Some tumors are best treated surgically, whereas others are best treated medically.

Simple excision or electrodessication and curettage are highly effective treatments. Cryotherapy is another destructive method that can be selectively used with good success. Medical therapies include the application of 5-fluorouracil, imiquimod, or 5-aminolevulinic acid followed by exposure to blue light. These all have been reported to be successful. The risk of recurrence is between 3% and 10% depending on the type of therapy used.