Cutaneous Malignant Neoplasms: Introduction
Pediatric Neoplasms
Many lesions are present at birth or shortly thereafter. Some have the potential for malignant transformation later in life; other lesions may be mistaken for a malignant growth.
Dermoid cysts may be seen at birth as smooth, cystic tumors that may have both solid and cystic components. The cysts are usually attached to periosteum, are lined with keratinizing epidermis, and may contain hair and fat in addition to keratinous debris. Clinical examination most often shows tumors located in the lateral periocular or nasal areas. Because of tumor fixation to the underlying periosteum, the tumor may feel immobile when palpated. Treatment is simple excision, which may be delayed until later in childhood.
Pilomatrixoma is usually a benign subcutaneous tumor that originates from the hair matrix and may show calcification. Clinical examination usually shows the tumors as stony-hard, slow-growing, deep subcutaneous masses that develop in early childhood. Rarely, invasive malignant variants with metastases have been reported. Treatment is simple excision.
Sebaceous nevi are noted at birth as linear, raised, and tan- to yellow-colored patches on the scalp, face, or neck. The nevi may be several centimeters in size or much larger. Regression of the nevi is common until puberty, when growth of the nevi accelerates and lesions become multinodular and darker. Benign syringocystadenoma papilliferum, as well as various types of malignant neoplasms including basal cell carcinoma, squamous cell carcinoma, and adnexal tumors, may arise in adulthood. To provide optimum cosmesis and to minimize the risk of these malignant growths, patients should be treated in preadolescence with simple excision of the nevi.
Neurofibroma may appear singly or may be multiple in von Recklinghausen disease or NF-1 (ie, neurofibromatosis with von Recklinghausen disease) and present as soft, skin-colored nodules composed of nerve cells, mast cells, and oval- to spindle-shaped nuclei in a wavy collagen matrix. The neurofibromatous nodules are usually unencapsulated and may infiltrate fat. Café au lait spots are associated with multiple neurofibromatous lesions and are usually excised for cosmetic or functional reasons. Neurofibrosarcoma may rarely develop in syndromic patients.
In infantile myofibromatosis, single or multiple fibrous, firm nodules composed of fibroblasts and smooth muscle cells are present at birth or in early childhood. The nodules are palpable, firm, and either cutaneous or subcutaneous. Lytic lesions of the cranium may occur in as many as one-third of children, and visceral nodules are associated with the multicentric form. Visceral nodules may be confused with a malignant growth; indeed, the visceral form of infantile myofibromatosis is frequently fatal. Lesions occurring in the superficial, nonvisceral form usually resolve. Lesions compromising function should be treated with biopsy or excision.
Congenital melanocytic nevi may be seen at birth or several months later as either flat or raised brown lesions, with or without hair, and usually with areas of deeper black or blue pigment. The estimated lifetime risk of developing melanocytic lesions is roughly proportional to the size of the nevus and may be as high as 8%; because of the predictable increased risk, early full-thickness surgical excision for large nevi is advocated where technically feasible.
Benign (typical) acquired nevi begin early in childhood and are usually smaller than 5 mm. They may be flat or raised, have symmetric, smooth, and well-defined borders, and have uniform pigmentation, which may range from flesh colored to brown. Evidence supports a higher lifetime risk of cutaneous melanoma in patients who have more than 50 benign nevi.
In children, malignant skin tumors may develop sporadically or occur in precursor syndromes with associated abnormalities in other organ systems. The most common precursor syndromes for malignant cutaneous tumors in children are nevoid basal cell syndrome and xeroderma pigmentosum.
Atypical nevi (dysplastic nevus syndrome) may be familial or occur sporadically. These nevi are usually flat, but they may have a raised center; they may be dark or pigmented in a variegated distribution. The nevi increase in number over years and show histologic features, such as melanocytic atypia and hyperplasia.
Patients with atypical nevi have an increased risk for either the familial or the nonfamilial forms of cutaneous melanoma; this risk is related both to a large number of nevi and to a family history of cutaneous melanoma. Individuals without a family history of melanoma have a 184-fold increased risk for the familial form of melanoma, whereas individuals with a family history of melanoma have a 500-fold increased risk of the disease. The estimated risk for the sporadic form of melanoma is related to the number of dysplastic nevi: a 12-fold increase in risk is estimated for individuals who have more than 10 dysplastic nevi.
Among patients with nevoid basal cell carcinoma syndrome, inactivation of the “patched” PTC tumor suppressor gene has been found in both the sporadic and the autosomal-dominant familial forms. Multiple areas of nevoid basal cell carcinoma may develop before the patient reaches 20 years of age. Clinically, in addition to having many basal cell nevi, patients may present with frontal bossing, mandibular cysts, palmar pits, calcified falx cerebri, and one or more skeletal abnormalities. Treatment for small, well-defined areas of basal cell carcinoma is simple excision; treatment is Mohs micrographic excision for recurrent or poorly defined lesions, or lesions located in anatomic areas at high risk for malignant disease.
Xeroderma pigmentosum syndrome is inherited as an autosomal-recessive trait in which defects are discovered during the repair of sun-induced DNA damage. Seven genes have been implicated in xeroderma pigmentosum, which manifests in a variety of phenotypes, depending on the specific patterns of mutation. Basal cell carcinoma, squamous cell carcinoma, and cutaneous melanoma may develop in large numbers (preceded by xeroderma pigmentosum) at an early age and in a general anatomic distribution similar to sporadic cases in adults. Clinically, children affected by xeroderma pigmentosum (1) have an onset of extensive freckling early in childhood, (2) are extremely photosensitive, and (3) have an estimated 2000-fold increase in basal cell carcinoma, squamous cell carcinoma, and cutaneous melanoma. These conditions in children occur most commonly on the face, head, and neck; squamous cell carcinoma occurs with notable frequency at the tongue tip. Treatment of xeroderma pigmentosum is total avoidance of the sun, a strategy that is necessary for reducing the number of new tumors.
Malignant cutaneous melanoma is rare in childhood but is more common among children who have a family history of melanoma, large congenital nevus, large or many dysplastic nevi, xeroderma pigmentosum syndrome, or a history of immunosuppression. In addition, convincing evidence indicates that the incidence of cutaneous melanoma is higher among children who have more than 50 benign melanocytic nevi. The essential aspects of clinical diagnosis are generally the same for children as for adults. Areas of pigment change, pain, or ulceration in large congenital nevi may indicate malignant change.
The overall treatment parallels adult guidelines and is based on the tumor thickness, the presence or absence of tumor ulceration, and the nodal status. However, the prognosis for cutaneous melanoma in children may be worse than in adults because a disproportionate number of nodular cutaneous melanoma cases in children are associated with a rapid vertical growth phase of the tumor.
In situ melanoma is excised with 7-mm margins or with Mohs micrographic frozen-section margins to minimize the surgical defect size. No further work-up is necessary.
Stage I primary tumors <2 mm without histologic evidence of ulceration can be excised with 1-cm margins. If ulceration is present, 2-cm margins should be used and a chest X-ray should be performed.
Stage II lesions are excised with 2-cm margins where feasible; for high-risk lesions, consideration should be given to computed tomography (CT) scanning of the neck as well as sentinel lymph node biopsy or neck dissection. Recent studies have shown benefits from using high-dose interferon alfa-2b in high-risk patients.
Stage III primary neoplasms can also be excised with 2-cm margins down to the fascia, with CT scanning performed and regional lymphatics treated surgically. The postoperative treatment should include radiation as well as high-dose interferon.
Stage IV melanoma carries an extremely poor prognosis, but an attempt should be made to control local and regional disease where possible, as well as defining the extent and the location of systemic disease in order to tailor individual treatment strategies.
The overall survival in childhood melanoma is related to the stage at presentation and generally parallels that of adults: the 5-year survival rate in Stage I disease is about 95%, with the rate dropping to 65% in Stage II and 45% in Stage III disease. There are essentially no survivors in those patients who present with systemic disease.
Subcutaneous rhabdomyosarcoma is a poorly differentiated sarcoma; the diagnosis may require immunohistochemical staining. Clinically, the tumor usually presents singly as a firm, reddish or brown, semifixed, noncompressible subcutaneous nodule that becomes enlarged and may deform local structures. These tumors are more common in females and at a mean age of 2–3 years. Currently, surgical excision is recommended where it is technically feasible. Alternatively, radiation and multidrug chemotherapy are recommended.
Adult Neoplasms
Many benign lesions of childhood (eg, nevi and vascular malformations) persist into adulthood and may undergo change or be difficult to distinguish from tumors more commonly seen in adults.
Seborrheic keratoses and chondrodermatitis helicis are the benign tumors most commonly confused with cutaneous malignant tumors. In addition, many varieties of benign skin tumors (eg, dermatofibroma and benign adnexal tumors) may be difficult to distinguish from nonmelanoma skin cancer unless a biopsy is performed.
Seborrheic keratosis is a tumor of unknown origin that is unique to adults. Histologically, it may exist in a variety of forms, all of which show hyperkeratosis, papillomatosis, and acanthosis. When the tumor is chronically irritated, whorls of squamous cells may be present with areas of keratin horn pearls and must be distinguished histologically from squamous cell carcinoma. Clinically, the lesions may be flat, raised, smooth, or verrucous and frequently appear to be “pasted” on the skin (Figure 9–1). Their color may vary from tan to black, and lesions containing pigment may mimic cutaneous melanoma. The lesions have no malignant potential. Treatment may be indicated for cosmetic reasons, and the lesions can be frozen with liquid nitrogen or removed by shave biopsy.
Chondrodermatitis nodularis helicis typically manifests as an ulcer filled with necrotic dermal debris as well as adjacent granulations with degenerative changes in cartilage. Dystrophic calcification also may be present. The lesions may be seen clinically on the auricular helix as nodules that can be quite painful and may be confused with squamous cell carcinoma. Treatment is intralesional steroid therapy or simple excision.
Cutaneous malignant lesions in adults are commonly classified as either nonmelanoma skin cancer or cutaneous melanoma. Many lesions have distinct clinical features that provide clues to the diagnosis; considerable overlap exists, however, and biopsy is almost always necessary to plan treatment. To some extent, the biopsy technique is dictated by the tentative clinical diagnosis: shave biopsy is an adequate treatment for exophytic nodules thought to be nonmelanoma skin cancer, whereas punch biopsy is necessary for flat lesions. Excisional biopsy with a 2-mm margin is preferred for pigmented lesions thought to present a high risk for cutaneous melanoma. Deep punch biopsies into subcutaneous fat in the deepest or darkest portions of the lesion also may be performed in selected lesions. Although no evidence exists showing an adverse effect of biopsy, shave biopsy in cutaneous melanoma is to be discouraged when melanoma is suspected. Moreover, wide, local excision may produce scarring that interferes with lymphatic drainage when sentinel node biopsy is later performed. An adequate amount of tissue must be obtained for processing with special stains in the event that an exact histologic diagnosis is difficult, as is frequently the case with rare or poorly differentiated nonmelanoma skin cancer. Photographs of the lesion or the biopsy defect may be valuable for identifying the exact location of the original lesion when definitive surgery is done at a later date.
Nonmelanoma skin cancer may be divided into common and rare categories. Basal cell carcinoma, the most common skin cancer, constitutes about 75% of nonmelanoma skin cancer cases; squamous cell carcinoma accounts for about 20% of cases. The remaining 5% of rare nonmelanoma skin cancer cases includes fibrohistiocytic and adnexal cancers. Basal cell carcinoma, squamous cell carcinoma, and some rare types of nonmelanoma skin cancers occur more frequently in sun-exposed areas and in light-skinned individuals with light eye and hair color; they are associated with unrepaired DNA mutations induced by UV-A and UV-B radiation. The incidence of both basal cell carcinoma and squamous cell carcinoma has steadily increased during the past several decades, and nonmelanoma skin cancer is now a clinically significant health problem and a source of morbidity. Both conditions are more common in patients exposed to ionizing radiation. Basal cell carcinoma and squamous cell carcinoma also occur more frequently in patients with HIV; patients with lymphoproliferative disorders, particularly chronic lymphocytic leukemia; and patients receiving long-term immunosuppressive drug therapy after organ transplantation.
Rare types of nonmelanoma skin cancers include fibrohistiocytic tumors, adnexal cancers, and rare cutaneous sarcoma. Special histochemical stains are frequently necessary for distinguishing varieties of nonmelanoma skin cancer, especially adnexal tumors.
Treatment of nonmelanoma skin cancer is determined by many factors, including the exact histologic subtype, the tumor size, the growth characteristics, and the anatomic location. Treatment is also determined by the previous treatment received, current medical problems, and patient expectations. Treatment options for nonmelanoma skin cancer can be categorized as nonsurgical and surgical.
Nonsurgical strategies include topical or injection chemotherapy (eg, with 5-fluorouracil [5-FU], a 5% preparation of imiquimod, or interferon), cryotherapy using liquid nitrogen, photodynamic therapy (PDT), and radiation therapy.
Topical 5% imiquimod is now widely used by dermatologists as primary treatment for actinic keratoses, superficial basal cell carcinoma, and squamous cell carcinoma in situ (Bowen disease). It may also be used for selected thin nodular basal cell carcinomas, but is not indicated for infiltrating or sclerosing basal cell carcinoma.
Cryotherapy is usually done by dermatologists or by primary care physicians. The results of this procedure are related to the skill and experience of the treating physician. The technique is especially useful for treating actinic keratoses, small nodular or superficial lesions of basal cell carcinoma, and squamous cell carcinoma in situ. Treatment is relatively inexpensive and fast but can be painful and leave dense, hypopigmented scars that may conceal deep, multifocal, persistent tumors.
PDT with 5 aminolevulinic acid or methyl aminolevulinate activated by unique light source is used to treat actinic keratoses, Bowen disease, and basal cell carcinomas (superficial and nodular types). PDT can be highly effective and cosmesis is typically superior to existing standard therapies.
Radiation therapy is used primarily in patients older than 60 years or who are not suitable candidates for surgery. Radiation therapy is also used postoperatively for aggressive tumors or where perineural spread is noted. Because this therapy is expensive and requires frequent visits over several weeks, it is often not an option for elderly patients with a limited support system. The control rates for basal cell and squamous cell carcinoma are generally reported to be greater than 90%, and the incidence of post-therapy recurrence increases with increasing tumor size. Recent use of the electron beam and more sophisticated techniques used to model treatment fields has improved cure rates and reduced the number of complications. Long-term cosmetic results may be poor, and the complications of tissue necrosis, chondritis, and osteoradionecrosis may occur. Because of the risk of a radiation-induced malignant growth that may occur later, radiation is generally not recommended as the primary treatment modality for patients younger than 50 years of age.
Surgical techniques for the treatment of nonmelanoma skin cancer include curettage and desiccation, simple or wide local excision, and Mohs micrographic surgery.
Dermatologists most often perform curettage and desiccation for small, well-defined, previously untreated areas of nodular basal cell carcinoma; this procedure is also used for some squamous cell carcinomas. The advantages of this technique are its low cost and rapidity of treatment. Its 5-year recurrence rate ranges from 10% to 20%. The disadvantages of the technique are poor cosmetic results, with hypertrophic scarring as well as multifocal tumor recurrence in the scars.
Simple excision with 5-mm margins is the appropriate treatment for most well-defined, primary nodular basal cell carcinomas; it is also recommended for low-risk squamous cell carcinoma in anatomic locations where adequate excision with primary closure can be achieved with a good cosmetic result. Five-year recurrence rates of about 10% can be expected. Simple excision is not indicated for tumors that recur after radiation or surgical treatment or for high-risk tumors (eg, sclerosing basal cell carcinoma or poorly differentiated squamous cell carcinoma). It is also not indicated for rare nonmelanoma skin cancer (eg, fibrohistiocytic or adnexal cancer).
Wide local excision generally connotes margins of 2–5 cm and is indicated primarily for (1) well-differentiated squamous cell carcinoma; (2) well-defined, large, nodular-ulcerative basal cell carcinoma; and (3) sarcomas, such as angiosarcoma and malignant fibrous histiocytoma.
Mohs micrographic surgery is a technique in which precise surgical margins are obtained by using inverted horizontal frozen sections in conjunction with tumor mapping. The bulk of the tumor is either excised or curetted, and the surrounding perimeter is excised around and deep to the tumor defect. The resulting disk of tissue is then separated into individual quadrants and is inked for orientation, producing a tumor map that is color-coded to represent the inked edges. Histotechnicians specially trained in the technique mount the sections, which are inverted and frozen at −30°C to −50°C. Thin frozen sections are obtained, showing the base in continuity with the epidermis. The slides are stained and are examined microscopically, and tumor locations are graphically noted on the map. Additional margins are then created in the same manner, but only in areas positive for a tumor. This process is repeated until all margins are negative for a neoplasm. The process may be enhanced using rapid selective stains. Some centers perform formalin-fixed horizontal sections (1) on final margins that are shown as negative by frozen section, (2) where the tumor histology is subtle, and (3) where tumor recurrence would be catastrophic. These centers convert selected tissue blocks obtained as frozen-section margins to rush paraffin–formalin fixed slides using the same inverted tissue sectioning techniques and tumor mapping to further ensure true negative final margins on difficult cases.
An advantage of Mohs micrographic surgery is its potential to achieve the highest reported control rates for nonmelanoma skin cancer while maximally conserving normal adjacent tissue. The precise surgical margin control used in Mohs micrographic surgery has largely replaced wide local excision for most nonmelanoma skin cancer; the use of an arbitrary margin size with wide local excision does not benefit the outcome for most skin cancers. The overall cure rates using Mohs micrographic surgery are 99% for primary basal cell carcinoma, 96% for recurrent basal cell carcinoma, and 98% for primary squamous cell carcinoma. Mohs micrographic surgery is the treatment of choice for sclerosing or recurrent basal cell carcinoma, large or poorly differentiated squamous cell carcinoma, and most cases of fibrohistiocytic and adnexal cancer. The disadvantages of this technique are its high cost, lack of easy availability, and long procedure time.
