Mark F. Hendrickson and Benjamin J. Boudreaux
DEFINITION
Squamous cell carcinoma and melanoma represent malignant transformation of specific cells in either cutaneous or noncutaneous regions of the body.
Both squamous cell carcinoma and melanoma demonstrate ability to extend locally, involve regional lymph node basins, and metastasize to distant sites.
In the upper extremity, the nail matrix is the noncutaneous location for these malignancies (FIG 1).
In 1886, Hutchinson first described subungual melanoma and initially termed it melanotic whitlow, because it often resembled an infection. Subungual melanoma is rare, accounting for only 1% to 3% of all cases of melanoma.
Critical to management of squamous cell carcinoma and melanoma of the hand and upper extremity are early diagnosis, accurate histopathologic evaluation, detailed staging, appropriate surgical, medical, and radiation management, and appropriate follow-up.
ANATOMY
Both squamous cell carcinoma and melanoma develop from different skin layers. Intact skin demonstrates histologic features of the epidermis and dermis that act as physiologic barriers to infection and malignancy.
Squamous cell carcinomas develop from epidermal keratinocyte cell layers but can develop in the nail matrix complex.
Melanoma cells derive from the dendritic cells of the epidermis; they originate from neural crest cells. These neural crest cell–derived melanocytes migrate to both cutaneous and noncutaneous locations. For the hand and upper extremity, the nail apparatus is a significant migration site. Melanomas are not always pigmented (amelanotic melanomas). However, melanomas are typically pigmented and reflect irregular color, surface, and perimeter.
PATHOGENESIS
Squamous cell carcinomas develop from epidermal keratinocyte cell layers. Risk factors include the following:
Damage from sun, heat, and wind
Severe burns and chronic ulcers
Increasing age
Immune compromise (organ transplantation and AIDS)
The typical squamous cell carcinoma lesion is a rapidly growing, firm, scaly papule or nodule that develops a central ulcer and an indurated raised border with some surrounding inflammation (FIG 2A–D).
In contrast to basal cell carcinomas, there is no pearly telangiectatic perimeter.
Major risks for melanoma include:
Personal or family history of melanoma. Patients with a history of melanoma have a 3.5% chance of developing a second melanoma.
The presence of a mole that has changed over time
Other general risk factors for skin cancer, including sun sensitivity; excessive sun exposure; immune compromise; prior basal cell or squamous cell cancers; or exposure to coal tar, pitch, arsenical compounds, x-radiation, or radium
FIG 1 • Thumb eponychial lesion treated as both an infection and mucous cyst. Histopathology demonstrated invasive squamous cell carcinoma. Treatment included amputation at the IP joint level and selective lymph node sampling.
FIG 2 • A. Radial view of invasive squamous cell carcinoma of right second MP joint area in a kidney-pancreas transplant patient. B. Dorsal view of invasive squamous cell carcinoma of right second MP joint area in a kidney-pancreas transplant patient. C. Dorsal view of invasive squamous cell carcinoma of left thumb MP joint area—web space. D. Ulnar view of invasive squamous cell carcinoma left thumb MP joint area— web space.
NATURAL HISTORY
In 2007, the American Cancer Society estimated 59,940 new cases of melanoma for both sexes, with an estimated 8110 deaths. Additionally, an estimated 48,290 cases of melanoma in situ were diagnosed.
The probability of developing melanoma from birth to death is 2.04 (1 in 49) in males and 1.38 (1 in 73) in females. Neither basal cell carcinoma nor squamous cell carcinoma is a reportable disease. Basal cell carcinoma is the most common form of skin cancer and squamous cell carcinoma is the second most common type.
For 2007, the American Cancer Society estimated more than 1 million new diagnoses of basal and squamous cell carcinomas of the skin. However, basal and squamous cell skin cancers account for less than 0.1% of patient deaths caused by all cancers.
Nail matrix and nail bed squamous cell carcinoma or melanoma account for less than 1% of respective cutaneous malignancies. The histologic features of the epidermis and dermis, including physiologic barriers, are absent in the nail complex. In the nail complex, the matrix is adherent to the underlying phalanx.
PATIENT HISTORY AND PHYSICAL FINDINGS
Patients typically present for evaluation of skin findings or after noting a change.
Change or variation in an existing lesion and the presence of other risk factors are the important components of patient history.
Changes in size, shape, or color of a skin or matrix lesion or the development of a new skin or matrix lesion over a limited time should be monitored.
Such changes over a limited time must be diagnosed by histopathology.
The lesion should be precisely characterized on physical examination. Critical findings include:
Irregularity or asymmetry
Diameter more than 6 mm
Presence of satellite lesions
Regional lymph nodes (epitrochlear and axillary) should be routinely examined in all suspected cases of squamous cell carcinoma and melanoma.
Close regional lymph node examination is required in cases of squamous cell carcinoma arising in sites of chronic ulceration or inflammation, burn scars, or sites of previous radiation therapy, especially for high-risk areas of the hand.
Melanoma and squamous cell carcinoma can metastasize. A full local, regional, and metastatic workup is necessary.
Nail matrix and nail bed squamous cell carcinoma or melanoma requires specific consideration during the physical examination.
The presence of the Hutchinson sign (extension of brownblack pigment from the nail bed, matrix, and nail plate onto the adjacent cuticle and proximal or lateral nail folds) is consistent with a subungual melanoma.
Subungual melanoma is also suspected when the nail bed contains a new or enlarging pigmented streak wider than 3 mm.
The absence of periungual pigmentation does not preclude the diagnosis of subungual melanoma.
Although there have been reports of amelanotic melanoma of the nail bed, the actual incidence is unknown and has never been reported in the literature.
IMAGING AND OTHER DIAGNOSTIC STUDIES
Radiographic evaluation with plain views can reveal bone involvement, especially for matrix lesions.
For both squamous cell carcinoma and melanoma, a chest radiograph, complete blood count, and liver panel should be obtained.
More detailed imaging studies (CT, MRI, and PET) are performed to evaluate specific organ systems (central nervous system, pulmonary, gastrointestinal, and others) as indicated.
Diagnosis of these pathologies requires adequate histopathologic evaluation. Full-thickness (surface to full depth) perimeter and core samples are required. Suspicious lesions must never be shaved, cauterized, or vaporized.
If the initial surgical pathologist is uncertain of the histopathology, the specimen slides and appropriate imaging studies must be forwarded to an independent qualified pathologist for review.
There is significant discordance among pathologists in the histologic diagnosis regarding melanoma and benign pigmented lesions. One study noted discordance in 37 of 140 cases examined by a panel of experienced dermatopathologists on melanoma versus benign lesions. Another study noted a 38% discordance rate in cases examined by an expert pathologist panel.
Squamous cell carcinoma is graded 1 to 4 based on the proportion of differentiating cells present, the degree of atypicality of tumor cells, and the depth of tumor penetration.
The clinicopathologic cellular malignant melanoma subtypes are (these are descriptive, not prognostic or therapeutic):
Superficial spreading: most common, 70%
Nodular: 15% to 30%, more aggressive
Lentigo maligna: most common subtype among Asians and African-Americans
Acral lentiginous (palmar–plantar and subungual)
Miscellaneous unusual types:
Mucosal lentiginous (oral and genital)
Desmoplastic
Verrucous
Malignant melanoma microstage is determined by histopathologic evaluation of the vertical thickness of the lesion in millimeters (Breslow classification) or the anatomic level of local invasion (Clark classification).
The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm. Estimates of prognosis should be modified by sex and anatomic site in coordination with clinical and histologic evaluation.
For cutaneous melanoma, Breslow thickness and presence of ulceration demonstrated the highest concordance. Discordance was significant for Clark level of invasion, presence of regression, and lymphocytic infiltration.
The Clark classification ranges from level I (in situ lesions involving only the epidermis) to level V (invasion through the reticular dermis into the subcutaneous tissue).
Micrometastases are diagnosed by elective sentinel lymphadenectomy; macrometastases are defined as clinically detectable lymph node metastases confirmed by therapeutic lymphadenectomy, or when any lymph node metastasis exhibits gross extracapsular extension.
Clinical staging includes microstaging of the primary melanoma and clinical or radiologic (or both) evaluation for metastases. By convention, AFCC stage should be assigned after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
With the exception of clinical stage 0 or stage IA patients (who have a low risk of lymphatic involvement and do not require pathologic evaluation of the lymph nodes), pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after sentinel node biopsy and, if indicated, complete lymphadenectomy.
DIFFERENTIAL DIAGNOSIS
Seborrheic keratosis
Pigmented actinic keratosis
Hemangioma
Dermatofibroma
Blue nevus
Basal cell carcinoma
Cutaneous T-cell lymphomas (eg, mycosis fungoides)
Kaposi sarcoma
Extramammary Paget disease
Apocrine carcinoma of the skin
Metastatic malignancies from various primary sites
The differential diagnosis of subungual melanoma includes chronic paronychia and onychomycosis, subungual hematoma, pyogenic granuloma, and glomus tumor.
NONOPERATIVE MANAGEMENT
Squamous Cell Carcinoma
Electrodesiccation and curettage, and cryosurgery may be useful for small, well-defined in situ tumors in patients with medical conditions limiting excisional surgery.
Depth of treatment may not correlate with depth of tumor and therefore may be inadequate.
Cryosurgery should not be used for carcinomas fixed to the underlying bone, cartilage, or tendons.
Proximity of nerves limits cryosurgery use, such as in tumors situated on the lateral margins of the digits and at the cubital tunnel.
Cryosurgery is complicated by significant morbidity, particularly edema, which is common after treatment. Permanent depigmentation and atrophy are common.
Radiation therapy is a logical treatment choice, particularly for medically compromised patients with primary lesions requiring difficult or extensive surgery.
Radiation therapy can be used for recurrent lesions after a primary surgical removal.
Radiation therapy is contraindicated for patients with xeroderma pigmentosum, epidermodysplasia verruciformis, or the basal cell nevus syndrome.
Topical fluorouracil (5-FU) may be helpful in the management of selected in situ squamous cell carcinomas (Bowen disease).
Deep follicular tumors may not be reached by topical 5FU. In these instances, recurrence or progression can occur. Close follow-up over time is required.
Carbon dioxide laser treatment may be useful in a subset of medically compromised patients with small squamous cell carcinoma in situ.
Since the CO 2 laser coagulates, this technique is valuable for patients with a bleeding diathesis.
Malignant melanoma can spontaneously regress, but the incidence of spontaneous, complete regressions is less than 1%.
SURGICAL MANAGEMENT
The fundamental oncologic principle of tumor clearance first and then reconstruction second should be followed without compromising tumor ablation.
Lymph node management is directed by clinical involvement or selective lymph node sampling results.
Cutaneous Squamous Cell Carcinoma
Wide local excision is recommended for melanomas.
The two primary methods of treatment are surgical excision with frozen or permanent histopathologic sections and Mohs micrographic surgery.
When surgically excising these lesions, the surgeon should maintain a 3to 10-mm margin of disease-free tissue (depending on the diameter).
Surgical excision without Mohs technique, using either frozen or permanent histopathologic control, is associated with a significant recurrence rate.
FIG 3 • Chronic matrix lesion treated for 2 years with oral and topical antibiotics and antifungals. Matrix biopsy demonstrated invasive squamous cell carcinoma.
The Mohs technique to microscopically track subclinical tumor extensions results in the highest cure rate with maximal preservation of normal tissue.
Nail Matrix Squamous Cell Carcinoma
For invasive squamous cell carcinoma of the nail matrix (FIG 3), the appropriate technique is amputation at the distal joint level for that digit.
However, Mohs technique with grafting has been reported in small series of invasive squamous cell carcinoma of the nail matrix with limited follow-up.
For noninvasive nail matrix squamous cell carcinoma, Mohs technique with grafting is performed.
Cutaneous Melanoma
Melanomas of the hands and feet less than 1.5 mm thick have a low incidence of nodal metastases and are treated effectively with wide excision of the primary tumor with a 1-cm margin.
Thicker melanomas are associated with a more than 50% rate of regional or systemic failure. In the absence of metastatic disease, these individuals should undergo local excision with a 2-cm margin and intraoperative lymphatic mapping followed by lymphadenectomy if the sentinel node is positive (FIG 4A,B).
Specific recommendations are individualized for each patient. Factors that affect these recommendations include the primary tumor's anatomic location, specific tumor features, healing ability, and medical risk factors.
The surgical goal is to minimize local and regional recurrence and metastasis while maintaining acceptable risks to minimize morbidity and mortality.
Nail Matrix Melanoma
Melanomas of the nail complex (FIG 5) are unique because of the lack of the biologic barriers of skin and the proximity of the underlying phalanx and tendons.
These features cause Breslow thickness and Clark level to be less useful.
Complete digital or ray amputations of the thumb or fingers result in significant functional deficits without significant survival benefit.
The respective digit is amputated proximal to the distal interphalangeal joint of the fingers and the interphalangeal joint of the thumb if the extent of nail apparatus involvement allows.
For more proximal digital melanoma with bone involvement or perineural invasion, either complete digital amputation or ray amputation is indicated for more proximal phalangeal or metacarpal bony involvement respectively or nerve invasion.
Without bony involvement or perineural invasion, the area of wide local excision is directed by the Breslow thickness.
FIG 4 • A. Invasive melanoma treated initially with cutaneous laser ablation. B. Intraoperative invasive melanoma lesion with margins marked out and after injection of isosulfan blue. Note visible adenopathy in anterior superior axilla.
FIG 5 • Invasive matrix melanoma with delayed presentation.
Specific recommendations are individualized for each patient. Other significant factors, such as the primary tumor anatomic location, specific tumor features, healing ability, and medical risk factors, must be considered. The surgical goal is to minimize local and regional recurrence and metastasis while maintaining acceptable risks to minimize morbidity and mortality.
Coverage and Reconstruction
After wide local excision, most wounds can be closed primarily without tension using minimal perimeter undermining and layered closure.
If time is required to establish final histopathology, a temporary negative-pressure wound system can be used.
Coverage and reconstruction must match requirements at the ablation site.
The coverage options progress from less to more complex: closure, skin graft, local flap, regional flap, then microsurgically transplanted flap.
Exposed vessels, nerves, tendons, and bone often necessitate flap coverage.
Surgical flaps benefit poorly vascularized and chronic (more than 3 weeks) wounds.
Skin grafting can be either split or full thickness depending on the wound bed vascularity, anatomic area, and aesthetics.
Digital V-Y flaps, cross-finger flaps, flag flaps, dorsal metacarpal artery flaps, and radial forearm flaps are commonly used local and regional flaps.
Preoperative Planning
To direct management of local tumor, regional lymph nodes, and metastatic disease, the patient must be staged for both squamous cell carcinoma and melanoma. The histopathology of the primary tumor is determined by an accurate histopathologic diagnosis.
Mohs micrographic surgery requires the assistance of a trained dermatologist.
Before resection, plans must be made for coverage.
Positioning
Positioning is supine with the upper extremity supported on an arm table.
Positioning should allow approach to the primary tumor and the regional lymph node basin.
A sterile tourniquet is used. When access to the axillary lymph nodes is required, the tourniquet is removed.
Approach
For wide local excision, the primary lesion is marked and the indicated margin is measured around the lesion using calipers.
Wide local excision includes the intact tumor or biopsy site en bloc with a defined perimeter of normal skin and underlying subcutaneous tissue. The underlying muscular fascia is not typically included.
Inadequate, narrow excisions increase the risk of local and regional failure and affect survival.
For primary closure, an ellipse is marked out incorporating the required margins for wide local excision.
The excised length-to-lesion-diameter is at least 3:1.
For amputation, the distal joint level is marked, along with the fish-mouth dorsal and volar flaps.
For selective lymph node sampling, a grid is marked over the axillary area. The point of highest radioactivity is marked on the grid.
TECHNIQUES
MOHS MICROGRAPHIC SURGERY
Remove all gross tumor.
Excise a thin layer of tissue with 2to 3-mm margins. Flatten the specimen with the beveled peripheral skin edge positioned in the same horizontal plane with the deep margin.
Map the tissue with color-coded three-dimensional orientation.
Send the specimen for frozen-section processing.
Both the deep and peripheral margins are examined in one horizontal plane by frozen-section analysis with total (theoretically 100%) margin control.
After histologic interpretation of the frozen-section specimens, the precise anatomic location of any residual tumor is identified and re-excised until tumor-free threedimensional margins are obtained.
POSTOPERATIVE CARE
Initial postoperative care focuses on pain control and protection of the operated part.
Occupational therapy is by protocol, depending primarily on the coverage performed.
Patients must be monitored.
Squamous cell carcinoma has metastatic potential. Depending on the relative risk for recurrence and invasion, patients should be re-examined every 3 months for the first several years, then every 6 months for 3 years, and then yearly indefinitely. Evaluation is for local recurrence, lymph node involvement, metastasis, additional nonmelanoma skin cancers, and melanomas. Laboratory evaluation, blood count, and liver enzymes may be useful for monitoring particularly aggressive squamous cell tumors.
For melanoma, the follow-up schedule for patients who have surgically resected disease is based on the primary lesion's Breslow thickness and the nodal involvement. Patients with thin primary melanoma and negative nodes are followed with clinical examination for evidence of occurrence every 6 months for the first 2 to 3 years and then yearly for 2 to 3 years beyond that. Patients with intermediate or thick melanomas and negative regional nodes are followed every 3 to 6 months for the first 2 to 3 years and every 6 to 12 months for the next 2 to 3 years. Patients with resected regional disease require follow-up every 3 to 4 months for the first 2 years, then every 6 months up to year 5, and yearly beyond that. All patients must maintain routine lifelong dermatologic screening. Patients with one melanoma remain at higher-than-average risk for a second primary melanoma and are at risk for basal cell and squamous cell carcinomas.
OUTCOMES
Squamous cell carcinoma is the second most common type of skin malignancy. Although the basal cell and squamous types of skin cancer are the most common of all malignancies, they account for less than 0.1% of cancer deaths.
The overall cure rate for squamous cell carcinoma is directly related to the stage of the disease and the type of treatment used. Since squamous cell carcinoma is not a reportable disease, precise 5-year cure rates are not known.
Melanoma 5-year survival rates are related to stage and range from 18% for stage IV to 99% for stage IA.
COMPLICATIONS
Sentinel lymph node biopsy is not without complications. The most common complications are hematoma and seroma. The rate of lymphedema after sentinel lymph node biopsy has been reported to be 0.7% to 1.7%, compared with 4.6% (axillary) and 31.5% (inguinal) with completion lymphadenectomy.
Inadequate margin for squamous cell carcinoma on final pathology is corrected by re-excision using the Mohs technique.
Inadequate margin for melanoma on final pathology is corrected by appropriate increase or expansion of the surgical margins.
Excessive tension on wound closure is corrected by skin graft or appropriate flap coverage.
REFERENCES
1. Abide JM, Nahai F, Bennett RG. The meaning of surgical margins. Plast Reconstr Surg 1984;73:492–497.
2. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm): results of a multi-institutional randomized surgical trial. Ann Surg 1993;218:262–269.
3. Cottel WI. Perineural invasion by squamous-cell carcinoma. J Dermatol Surg Oncol 1982;8:589–600.
4. Essner R, Conforti A, Kelley MC, et al. Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 1999;6:442–449.
5. Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;17:976–983.
6. Hochwald SN, Coit DG. Role of elective lymph node dissection in melanoma. Semin Surg Oncol 1998;14:276–282.
7. Lee ML, Tomsu K, Von Eschen KB. Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 2000;10:81–92.
8. Leo F, Cagini L, Rocmans P, et al. Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 2000;83:569–572.
9. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg 2005;242:302–313.
10. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al. Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol 1998;134:983–987.
11. Ollila DW, Hsueh EC, Stern SL, et al. Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 1999;71:209–213.
12. Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992;327:1649–1662.
13. Thomas RM, Amonette RA. Mohs micrographic surgery. Am Fam Physician 1988;37:135–142.
14. Thomas JM, Newton-Bishop J, A'Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350:757–766.
15. Veronesi U, Cascinelli N. Narrow excision (1-cm margin): a safe procedure for thin cutaneous melanoma. Arch Surg 1991;126:438–441.
16. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma: comparison of excision with margins of 1 or 3 cm. N Engl J Med 1988;318:1159–1162.
17. Wagner JD, Gordon MS, Chuang TY, et al. Current therapy of cutaneous melanoma. Plast Reconstr Surg 2000;105:1774–1801.