Squamous cell carcinoma (SCC) is the most frequent malignant skin tumor that arises in the hand, followed by basal cell carcinoma (BCC) and malignant melanoma (MM). Meticulous history taking and careful physical examinations of skin lesions with suspicion are important, as these lesions can easily be misdiagnosed as simple ulcers or benign pigmented lesions. Once the diagnosis is confirmed, general metastasis workups are required especially for MMs. Sentinel biopsy of the axillary lymph node should be performed for high-risk groups. Complete excision of the tumors with an adequate surgical margin is the treatment of choice. The safety margin is largely determined on the basis of the size of the tumors for BCCs and SCCs and the depth of the tumors for MMs. The complete excision should be followed with reconstructive surgery to preserve hand function. The overall prognosis is poor especially for MMs with deep invasion or subungual lesions.
KeywordsThumb Basal cell carcinoma Squamous cell carcinoma Melanoma
Basal Cell Carcinoma
Basal cell carcinoma (BCC) is the most common skin cancer, but the incidence of BCC of the hand is much lower than that of squamous cell carcinoma (SCC) at this area. BCCs are malignant epithelial neoplasms arising from the basal layer of the epidermis or pilosebaceous adnexa. Characteristic cells are observed that have a large basophilic nucleus with minimal cytoplasm. In any nest of cells, peripheral tumor cells are aligned with long axis perpendicular to the nest, showing a “picket fence” appearance. Excessive sun damage is the most common factor predisposing to the development of BCC. Although BCC is more common in adults, it can also occur in children, especially in those with certain syndromes (e.g., nevoid basal cell syndrome and Bazex syndrome). BCC is also associated with xeroderma pigmentosum, irradiation, burn scars, and chronic exposure to arsenic .
BCCs are generally observed as ulcerated lesions on the skin with elevated and pearly edges with erythema in middle-aged and older individuals. Specifically, circumscribed or diffuse lesions are primarily presented. BCCs of the hand usually occur in hair-bearing dorsal locations .
BCCs are classified into circumscribed and diffuse types as previously described. Nodular and circumscribed lesions are generally less virulent than diffuse lesions. Moreover, diffuse BCCs have increased recurrence rate compared to circumscribed lesions because they extend deeply into the dermis further from the clinically visible or palpable border. More specifically, BCCs can be classified into five major types; fibroepithelioma, morpheaform, nodulo-ulcerative, pigmented, and superficial BCC . Nodulo-ulcerative type is the most common form of BCC. It is dome-shaped with well-defined borders and often appears as a pink-red papule displaying a “pearly” appearance with telangiectasia. Although its growth pattern is circumscribed, nodular BCC may be poorly differentiated histologically. Superficial BCC has multiple foci that are actually connected with each other. Its extension beyond clinically visible borders makes it highly recurrent after surgical treatment.
BCCs should be differentiated from factitious ulceration, eczema, actinic keratosis, psoriasis, and fungal infection. Nodular pigmented BCC may resemble melanoma in appearance which makes it more difficult to be distinguished.
Excision is commonly recommended as a treatment option. Surgical excision offers a greater than 90% cure rate . For a less than 1 cm in diameter nodular lesion, a 2-mm surgical margin may be sufficient. For lesions up to 2 cm, however, a 3–5-mm margin is more appropriate. In this case, the deep margin should extend into a subcutaneous fat. Lesions greater than 2 cm and those with aggressive growth patterns (e.g., morpheaform and superficial “multicentric” BCC) may require 10-mm resection margins . Curettage and electrodessication is the technique for treating BCC but is limited for primary lesions less than 1 cm in diameter. This technique is appropriate for lesions of the hand extremity. Cryosurgery can be applied to well-defined lesions . However, neuropathy is a potential risk of cryosurgery due to uncontrolled depth of freeze. For this reason, cryosurgery should not be applied on digits and around the ulnar nerve at the elbow. Cure rate for curettage, electrodessication, and cryosurgery for small lesions has been reported to be as high as 97%. However, these techniques have an inherent disadvantage of lacking a microscopic verification of complete tumor removal.
BCC arises without a precursor lesion and is usually slow growing, locally destructive, and recurrent. However, it is not clinically aggressive and metastasis is rare . Regular follow-up is indicated to identify recurrences and new lesions.
Squamous Cell Carcinoma
SCC is known as the most common malignant tumor of the hand . In general, SCC is a skin-colored or pink lesion that is usually found on the dorsal surface of the hand. SCC can occur from premalignant lesions (actinic keratosis), in situ variant (Bowen’s disease), or de novo .
Risk factors of SCC include solar radiation, ionizing radiation, chronic inflammation, exposure to chemicals (e.g., arsenicals), certain disease states (e.g., xeroderma pigmentosum, Bowen’s disease, leukoplakia, and epidermodysplasia verruciformis), human papillomavirus, Caucasian race, and smoking . Immunocompromised patients, especially those with renal and heart transplants, are 65% more susceptible to develop SCC compared with those who are healthy. These patients may also have multiple lesions and more aggressively behaving SCCs. Histological evaluation of the primary tumor is important in predicting the prognosis of SCC. High grade of differentiation ratio (grade 3 and 4), tumor size greater than 2 cm, tumor depth extension into the subcutaneous layer (or greater than 4 mm), perineural invasion, and paronychia are high-risk factors associated with tumor recurrence and metastasis .
Within the first 5 years after SCC development, metastasis is detected in 5% of patients. It is estimated that 2–5% of upper extremity SCCs metastasize to axillary nodes. The mortality rate for SCC of the hand is higher than that of other anatomic sites . Factors affecting recurrence and metastasis include tumor size and thickness, histologic differentiation, site of the primary tumor, immune status of the host, carcinoma arising from scar tissue (Marjolin’s ulcer), and neurotropic SCC . Five-year survival rate decreases to 40% in the presence of axillary node metastases. However, since the incidence of lymph node metastasis is low, elective node dissection or sentinel lymph node biopsy has no advantage in treating SCC, unless nodes are clinically enlarged . SCCs show slower invasion than cutaneous malignant melanomas and, hence, do not easily invade deeper tissues. Superficial dermis and epidermis lack lymphatic drainage, making SCC less likely to spread via lymphatics. Long-term follow-up after treatment of SCCs is critical to assess for recurrence or metastatic spread because metastasis can be found occasionally, even up to 10 years after the primary resection of the tumor.
The incidence of cutaneous melanoma has been rapidly increased during the last decades compared with other malignant neoplasms, while melanoma of the hand shows relatively stable pattern of incidence . Public medical education on the significance of early detection of melanoma has greatly contributed to the increase of the percentage of cases diagnosed at early stage. However, melanoma shows high rate of recurrence or metastasis even after curative treatment. Melanoma of the hand is known to have poorer prognosis compared with melanoma of other areas of the body .
Meticulous clinical examination and patient history are the most important factors in the diagnosis of melanomas. Dermoscopy, which magnifies the pigmented lesions with handheld dermatoscope, is a noninvasive and useful method to differentiate between benign and atypical pigmentations. Dermoscopy can increase the diagnosis accuracy by approximately 10%, and various algorithms can increase the sensitivity and specificity over 80% by adopting a scoring system .
Diagnosis is confirmed by incisional or excisional biopsy. Breslow thickness is measured in millimeter as a distance from the granular layer of the epithelium to the deepest portion of melanocytic invasion. Importantly, Breslow thickness is correlated with lymphatic invasion and the risk of distant metastasis.
Clinically palpable ipsilateral axillary lymph nodes should be meticulously evaluated, and elective lymph node dissection is recommended in patients with positive results. For occult lymph nodes, retrospective studies have revealed the benefit of elective lymph node dissection in the treatment of intermediate-thickness cutaneous melanoma (1–4 mm) . Sentinel lymph node is the first node where lymphatic drainage occurs in an orderly manner and melanoma metastasize to; hence, sentinel lymph node biopsy is widely used to facilitate diagnosis and treatment of lymph node metastasis . Sentinel lymph node biopsy has demonstrated an ability to reduce the morbidity of lymphedema in breast cancers or melanomas and has shown a good negative predictive value . Melanomas thicker than 1 mm, with ulceration, high mitotic rate, lymphatic invasion, and microsatellites have shown a 14% risk of occult metastatic disease . Therefore, sentinel lymph node biopsy is recommended for patients with melanomas with intermediate thickness or with greater than 25% risk of lymph node metastasis .
In melanomas with invasion depth more than 4 mm, the risk of nodal metastasis is very high (60–80%). In high-risk patients, general metastatic workups should be performed to exclude any nodal or distant metastasis. Since the lung is the most common site of distant metastasis, chest radiography is recommended for screening and postoperative follow-ups. Ultrasonography is useful in screening axillary lymph nodes and liver state. Laboratory evaluation, including evaluation of alkaline phosphatase and lactic dehydrogenase (LDH) levels, is also recommended to identify advanced stage melanomas. In highly suspicious patients for distant metastasis, chest computed tomography and positron emission tomography can be performed.
The TNM staging system, developed by the American Joint Committee on Cancer (AJCC), is the most commonly used method to determine clinical and pathologic stage of cutaneous melanoma. In the recently revised 8th edition, T1 is subcategorized into T1a, including non-ulcerated melanomas less than 0.8 mm in thickness, and T1b, including melanomas 0.8–1.0 mm in thickness with or without ulceration or less than 0.8 mm with ulceration. Furthermore, tumor mitotic rate is no longer a staging criterion for T1 tumors. As the N category also becomes more complicated in the 8th edition, stage III grouping is subdivided into four rather than three subgroups (A, B, C, and D). Lastly, the M category becomes more elaborate as central nervous system metastasis is re-categorized as M1d, and elevated LDH level is applied as a prognostic factor in each M subcategory. For example, brain metastasis with elevated LDH level is classified as M1d .
Recommended safety margin of cutaneous malignant melanomas based on the tumor depth (Breslow thickness)
Tumor depth (Breslow thickness)
An early study has demonstrated an increased 5-year survival rate following elective lymphadenectomy for clinically occult lymph nodes compared to delayed lymphadenectomy for clinically palpable nodes . However, a recent long-term randomized control study has presented no increase in the melanoma-specific survival of patients who had immediate completion of lymph node dissection after positive results from frozen section biopsy .
Melanoma is considered relatively radioresistant, but radiation therapy can provide effective treatment modality in some clinical settings. Primary curative radiotherapy can be attempted for localized inoperable mucosal melanoma. Adjuvant radiotherapy is effective in reducing the risk of recurrence in primary tumors or regional lymph node metastasis . Radiotherapy can also be used for palliation, to reduce signs and symptoms related to melanoma .
Classical cytotoxic chemotherapy (e.g., dacarbazine and cisplatin) has resulted in regression of disseminated melanoma in very few patients with no evidence of long-term survival gain. Conventional immunotherapies, such as interleukin-2 and interferon, are still useful for limited indications but are ineffective in the majority of patients because of drug-related general toxicity. Ipilimumab is an immune checkpoint inhibitor that activates immune system by targeting a cytotoxic T-lymphocyte-associated antigen (CTLA-4). Pembrolizumab is an anti-programmed cell death (PD-1) immunotherapeutic agent. In patients with BRAF gene mutation, which can accelerate tumor cell growth, a BRAF inhibitor (Zelboraf) has been approved for prescription by the Food and Drug Administration. Recent clinical trials have shown a long-term survival gain following the combination of these agents . Ongoing clinical trials and genetic studies will provide further data on these agents, showing a long-standing remission of melanoma.
Subungual melanoma, arising beneath the nail plate, should be categorized as a single separate entity of acral lentiginous melanoma due to its unique anatomical location and poor prognosis. Subungual melanoma represents around 2% of all the cutaneous melanoma but shows a high prevalence in Black populations (15–20%) or Asians. Subungual melanoma can occur from any nail matrix of fingers or toes, but the thumb and the great toe are the most frequent sites of tumor development. The patients show pigmented strip-like lesions in the early stage, and they sometimes accompany nail deformity, pain, bleeding, and ulceration as the tumor progresses. To rule out benign pigmented nail bands, investigators have presented the ABCDEF mnemonic that suggests a malignant melanoma. This mnemonic stands for age greater than 40 years; African American; band width greater than 3 mm; border irregularity; change; digit involvement in the thumb, hallux, or index finger; extension onto the surrounding skin; and family history . Hutchinson’s sign, which is the extension of the pigmented lesion onto the nail fold or hyponychium, strongly suggests a malignant lesion . The poor prognosis of subungual melanoma is believed to be due to its delayed diagnosis. Subungual lesions are easily misdiagnosed as subungual hematoma, fungal infection (onychomycosis), inflammatory lesion, or other benign pigmented lesions (e.g., melanonychia). Moreover, a recent history of minor trauma of fingers or toes can mask the malignancy, and amelanocytic subungual melanoma can make diagnosis even more difficult. Therefore, a failure of subungual hematoma to disappear in several months commonly precipitates a biopsy of the nail matrix. Accurate diagnosis of subungual melanoma can be delayed for more than 2 years, and, hence, more than 1/4 of patients have metastasis .
General metastatic workup is required as aforementioned. Clinically palpable ipsilateral axillary lymph nodes should be meticulously evaluated in the intermediate tumor depth, and elective lymph node dissection is recommended following positive results. However, the Breslow thickness is hard to be applied in the subungual melanoma due to the lack of the granulosum layer in the nail matrix. The thickness of the nail matrix down to the periosteum has been found to be less than 2 mm in a cadaver study . The overlying nail plate and bony structure underneath can affect the growth and progression of subungual melanoma. Further studies are required to determine the unique anatomy and the clinical relevance of the nail bed. The authors suggest that a separate treatment guideline should be established for subungual melanoma in the future.
The prognosis of subungual melanoma is poor irrespective of races. According to Klausner et al., the 5-year overall survival rate for subungual melanoma was 28–30%, and the 10-year overall survival rate was 0–13% . In the Asian group, the 5-year overall survival rate for subungual melanoma was 41%, which was 30% lower than that for other cutaneous melanomas .
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