Basics of Melanoma Diagnosis

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

An accurate melanoma diagnosis has far-reaching implications for patients and clinicians alike. Most patients have early-stage, highly curable disease at initial diagnosis. An accurate diagnosis avoids unnecessary delays that may allow the disease to grow into a less curable state.

Diagnostic accuracy also helps avoid unnecessary testing, ineffective treatment, and associated costs and morbidity. Melanoma misdiagnosis accounts for more pathology and dermatology malpractice claims than any other type of cancer except breast cancer.

Biopsy Technique

The National Comprehensive Cancer Network (NCCN) recommends three types of excisional biopsies for suspicious pigmented lesions: elliptical, punch, and saucerization (deep shave). The excision should result in narrow negative margins of 1 to 3 mm. Wider margins are discouraged because of their potential to interfere with lymphatic mapping and sentinel lymph node biopsy. Biopsy orientation should reflect consideration of treatment planning -- that is, longitudinal orientation with the extremities, parallel to the lymphatics.

Excisional biopsy might be undesirable or inappropriate for certain sites, such as the face, palms, soles of the feet, or under a toenail or fingernail, as well as for large lesions. In such cases, full-thickness incisional or punch biopsy is an acceptable alternative, provided that the procedure allows for accurate primary tumor microstaging and does not interfere with treatment planning. A superficial shave biopsy can compromise the diagnosis and assessment of Breslow thickness, but is acceptable for low-suspicion lesions.

No compelling evidence exists to suggest that one type of excisional biopsy is superior to the others. A recent meta-analysis to examine the relationship between biopsy technique and four melanoma outcomes showed a small but significant increase in all-cause mortality with punch biopsies. However, no association was observed with the other outcomes, and the authors concluded the finding was "most likely due to small sample sizes and demographic differences in the included studies."

Pathology Report

A pathology report should include all "essential" information. The NCCN recommends that the report include Breslow thickness, ulceration status, mitotic rate, deep and peripheral margin status, presence or absence of microsatellites, pure desmoplasia (if present), and Clark level for nonulcerated lesions ≤1.0 mm with undetermined mitotic rate. Mitotic rate should be determined whenever possible because of its emerging significance as an independent predictor of outcome. The American Academy of Dermatology recommends several other types of information, including vertical growth phase, tumor-infiltrating lymphocytes, and regression.

Multiple studies have explored factors predictive of survival in melanoma. Three tumor-specific factors have consistently emerged from these studies: Breslow thickness, ulceration, and mitotic rate. Multivariate analyses have confirmed all three as independent predictors of outcome.

Recognition that genetic mutations drive the evolution and progression of tumors has transformed the management of cancer, including melanoma. Nonetheless, genomic assessment has a limited role in characterizing a primary melanoma, according to the NCCN. Comparative genomic hybridization or fluorescence in situ hybridization might be helpful in detecting specific mutations in lesions with uncertain histology. Routine genetic testing of primary tumors is not recommended outside of clinical trials.

Key Terminology

Recognizing and understanding key terms associated with melanoma will facilitate comprehension and interpretation of a report and aid in conveying diagnostic and staging information, as well as implications, to patients with melanoma.

Clark Level

The original system for describing depth of invasion, Clark levels remain in use as a standardized method to convey melanoma aggressiveness or risk. The system characterizes level of invasion relative to layers of skin.

• Level 1: Confined to the epidermis (in situ)

• Level 2: Invasion of single cells or small clusters into the papillary dermis

• Level 3: Filling and expansion in the papillary dermis

• Level 4: Invasion into the reticular dermis

• Level 5: Invasion into subcutaneous fat

Breslow Depth (or Thickness)

Successor to the Clark levels as a more accurate classification system, Breslow Depth uses the actual measured thickness of a melanoma lesion to reflect disease stage and likelihood of spread. Alexander Breslow backed up his system with evidence that thinner melanomas were associated with better survival and a lower risk of regional or distant metastasis.

Introduced as a five-stage classification, the Breslow system has evolved over time and currently encompasses four categories or levels.

• Level 1: ≤0.75 mm (Clark II)

• Level 2: 0.76-1.50 mm (Clark III)

• Level 3: 1.51-4.0 mm (Clark IV)

• Level 4: ≥4.0 mm (Clark V)

Disease Stage

Stage refers to the extent of cancer at diagnosis. Stage ranges from 0 to IV and may include letters A through D to define the stage more specifically (thickness or depth, ulceration status, and extent of nodal involvement, if any). In general, higher numbers and letters reflect more extensive or advanced disease (higher risk for metastasis). Accurate assessment of stage is essential to treatment planning.

• Stage 0: Limited to the epidermis (in situ)

• Stage I: Localized, only in skin, thin

• Stage II: Localized, but thicker than stage I

• Stage III: Spread to one or more lymph nodes, in-transit (subcutaneous) metastases, or microsatellites

• Stage IV: Distant metastasis, including non-regional lymph nodes

Stage III is particularly heterogeneous in terms of thickness and extent of nodal involvement. Patients with palpable regional lymph nodes, in-transit disease (between the primary tumor and regional nodal basin), or microsatellites (clusters or nests of neoplastic melanocytes separated by normal dermis) have stage III melanoma. The various substages are associated with the letters A-D, which reflect increasing extent of invasiveness and risk. Similarly, stages IA and IB represent different degrees of metastatic potential within early-stage disease. Consult with the pathologist if any details or interpretation is unclear (substages).

Ulceration

Ulceration refers to any full-thickness loss of epidermis overlying any portion of a melanoma lesion and should be determined from the initial biopsy. In general, ulceration is a negative prognostic factor.

Histologic Subtype

In contrast to other types of cancer, melanoma histology often is absent from pathology reports. The American Joint Committee on Cancer staging manual does not mention melanoma histologic subtype. The lack of attention to histology has its roots in the assumption that any increased risk associated with histology is confounded by the effects of lesion thickness and ulceration status. However, some clinicians still consider histologic subtype a key element of melanoma diagnosis and the pathology report.

Four principal subtypes have been identified:

• Superficial spreading melanoma -- Accounts for about 70% of all melanomas, commonly found on the trunk and proximal extremities; predominantly epidermal and characterized by slow, horizontal growth

• Nodular melanoma -- Accounts for 15-20% of melanomas and appears as a firm bump or node rising above the skin surface; more common in people with fair complexion and in older individuals and has a more rapid vertical growth and proliferation as compared with other histologies

• Desmoplastic melanoma -- Appears as a firm plaque, often on the face or scalp, more common in older individuals

• Lentigo maligna melanoma -- A type of melanoma associated with chronic sun exposure; often appears as an irregular brown patch on the head or neck of older patients; evolves from lentigo maligna (in situ disease) to lentigo maligna melanoma when invasive characteristics appear

• Acral lentiginous melanoma -- Overall, a rare type of melanoma, but more common among individuals with darker skin; arises in atypical sites, such as palms, soles, fingertips, and under nails (subungual)

A recent retrospective review provided evidence to suggest that melanoma histologic subtype may influence outcome. Limited to the two most common histologic subtypes (superficial spreading and nodular), the analysis included 118,508 cases of stage I-III melanoma diagnosed from 1973 to 2013 (SEER national database), and a 1,621-patient single-center-cohort control group. Data from both sources showed that nodular histology was an independent predictor of worse survival.

Imaging Studies

Routine imaging for stages 0, I, or II melanoma is not recommended. Imaging for stage III subgroups might be considered for establishing baseline tumor characteristics, detecting clinically occult distant metastasis, and assessing the potential for distant metastasis.

However, available data suggest that cross-sectional imaging has limited ability to detect metastatic disease at diagnosis of stage III disease. Imaging has greater utility as an adjunct to sentinel lymph node biopsy and in planning and assessment of treatment.

Laboratory Testing

Routine blood tests are not recommended for patients with melanoma in situ, stage I, or stage II disease. Laboratory tests are used more often to aid treatment planning and to assess response to treatment.

Read previous installments in this series:

Part 1: Melanoma: Epidemiology, Diagnosis, and Treatment

Part 2: Recognizing Melanoma: What It Is, What It Isn't