Melanoma: From Patient Presentation to Pathology Report

Abstract

Melanoma is an increasingly common and potentially fatal malignancy of the skin and some mucous membranes. Early detection and diagnosis based on patient or primary care physician awareness can potentially reduce both related morbidity and mortality. This article will detail a basic clinical approach to pigmented skin lesions followed by a discussion of pathologic analysis and staging

Introduction

Melanoma is estimated to strike 1 in 53 people over their lifetime. In Missouri, statistics on persons with melanoma are tracked yearly and show an increase in incidence and an increase in mortality (See Figures 1A and 1B). The diagnosis of melanoma is more common with advancing age, but no age group – from newborn on – is spared. Detection and removal of an early lesion can be curative, however little can currently be offered to patients with metastatic disease for which there is a less than 5–15% five-year survival. ^1,2

Figure 1.

Top: Incidence of melanoma in Missouri by county (http://statecancerprofiles.cancer.gov).

Bottom: B) Bar graph showing 5 year rate changes (http://statecancerprofiles.cancer.gov)

Presentation

A patient may present with concern over the appearance of a pigmented lesion of their skin, or a physician may discover a clinically suspicious lesion during a complete skin examination. The initial step in evaluating a pigmented lesion is to obtain an accurate history. The history of the time course of the lesion and any associated changes should always be elicited. Personal history of skin cancer, family history of melanoma, immuno-suppression, and UV exposure history (including tanning bed use) are important aspects of the history

A total body skin exam performed regularly by a patient’s primary care physician has the added advantage of providing an estimate of overall photodamage, providing an overview of the number and gross morphology of a patient’s nevi, and finally providing an opportunity to discover lesions that the patient has not noted

When examining a pigmented lesion, the lesion should be exposed with adequate lighting and cleaned of any potential dirt or serum. The use of polarized dermoscopy to provide optically aided examination is proving useful in the experienced clinician’s hands,^3,4 although to an untrained user, it serves at best as a magnifying aid. Consideration of entities other than melanoma is pertinent, as a clinically pigmented lesion could also be a nevus, a pigmented seborrheic keratosis, an angiokeratoma, or a pigmented basal cell carcinoma. Differentiating melanoma from its close clinical mimics can often be challenging and must be done with the backing of sufficient clinical experience. The purely clinical diagnosis of pigmented lesions is beyond the scope of this article.⁵

After examination and assessment, the primary care physician can either refer the patient to a specialist for an additional opinion, biopsy the worrisome clinical lesion, observe the lesion for a defined period of time assuming the patient will reliably return for follow-up, or reassure the patient regarding the nature of the lesion. The decision must be based on patient factors, confidence in the diagnosis, location and size of the lesion, and access to specialists

If the physician elects referral, direct physician-to-physician referral is preferable as this allows a dermatologist to be aware of the urgency of a visit, allows for transfer of clinical notes, and ensures scheduling follow-up. If a colleague observes a worrisome pigmented lesion, with rare exception, a majority of dermatologists will see the patient in a timely fashion. The direct physician-to-physician approach avoids the problems encountered when a patient is instructed to independently call a dermatologist for an appointment. For example, the dermatologist’s office can do little to triage patients without direct examination, and patients may postpone calling out of fear

Biopsy

The first goal of any biopsy to is to confirm or arrive at a diagnosis. It is helpful for the clinician to understand that a pathologist assessing a melanocytic proliferation uses microscopic features that parallel those used clinically to determine atypia (i.e. size, side-to-side pattern, changes at the edge of the lesion, etc.) Consequently, whenever possible, the entire clinical lesion should be included in the biopsy. There are several pitfalls for the pathologist, and consequently to the patient and patient’s physician, if a partial biopsy is submitted. As examples, the portion of the lesion that looks most clinically worrisome could lack sufficient microscopic features to assign a definitive diagnosis. Since melanoma sometimes arises at the site of a nevus, partial sampling also may show only the associated benign lesion, leading to a false negative result and a false sense of security by the clinician and the patient. Similarly when possible, superficial sampling of a pigmented lesion should be avoided. If a shave biopsy is performed and the tumor is transected, the Breslow thickness of the tumor cannot be accurately determined, depriving the patient of prognostic information and, potentially, to adjuvant therapies

There are three basic biopsy techniques used to evaluate a pigmented lesion: punch biopsy, elliptical biopsy, and saucerization.^6,7 Pigmented lesions should not be biopsied by curettage or by electro-cautery since tissue submitted by either of these approaches has usually lost architectural features required for pathologic diagnosis and has distorted cytologic features, such that any reasonable assessment of prognostic parameters if the lesion is a melanoma is precluded

The punch biopsy technique involves using a circular blade to take a core of skin, dermis, and subcutis. This technique offers the advantage of ready-to-use, disposable tools that obtain a biopsy with a precise diameter. Because microscopic margins often extend beyond clinically visible margins, in general, a punch tool larger than the clinical lesion is preferred. This method avoids the relatively common pitfall of partial sampling and yields higher rates of negative margins. As previously mentioned, a partial punch biopsy is not appropriate

The elliptical biopsy technique involves using a scalpel to cut around the lesion, often in an elliptical fashion, and to include the epidermis, dermis, and subcutis. This technique is often employed when the lesion is larger than 8 mm. If orientation information is desired, a suture placed at one end of the ellipse allows the pathologist to discuss specific margins (eg, lateral, medial, etc.)

The saucer biopsy technique involves using a scalpel or flexible blade to ‘scoop’ the entire clinical lesion out both on the surface and into the dermis. This technique involves the fewest instruments and sutures are not required. Proponents of this method advise that it is relatively easy to remove the lesion with a rim of clinically “normal” skin, allowing for adequate pathologic evaluation. If this method is employed, the thickness of the saucer should equal or exceed 1 mm to allow for reasonable staging information; a shallow saucer risks transecting the tumor

Indications for a partial shave biopsy are probably limited to cosmetically sensitive areas, such as the face. If this biopsy approach is taken, the physician must accept the consequent limitations of the pathologic diagnosis

From a pathologist’s point of view, there is no best biopsy technique. The best biopsy is simply the one that provides the entire clinical lesion for pathologic evaluation. Therefore, the decision of which biopsy technique to utilize/perform is often based on numerous factors including, but not limited to, clinical familiarity with the technique, suspected depth of the tumor, cosmetic outcome, and ability of the patient to return for suture removal

After biopsy, the specimen is placed in neutral buffered formalin, and the specimen should occupy less than 10% of the solution to achieve proper fixation. The sample, accompanied by the completed pathology tissue requisition form can then be submitted. The pathologist will rely on information from the requisition form to assess patient’s race/background pigmentation, cutaneous cancer history, and degree of clinical suspicion. Information such as clinical lesion size and area biopsied is particularly important if the biopsy was intended to provide only a partial sample

Histopathologic Diagnosis

Once the tissue arrives in the laboratory, a complete description of the gross appearance of the specimen is performed, including description of the pigmentation of the provided normal skin, size and complete description of the pigmented lesion, and proximity of the lesional tissue to the margin. In our laboratory, all specimens are inked prior to processing to aid in embedding. Sectioning of a punch/shave biopsy is preferably done along its longest epidermal axis to provide optimal microscopic evaluation and sectioning through the lesional tissue to best illustrate margins is recommended. Biopsies that are less than or equal to 3 mm in greatest epidermal size are not bisected because, in our hands, serial sections of intact tissue of this size yield the best results. Partial sampling of large lesions/specimens by the pathologist is discouraged for the same reasons that clinical partial sampling is undesirable. Complete diagnostic and prognostic information is best obtained when the entire lesion has been examined

The microscopic interpretation of a melanocytic proliferation is complex and sometimes controversial. The different schools of thought are illustrated by the proliferation of verbiage and confusion that center on the concept of a “dysplastic” nevus. Whether a pathologist subscribes to this concept, which terminology the pathologist employs, and which clinical approach the clinical physician employs regarding the lesion depends in part on training and practice environment. In brief, the terminology used to diagnosis a single lesion with features of a junctional or compound melanocytic nevus with nests that arise at the sides of or between rete, nests that bridge or fuse rete tips, lamellar fibroplasia, and non-confluent lentiginous melanocytic hyperplasia include: dysplastic nevus, nevus with architectural disorder, Clark’s nevus, and lentiginous melanocytic nevus. Regardless of terminology, in the patient with a familial melanoma history and/or multiple (hundreds of) nevi, including nevi in unusual sites, the lesion is considered to be an indicator of a very high risk of developing melanoma. It should be noted that in this setting removal of associated multiple nevi is not indicated as a primary melanoma can arise on any cutaneous surface without an association with a pre-existing nevus. In other words, removing the existing nevi does not remove the risk of developing melanoma. Nevertheless, regular skin examinations and removal of selected changing/growing nevi is required for these patients

The microscopic examination of a melanocytic proliferation includes side-to-side and top-to-bottom assessment. Criteria used in the diagnosis of a melanocytic proliferation include: symmetry; circumscription; number of individual melanocytes as compared to nested melanocytes; size, shape and distribution of nested melanocytes; and maturation. A benign lesion is usually symmetric; a malignant one is usually not symmetric. To assess symmetry, a pathologist notes at low power the appearance of the epidermis, the amount of pigment, the pattern of the nests of melanocytes, the presence and distribution of an inflammatory infiltrate, etc. In general, melanoma arises in the epidermis and therefore assessment is performed of the number of individual melanocytes and their arrangement in the epidermis, as well as size/shape/distribution of nested melanocytes. Benign lesions are generally nested and the nests have an organized appearance; malignant lesions generally have more individual melanocytes than nests, and the individual melanocytes are randomly scattered throughout the epidermis or in a solid line at the base of the epidermis. No one criterion can be used exclusively to determine benignancy or malignancy. Exceptions exist to one or more criteria in the various subtypes of nevi and melanomas, and these attributes contribute to the potential for various opinions regarding a benign or malignant diagnosis. The variation also suggests that evaluation of a melanocytic lesion is best done by pathologists who are experienced in the interpretation of melanocytic lesions

Once a lesion has been diagnosed as a melanoma, the current standard of practice is to provide a histologic subtype and provide as complete staging information as is possible. Figure 3 illustrates the most common subtypes of melanoma, including superficial spreading, lentiginous/lentigo maligna, and nodular melanoma. A complete list of melanoma subtypes, as provided by the AJCC includes: melanoma in situ, superficial spreading, lentigo maligna/lentiginous, nodular, acral lentiginous, desmoplastic, epithelioid, spindle cell, balloon cell, blue nevus, and malignant melanoma in a giant pigmented nevus. We also routinely comment on the presence of common morphologic patterns such as rhabdoid, myxoid, Spitzoid or nevoid

Figure 3.

A) Clinical example of a melanoma

B) Superficial spreading melanoma

C) Nodular melanoma, ulcerated

D) Lentiginous melanoma (lentigo maligna melanoma)

Pathologic staging information that is generally obtained from the primary excisional biopsy includes the presence or absence of ulceration, the Breslow thickness as measured with a calibrated ocular micrometer, and the presence or absence of satellite metastases. As a feature of the primary tumor, the Breslow thickness remains a strong predictor of outcome. However, the practice of sentinel node biopsy has refined staging and the presence or absence of a positive sentinel node(s) may currently be a better overall predictor of survival.⁸ While a thorough discussion of sentinel lymph node biopsy is beyond the scope of this article, our protocol consists of transecting the node(s) through the hilum and routine (H&E) staining of the first complete histologic section (hopefully after only minimal facing of the block), at approximately 40 microns into the block and 80 microns into the block. Unstained slides with the histologic section immediately following each of these levels are saved for potential immunohistochemical evaluation. If melanoma is definitively seen on any of the initial three H&E stained slides, the node(s) is reported as positive for metastatic melanoma. If no melanoma is seen in the initial three H&E stained slides an immunohistochemical stain for Mart-1/Melan-A/A-103 is performed on the reserved slides from each level of the node. If, after evaluation of these three additional slides, no melanoma is seen, the node is determined to be free of metastasis. While there are certainly other valid approaches to sentinel node evaluation, most institutions have documented that the most likely area of the node to harbor a metastasis is the center of the node and that occult metastasis are best detected by special stains. Currently we do not perform, nor do we encourage, the use of molecular testing of sentinel nodes due to the potential interference introduced by incidental, benign, nodal nevi

Molecular Testing/Advances

Although routine examination of H& E stained tissue sections remains the gold standard in diagnosing melanoma, recent advances have provided tools to help discriminate borderline cases. Comparative genomic hybridization (CGH) studies have demonstrated that within specific types of melanomas there are relatively reproducible gains and losses of chromosomal segments.⁹ These chromosomal alterations are not found in benign melanocytic nevi, and are relatively specific within melanomas that arise on chronically sun-damaged skin versus intermittently sun-damaged skin versus non sun-exposed skin. The CGH results have been transitioned into clinical use via the technique of fluorescence in situ hybridization (FISH). In surgical pathology, FISH is routinely used to examine copy number of specific chromosomal regions to illustrate characteristic gains and losses of specific regions of the genome. Melanoma tends to have chromosome losses in chromosomes 9p (82%), 10q (63%), and 6q (28%) and increases in 7 (50%), 8 (34%), and 6p (25%); other alterations are less frequently noted, but include gains in 1q, 17q, and 20q and losses/deletions in 9p. Spitz nevi, which are sometimes difficult to differentiate from melanoma, do not show this pattern of copy number changes, but instead harbor increases in 11p.¹⁰ FISH testing is useful in cases of borderline melanocytic tumors because it often helps in diagnosis, although further data is needed to determine if the testing should become routine medical practice

Treatment/Follow-up

Once a diagnosis of melanoma has been established, the appropriate treatment includes excision of the primary site with margins determined by the Breslow thickness, with concurrent sentinel lymph node biopsy. A new 2009 AJCC/UICC TNM staging system has just been released.^11,12 NCCN guidelines¹³ for the treatment/management of patients with melanoma are available and are updated regularly, and can be a valuable resource for a physician seeking guidance in treating a patient with a diagnosis of melanoma. Appropriate treatment includes follow-up examination of the patient at regular intervals that range from yearly for patients with melanoma in situ, to every three to six months for the first two years for patients with higher stage disease. Patients with melanoma should also be advised that they are at increased risk of a second melanoma, and that continued careful self-examination of their skin is needed

Biography

Omar W. Jassim, MD, is Dermatology Resident, Division of Dermatology, Department of Medicine. Anne C. Lind, MD, is Assistant Professor and Section Head, Dermatopathology, Department of Pathology and Immunology. Both are at Washington University School of Medicine in St. Louis.

Contact: ojassim@dom.wustl.edu