Melanoma prognostic factors found in the dermatopathology report
Introduction
The information obtained from the histologic exam and detailed in the dermatopathology report of a cutaneous malignant melanoma (CMM) provides invaluable prognostic indicators for the clinical dermatologist to help educate patients and guide therapy. Herein, we review the prognostic information contained within a standard melanoma dermatopathology report.
Section snippets
Age
Most melanoma studies in adults support a worse prognosis with increasing patient age at the time of diagnosis. In an Italian study of 428 patients, age 60 years or older carried a 1.45-fold increased risk of death at 5 years than age younger than 60 years.1 Similarly, between 1990 and 1999 in Sweden, patients aged 70 years and older had a 1.59-fold increased risk of death versus patients younger than 50 years.2 In a retrospective study of 442 patients, persons older than 65 showed a
Anatomic location
Many studies have demonstrated that extremity lesions offer a better prognosis than truncal lesions.8, 9, 10, 11, 12 A study of 711 patients in 2001 demonstrated that location on the extremities had an odds ratio of 0.8 for overall survival versus trunk lesions, and although location significantly affected survival, it was not determined to be an independent risk factor.13 An investigation of 298 patients with CMM demonstrated that melanomas located on the trunk were associated with significant
Sex
Many studies have demonstrated that female sex confers a better prognosis than male sex. One study found the respective 5-and 10-year overall survival rates for men were 69% and 61%, compared with 82% and 75% for women.28 Women had at least a 10% better survival rate versus men in every age category except for patients aged 75 years and older, suggesting that given any particular age younger than 75, women hold a better prognosis. In a 2004 study, women were 0.71 times as likely as men to die
Breslow tumor thickness
The Breslow measurement is taken from the top of the granular layer or, in the event that the surface is ulcerated, from the base of the ulcer to the deepest portion of invasion using a calibrated ocular micrometer.33 Adventitial dermal invasion is not measured unless it is the only site of dermal invasion, in which case the measurement is made from the inner luminal surface of the adnexal gland or duct or the inner aspect of the outer root sheath epithelium of the hair follicle.33, 34
Breslow
Clark’s anatomic level
In 1969 Clark et al72 defined five levels of melanoma invasion within the skin: I—intraepidermal melanoma; II—melanoma cells within the papillary dermis; III—melanoma cells fill the papillary dermis and extend to the interface between the papillary and reticular dermis; IV—melanoma cells within the reticular dermis; and V—melanoma cells extending into the subcutaneous tissue. He observed a correlation between a tumor's anatomic depth of invasion and prognosis (Table 2).
Since then, a number of
Tumor volume
Tumor volume refers to the total three-dimensional space occupied by a melanoma lesion. In 1970 Breslow approximated tumor volume by calculating maximal cross-sectional area (CSA) and demonstrated that volume was inferior to both tumor thickness and level of invasion.33 A more recent study80 demonstrated that CSA of 12 mm2 or less carried a 2-year metastasis-free survival rate of 92% ± 2% compared with 41% ± 8% for tumors with a CSA exceeding 12 mm2. Overall survival was also significantly
Cross-sectional profile
Cutaneous malignant melanomas can assume a variety of local growth patterns, including polypoid, verrucous, hemispherical, dome-shaped, and plaque-shaped, which can be assessed by looking at a tumor's cross-sectional profile.
Polypoid (also known as pedunculated) melanomas are an unusual variant of nodular melanoma that have an exophytic growth pattern composed of a nodule that is connected to underlying skin by a stalk; the nodular aspect is filled with melanoma cells and is often ulcerated and
Ulceration
Histopathologic ulceration is defined as an interruption of the full thickness epithelium.13 Ulceration is believed to develop from tumor ischemia secondary to rapid tumor growth,34 suggesting that CMMs with ulceration may be more aggressive neoplasms.
Most studies have demonstrated that ulceration is a significant predictor of decreased overall survival in multivariate analysis38,91, 92, 93, 94, 95 as well as a significant predictor of relapses.96 In one study, ulceration was a significant
Number of mitoses
Tumor mitotic rate has been used as an estimate of a tumor's proliferative state. The mitotic rate is expressed as a mitotic index, which is the maximum number of mitoses per square millimiter.107 On most standard light microscopes, 1 mm2 correlates to between 3 and 10 high power fields.34 At our dermatopathology laboratory, we historically counted mitoses per 10 high power fields. When we measured the × 20 field, however, it was approximately equivalent to 1 mm2 and we have adopted the
Radial and vertical growth phase
Radial growth phase describes melanomas that are primarily within the epidermis, and if there are solitary or clusters of melanoma cells in the papillary dermis, none are larger than any of the intraepidermal nests and none demonstrate mitoses. In the vertical growth phase, aggregates of melanoma cells are identified in the dermis, and at least one nest in the dermis is larger than the largest intraepidermal nest, or mitoses are identified in any of the dermal melanoma cells demonstrating
Regression
Regression is a histologic consequence of the interaction between malignant tumor cells and the host immune system resulting in the replacement of tumor tissue with a variable combination of haphazard fibrosis, degenerative melanoma cells, melanophages, lymphocytic proliferation, and telangiectasia.34, 68 In areas of complete regression, malignant melanoma cells are totally absent in both the dermis and overlying epidermis.34
A number of studies have shown that regression is a poor prognostic
Host inflammatory response
Tumor-infiltrating lymphocytes (TILs) are a key manifestation of the immune response to melanoma.137 The host inflammatory response is divided into three categories:
- 1.
a brisk infiltrate—either a diffuse infiltrate of lymphocytes throughout the vertical growth phase or the presence of infiltrating lymphocytes along 90% of the circumference of the lesion base;
- 2.
a nonbrisk infiltrate—an infiltrate composed of only focal infiltration; and
- 3.
an absent infiltrate—(no lymphocytes are admixed with melanoma
Tumor vascularity
As tumors enlarge, growth becomes dependent on angiogenesis, which is new blood vessel formation.149, 150, 151 Angiogenesis occurs in the dermis at the base of the invasive vertical growth phase of the tumor68 in response to tumor-derived growth factors, with vascular endothelial growth factor (VEGF) being a major regulator of both physiologic and pathologic angiogenesis.152 Expression and release of VEGF expression are known to increase during the transition of a melanoma from the radial
Angiotropism
Extravascular migratory metastasis is a mechanism by which melanoma cells can spread to nearby or distant sites by migrating along the external surface of vessels.169, 170, 171 Evidence for extravascular migratory metastasis comes from immunopathologic studies that demonstrate melanoma cells abutting the external surfaces of endothelial cells in a pericyte-like position but without evidence of vascular invasion, as well as from ultrastructural studies that show the melanoma cells linked to the
Vascular invasion
Vascular invasion is defined as the presence of tumor cells within the vessel lumen.114, 184, 185 Although vascular invasion can be observed on routinely stained slides,114 there are potential artifacts from either tortuous vascular channels folding back into the vascular lumina or tissue shrinkage, both of which can result in the false appearance of a vascular space.169
A handful of older studies have shown conflicting results with respect to the role of vascular invasion,55,186, 187, 188, 189
Histologic tumor type
Clark et al72 was the first to describe three different CMM morphologies: superficial spreading melanoma, nodular melanoma, and lentigo maligna melanoma. In 1977 a fourth subtype was added, acral lentiginous melanoma.194 Initially these subsets were well received; however, not all CMMs can be easily classified into these subtypes. This classification also carries controversial prognostic significance; therefore, the utility of this classification has been debated.34, 195
Superficial spreading
Cell type
Cutaneous malignant melanomas have a wide array of cytological presentations, often with one being the dominant cell type. We discuss the more common dominant cell types: amelanotic, spindle, spitzoid, signet-ring cell, minimal deviation, nevoid, and small cell.
Amelanotic melanoma
In some cases, melanoma may be devoid of pigmentation;84 the incidence was 1.8% in one series of 2881 CMMs.203 A 1981 study from Sydney showed that amelanotic tumors (7.2% of tumors analyzed) carried a 5-year survival rate of 61.7% versus 79.8% for nonamelanotic tumors; however, only 11.3% of the amelanotic lesions were less than 1.5 mm thick compared with 56.0% of the pigmented lesions.204 Other studies have failed to demonstrate a survival disadvantage associated with absence of pigmentation.
Spindle cell melanoma
Spindle cell melanomas are characterized by the presence of prominent spindle cells with little stroma.84 In a study of 384 patients, CMMs that were predominantly spindle, small, or “other” cell type demonstrated a 10-year disease-free survival rate of 78%, but epithelioid cell CMMs demonstrated a rate of 64%. The result was significant by univariate but not multivariate analysis.207
Spitzoid melanoma
Spitzoid melanomas are composed of enlarged epithelioid and fusiform melanocytes that resemble the cells of Spitz nevi.84 In a study of 82 children diagnosed with spitzoid melanoma, the 5-year survival rate was 88% for children aged 0 to 10 years versus 49% for the 11 to 17 age group.208 Two other cases of spitzoid melanoma in teenagers demonstrated that the prognosis of this variant is no better than other CMMs if the follow-up is prolonged enough, as the two patients died at 8 and 15 years,
Signet-ring cell melanoma
Signet-ring cell melanomas are rare tumors characterized by cells in which the nuclei are displaced to the periphery by a large vacuole210 that is formed by the accumulation of cytoplasmic vimentin positive intermediate filaments.84 Signet-ring cells are more commonly found in metastatic and recurrent melanomas than in primary lesions211, 212, 213 and thus are probably a poor prognostic feature.
Minimal deviation melanoma
Minimal deviation melanomas (MDM) are lesions that have a vertical growth phase composed of a uniform population of cells whose cytologic features deviate only minimally from those of nevus cells.84 They may represent a part of a continuum from benign nevi to unequivocal melanoma.214 A study of 31 patients with MDM found only 20% of those who underwent lymphatic mapping had a positive SLN.214 Other studies have also suggested that MDMs carry a better prognosis than conventional melanomas.215
Nevoid melanoma
Nevoid melanomas are tumors that at scanning magnification resemble ordinary compound or dermal nevi.84 In a study of 33 patients with nevoid melanoma, metastases developed in 15, and eight died of disseminated disease.216 Another study of 20 cases of nevoid melanoma showed at 3-year follow-up a metastasis and mortality rate of 37.5% as well as a local recurrence rate of 75%.217
Small cell melanoma
Small cell melanoma refers to a heterogeneous collection of melanomas composed primarily of small cells.84 A review of 94 patients with CMMs that were 0.76 mm or larger who underwent SLN biopsy evinced that the presence of small cells conferred a 56.9% chance of SLN metastasis and was a significant predictor of SLN metastasis in both univariate and multivariate analysis.102 The risk of metastasis increased to 86.3% for lesions with both small cells and ulceration. There was no significant
Desmoplasia
Desmoplastic melanoma (DM) is a rare variant of melanoma characterized by the presence of fusiform melanocytes dispersed in a prominent collagenous stroma.218 Since its first description by Conley in 1971, more than 600 cases of DM have been reported.219 Clinically, DM tends to occur on sun-damaged skin in the head and neck region, and the mean age of onset is consistently 10 years older than it is for patients with conventional melanoma.220, 221, 222, 223, 224, 225, 226 Histopathologically,
Neurotropism
Neurotropism is defined as neoplastic infiltration of nerve fibers with subsequent extension of the tumor along the surrounding nerves.228, 232, 238 Neurotropic melanomas, those melanomas that have strictly perineural or endoneural involvement without desmoplasia, or both,228 have been reported but are very rare and constitute less than 1% of all melanomas.239 Given their rarity, neurotropism in the literature is frequently studied in the context of the DNM subgroup of DM, which are uncommon
Cellular atypia
Only a few studies have specifically evaluated the prognostic significance of cellular atypia in melanomas. For example, in one study, 669 cases of CMM were assigned one of three values for cellular atypia: minimal atypia, marked atypia (anaplastic cells), or moderate atypia (in-between).246 The authors used the most atypical cells to assign a grade, even if those cells occurred in only a limited portion of the tumor. Lesions determined to have moderate atypia had a 10-year survival rate of
Association with a preexisting melanocytic nevus
Histologic reports indicate that approximately 25% of CMMs arise in association with a preexisting nevus, with an overall transformation rate of a single nevus into a melanoma of 0.0005% to 0.003%, depending on the patient's age.247
A study in the mid-1980s of 557 patients determined that the 5-year disease-free survival was significantly different in de novo (78%) versus nevus-associated (91%) melanomas, and rates of metastasis and death were 18.3% and 7.7%.248 More recently, another group
Paratumoral epidermal hyperplasia
The prognosis for melanoma may be related to architectural changes induced by the CMM on its local tissue environment. One such architectural change is hyperplasia of the epidermis surrounding the tumor. In a study looking at paratumoral epidermal hyperplasia (PTEH) as a potential prognostic factor, PTEH was defined as the difference between the deepest paratumoral epidermal penetration and the thickness of the adjacent normal epidermis.249 Paratumoral epidermal hyperplasia was assessed in 16
Satellite versus in-transit metastasis
A satellite metastasis is a tumor aggregate of at least 0.05 mm in diameter that is separated from the primary tumor by normal tissue but confined to a radius of 2 cm or less from the primary tumor. In-transit metastases are melanoma cells separated from the main tumor that are located outside the radius of 2 cm and usually occur as a result of intralymphatic trapping of melanoma cells between the primary tumor and regional lymph nodes.254
Most articles suggest that the presence of in-transit or
Conclusions
Abundant prognostic information is available in a routine CMM dermatopathology report. In our melanoma clinic, we routinely review this report with the patient so that he or she understands the nature of the neoplasm. We also use this information in formatting the frequency of our follow-up and individualized treatment plan for the patient. Table 7 summarizes and generalizes the significant prognostic information available in the melanoma dermatopathology report.
References (261)
- et al.
Skin melanoma in Italy: a population-based study on survival and prognostic factors
Eur J Cancer
(1998) - et al.
Individualized prognosis for melanoma patients
Hum Pathol
(2000) - et al.
Prognostic parameters in localised melanoma: gender versus anatomical location
Eur J Cancer
(1995) - et al.
Clinical outcomes of localized melanoma of the foot: a case-control study
J Clin Epidemiol
(1998) - et al.
The prognostic implications of location for scalp melanoma
Am J Surg
(1991) - et al.
Prognosticators of melanoma, the melanoma report, and the sentinel lymph node
Mod Pathol
(2006) - et al.
A prognostic model for clinical stage I melanoma of the trunk. Location near the midline is not an independent risk factor for recurrent disease
Am J Surg
(1981) - et al.
Prognostic histopathological factors in malignant melanoma
Pathology
(1985) - et al.
Prognostic factors in primary cutaneous melanoma
Surg Clin North Am
(2003) - et al.
Influence of level and depth on recurrence rate in thin melanomas
Am J Surg
(1993)