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Superficial Spreading Melanoma
13 Superficial Spreading Melanoma Pedram Gerami
OUTLINE Clinical Findings, 158 Histopathologic Findings, 158 Differential Diagnosis, 165 Superficial Spreading Melanoma Versus Dysplastic Nevus, 165 Distinction of Superficial Spreading Melanoma From Superficial Spitz Nevi, 165
Distinction of Superficial Spreading Melanoma Versus Other Melanomas, 166 Molecular and Cytogenetic Findings, 166 Fluorescence In Situ Hybridization for the Diagnosis of Superficial Spreading Melanoma, 166 Gene Expression Profiling, 166
The term superficial spreading melanoma (SSM) is commonly used to refer to melanomas characterized by a combination of clinical and histopathologic findings. They usually occur at intermittently sun-exposed sites, manifest as peripherally spreading surface lesions, and display an intraepidermal growth of melanocytes characterized by the presence of nests and/or pagetoid melanocytes. SSM is the most common melanoma variant among adolescents and young to middle-aged adults. In prepubertal children, nodular melanoma (NM) predominates. In adolescence the ratio of SSM to NM is approximately 2 : 1, and in adults the ratio is closer to 5 : 1, with SSM constituting approximately 60% to 70% of all melanomas in mid adulthood.1 SSM may occur in all areas of the body but are most frequent on the trunk and extremities. Ultraviolet (UV) light plays a role in the risk for developing an SSM. The odds ratio for developing an SSM is nearly 2 : 1 for individuals with a tendency to burn to those who never burn, when controlled for phototype. The odds ratio is nearly 2 : 1 for patients with their first burn before 15 to those with their first burn after age 15, also controlled for phototype.2 Another related risk factor for SSM is an elevated total body nevus count. From a pathomechanistic and epidemiologic perspective descriptive reporting of melanoma growth pattern as SSM versus lentigo maligna or acral melanoma has some value and follows tradition. However, for most clinical purposes this classification is of limited or no relevance. What clinically matters in a melanoma pathology report is the correct diagnosis of a tumor as melanoma and key prognostic parameters for American Joint Committee on Cancer (AJCC) tumor staging. In this textbook, melanoma subclassification mainly serves didactic purposes. The chapter on SSM is an opportunity to discuss diagnostic issues related to nested and pagetoid growth of melanocytes in the epidermis.
includes atypical pigment network, streaks, irregular blotches, and peripheral brown structureless areas (Table 13.1). The other structures such as negative pigment network, chrysalis, atypical dots and globules, blue white structures, and atypical vascular structures may be seen in SSM but are also frequent in other subtypes of melanoma (Figs. 13.2–13.4, see also Fig. 13.1). Most lesions of SSM arise de novo, but approximately 30% to 40% may develop in association with a precursor melanocytic nevus. There is currently no way to determine which nevi are most likely to be associated with a subsequent melanoma. The probability of a melanoma to arise in association with any given nevus, whether a common nevus, dysplastic, or other nevus, is extremely low. There are approximately 90,000 new cases of melanoma in the United States per year, of which 30% may have developed in association with a nevus (0.3 × 90,000 = 27,000 nevus-associated melanomas per year). If one considers 27,000 as the number of nevus-associated melanomas in the numerator of a fraction and the total number of dysplastic nevi in the United States (a number difficult to estimate) in the denominator, it is apparent that the fraction of dysplastic nevi with subsequent development of melanoma per year is a rare event.
CLINICAL FINDINGS SSM is the type of melanoma for which the ABCD rule for clinical melanoma diagnosis is most useful. Asymmetry, with irregular border, multiple colors, and diameter greater than 6 mm are clinical features that suggest melanoma (Fig. 13.1).3 Many of the 10 melanoma-specific dermoscopic structures are most relevant to identification of SSM. This
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HISTOPATHOLOGIC FINDINGS Histopathologically, SSM is distinguished from other melanoma types by the features of its in situ component. In SSM the intraepidermal tumor cells typically form nests and solitary units of atypical epithelioid melanocytes which are seen in the spinous cell layer in a pattern often referred to as “pagetoid” (e.g., similar to what is seen in Paget disease). The proportion of nests and solitary units may vary (Figs. 13.5–13.10). In some lesions, melanoma cells distributed in a pagetoid pattern constitute most of the intraepidermal tumor cell population. In others, nests may predominate. In most lesions, there is a mix of nests and solitary units. As with other melanoma variants, its silhouette is often asymmetric and its peripheral margin(s) ill defined. The asymmetry in the distribution of melanocytes may be accompanied by irregular melanization. Often SSMs will have effacement of the epidermis in focal areas. This may be seen in either the center of the lesion or at one lateral edge. Text continued on p. 165
CHAPTER 13 Superficial Spreading Melanoma
Keywords superficial spreading melanoma FISH gene expression profiling
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A
B
C
D
E Fig. 13.1 Pigmented Superficial Spreading Melanoma. (A) Non-polarized dermoscopy. Clinical appearance: asymmetric pigmented lesion with irregular borders and variations in color. (B) Polarized Dermoscopy. (C) Histopathology: asymmetric silhouette of a broad proliferation of melanocytes associated with inflammation. (D) Large junctional nests of atypical melanocytes are present at the dermoepidermal junction, varying in size and shape. Solitary units of melanocytes are scattered in the spinous cell layer. There is irregular distribution of melanin pigment, with melanophages associated with invasive melanoma. (E) There is discohesion of melanocytes within nests. The melanocytes display nuclear atypia and contain dusty cytoplasmic melanin pigment.
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TABLE 13.1 Distinguishing Features of Superficial Spreading Melanoma, Dysplastic Nevi, and
Spitz Nevi
Dermoscopic Features
Histologic Features
Molecular Features
Superficial Spreading Melanoma
Favors melanoma: • Atypical pigment network • Asymmetric streaks • Irregular blotches • Peripheral brown structureless area • Atypical vasculature • Inverse pigment pattern • Chrysalis • Blue gray veil • Regression structures • Atypical dots and globules
• Often has predominant growth pattern of single cells over nests with lentiginous or pagetoid growth pattern. Lesion maybe poorly circumscribed laterally. • Destructive features of the epidermis such as effacement or epidermal consumption favor melanoma, though recurrent or traumatized nevus needs to also be considered • Nested patterns should have quite notable nuclear atypia and often closely opposed nests along the rete ridges, which often expand the interretial space.
• Majority have driver mutations in BRAF, although NRAS driver mutations may also be seen. Subsequent genetic alterations include TERT promoter mutation or amplification, homozygous deletions or mutations of CDKN2A, and/or deletions or mutations in PTEN. • FISH positivity such as clonal gains in 6p25, 11q23, 8q24 or homozygous deletions in 9p21 all favor a diagnosis of melanoma.
Dysplastic Nevus
• May have 1 or 2 of the dermoscopic structures typical of melanoma, such as focal chrysalis or atypical network, irregular dots, or globules. • Typically will maintain some symmetry of dermoscopic structures at least in one axis.
• Typically have a predominantly nested pattern. • May have focal upward migration of melanocytes, typically toward the center of the lesion or around follicular units. • Some level of lateral circumscription is maintained.
• May have driver mutations in NRAS or BRAF and can have heterozygous deletions in CDKN2A but lack many of the other mutations typically of fully transformed lesions.
Spitz Nevus
• Dermoscopic symmetry is a key factor. • Frequent patterns include symmetric inverse pigment pattern with or without chrysalis, symmetric starburst pattern, and symmetric tiered globular pattern.
• Histomorphology can vary depending on the subtype, but generally some level of symmetry at the histologic level, as well as some level of lateral circumscription, should be present. • Epidermal hyperplasia is frequent and Kamino bodies are characteristic. • Clefted spaces between the epidermis and junctional melanocytes is frequent. • Single cells or nests can predominate in the epidermis but again some lateral circumscription should be present. Focal effacement of the epidermis may occur but broad effacement with epidermal consumption would raise concern for melanoma.
• HRAS mutations and/or HRAS copy number gains or fusions in ALK, NTRK, ROS, BRAF, or RET, NTRK3, and MET.
CHAPTER 13 Superficial Spreading Melanoma
A B
C
D Fig. 13.2 Superficial Spreading Melanoma. (A) Clinical appearance: postauricular pigmented lesion from a man with CDKN2A germline mutation. (B) Dermoscopy shows some residual network. There is a broad structureless area as well with a vascular blush. Some small irregular dots, some of which are black in color, are seen within the structureless area. In addition, superiorly, there is an area of peripheral brown structureless changes. (C) Histopathology: the melanocytic neoplasm shows flattening of the rete ridges, more confluent growth of atypical melanocytes, and pagetoid changes, likely corresponding to the structureless area. (D) Lesional area with complex melanocytic growth, including pagetoid spread of atypical melanocytes.
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B
C
D
E Fig. 13.3 Amelanotic Superficial Spreading Melanoma. (A) Clinical findings: irregular erythematous lesion. (B) Dermoscopy reveals shiny white structures. (C) Histopathology: asymmetric silhouette and complex growth of melanocytes in the epidermis and dermis, with a predominance of junctional nests at the dermoepidermal junction. No melanin pigment is seen. (D) Architectural disorder of melanocytes in the epidermis and dermis associated with dense inflammation. (E) At the periphery of the lesion, there is prominent pagetoid spread of melanocytes with nuclear atypia.
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Fig. 13.5 Superficial Spreading Melanoma With Dominant Pagetoid Spread of Single Tumor Cells. Large atypical melanocytes are predominantly distributed as solitary units at all layers of the epidermis.
A
Fig. 13.6 Superficial Spreading Melanoma With Dominant Nested Pattern. Melanoma cells are predominantly arranged in nests in the epidermis and dermis. A few pagetoid melanocytes are also seen.
B Fig. 13.4 Melanoma of Small Clinical Diameter. (A) Dermoscopy of a 2-mm macule reveals globules highly variable in size, shape, and color. (B) Histopathology: there is prominent pagetoid spread of atypical epithelioid melanocytes in the epidermis. There is associated inflammation and fibrosis in the dermis, and tiers of parakeratosis are present. A small nevus remnant is present underneath the fibrosis.
Fig. 13.7 Paucicellular Melanoma In Situ. A paucicellular proliferation of melanocytes distributed as solitary units at all layers of the epidermis is present. A similar picture was present throughout a broad area of the entire lesion.
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A
A
B
B
C
C Fig. 13.8 Melanoma With Sharp Circumscription and Minor Spitzoid Features. (A) Silhouette of the lesion. Large irregular nests are present in association with epidermal hyperplasia. (B) Cytologic atypia and mitoses are seen, as well as pagetoid spread. (C) Atypical intradermal melanocytes, some in mitosis. FISH studies of this tumor (not shown) revealed greater than 70% of melanocytes with clonal copy number gains at 6p25 (RREB1).
D Fig. 13.9 Melanoma With Nested Growth. (A) Clinical findings: large irregular and darkly pigmented papuled on the left flank. (B) Dermoscopy shows a peripheral ring of globules in combination with and area of blue gray veil towards the center of the lesion. There are also areas of atypical network. (C) Pathology: silhouette of a broad junctional melanocytic proliferation with nested growth. (D) Expansile and oddly shaped nests of melanocytes with abnormal melanin pigment distribution and nuclear atypia.
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B
A
Fig. 13.10 Melanoma With Predominant Nested Growth Pattern. (A) Asymmetric silhouette and complex growth of nests of various size and shapes at the dermoepidermal junction. The melanocytes are cytologically atypical and mitotically active. (B) FISH studies targeting 6p25 (RREB1) showed clonal copy number gains consistent with melanoma.
Most lesions measure more than 4 mm in diameter, but on occasion an SSM may present as a small macule (see Fig. 13.4). The cell density of most SSMs is high, but some early lesions may be paucicellular (see Fig. 13.7). Associated inflammation and/or fibrosis are common stromal changes. Secondary epidermal changes include epidermal hyperplasia, effacement of rete ridges (aka “consumption of the epidermis”), and ulceration. Some lesions of SMM are associated with a nevus remnant. The presence of a banal nevus remnant facilitates recognition of the melanoma because of the contrast in cytology and/or growth pattern.
DIFFERENTIAL DIAGNOSIS Superficial Spreading Melanoma Versus Dysplastic Nevus A common diagnostic challenge is the distinction of early SMM (de novo or in association with a melanocytic nevus) from a melanocytic nevus with atypical features, in particular a dysplastic nevus. This distinction can be difficult and arbitrary with regard to how many pagetoid melanocytes may be necessary to designate a lesion as “early melanoma in situ” versus “junctional nevus with atypical features.” A rare suprabasilar melanocyte, especially around follicular ostia or associated with features of irritation/trauma (parakeratosis, subepidermal fibrosis, hemorrhage) in the center of a junctional melanocytic proliferation, should not lead to a diagnosis of melanoma in situ when the remainder of the lesion shows features typical of a junctional dysplastic nevus. Florid pagetoid spread, or pagetoid spread in combination with other features associated with melanoma (lesional asymmetry, consumption of the epidermis, pagetoid spread located at the edge of the lesion), would favor a diagnosis of melanoma. However, it needs to be emphasized that pagetoid spread per se does not constitute proof of melanoma in situ because it can also be seen in traumatized nevi or in congenital nevi of children. When the histopathologic findings seem too subtle for unequivocal melanoma but too atypical for a simple designation of the lesion as a “nevus,” one may use such terms as “atypical intraepidermal melanocytic proliferation,” “junctional melanocytic proliferation insufficient for a
diagnosis of melanoma in situ,” or “de novo melanocytic dysplasia” to report such atypical junctional melanocytic proliferations (see Fig. 13.7). Although pagetoid melanocytes do not necessarily reflect melanoma in situ, their absence does not ensure the presence of a nevus. Some cases of SSM may have a predominantly nested pattern with little or no pagetoid spread (see Figs. 13.9 and 13.10). In such cases, attention to the overall symmetry of the lesion, the presence of expansile nests with mitotic activity, coalescence of large melanocytic nests with consumption of the epidermis, or marked nuclear atypia are helpful clues to the diagnosis of melanoma. Clinical and dermoscopic information may also provide another category of evidence to support one diagnosis over the other. For example, a clinical history of a previously stable lesion that has more recently been continually changing may be significant. Not all types of change are of equal value, and as a whole the parameter of change has a specificity of only approximately 20% for melanoma. The presence of melanoma-specific structures on dermoscopy is important and should be taken into account for histopathologically ambiguous or borderline lesions. For example, a melanocytic neoplasm with a histomorphologic differential diagnosis of dysplastic nevus with severe atypia versus early radial growth phase SSM is more likely to be SSM, if dermoscopic exam shows the presence of asymmetric streaks (either in the form of radial streaming or pseudopods), a notable peripheral brown structureless area, or a peripheral black blotch occupying more than 10% of the lesion or gray blue veil. The presence of a nevus remnant with a malignant melanoma growing from one lateral component is what often results in the asymmetry both at the gross and dermoscopic level.4 Alternatively, dermoscopically symmetric lesions or lesions matching one of the recognized benign nevus categories with a history of being clinically stable would clearly favor a diagnosis of dysplastic nevus.
Distinction of Superficial Spreading Melanoma From Superficial Spitz Nevi De novo SSM in situ needs to be distinguished from a pagetoid Spitz nevus. In a pagetoid Spitz nevus, the lesion may consist entirely of single melanocytes, but the cells should have a spitzoid cytology, with
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abundant eosinophilic cytoplasm, open nuclear chromatin, and lack of severe nuclear atypia. The cells should be somewhat evenly spaced out across the lower part of the epidermis, often clustered in the rete pegs and have somewhat of a well-defined start and stop. Some lesions of invasive SSM cases may also display minor spitzoid features (see Fig. 13.10). If the clinical and dermoscopic findings favor melanoma, the histopathologic silhouette is asymmetric, prominent irregular pagetoid spread is noted, and the advancing edge of the lesion is ill-defined, a diagnosis of melanoma can be established irrespective of the presence of spitzoid cytologic features. The distinction is more difficult for lesions with a nevoid silhouette with relatively sharp lateral borders. In those cases, ancillary studies, in particular cytogenetic studies, may be helpful to establish a diagnosis of melanoma. Dermoscopy can also assist in the distinction of spitzoid SSM from Spitz nevi. Asymmetric presence of streaks, peripheral blotches occupying greater than 10% of the lesion, peripheral brown structureless areas, or gray blue veil all favor a diagnosis of melanoma. Conversely, the presence of a symmetric inverse pigment pattern with or without chrysalis or a symmetric starburst pattern are acceptable patterns in benign spitzoid neoplasm.5 Demographic features also merit consideration to assess the odds of melanoma versus nevus. If a spitzoid lesion is located on the extremity of a young patient, it is more likely benign compared with a truncal location of an older individual or in an area of skin with notable solar damage. Because Spitz nevi can go through very rapid proliferative phases and not uncommonly have a history of scaling, scabbing, or bleeding, the presence of such features does not imply malignancy and limits the use of these findings for diagnostic purposes.
Distinction of Superficial Spreading Melanoma Versus Other Melanomas Not all melanomas of low to intermittently sun-damaged skin display histopathologically prominent intraepidermal nested or pagetoid growth. Their in situ component may show a predominant lentiginous junctional distribution of tumor cells. These melanocytic neoplasms can be recognized as melanomas in spite of the absence of pagetoid spread, because of marked variations in the density and pattern of lentiginous junctional growth, irregular distribution of melanin pigment, and/or associated stromal (fibrosis, inflammation) or epidermal (consumption of the rete ridges) changes conveying asymmetry. Ill-defined lentiginous junctional growth of melanocytes at the periphery of the lesion contributes to poor circumscription, which also raises the suspicion for melanoma. Clinical context, in particular dermoscopic findings, are helpful for the diagnosis of these lesions. Furthermore, not all melanomas with pagetoid or nested growth are SSM. Nests and pagetoid melanocytes can also be found in lentigo maligna, acral melanomas, and focally in NMs. Attention to anatomic site, extent of solar elastosis, and/or the predominant lentiginous growth pattern of the remainder of the lesion facilitate the distinction of lentigo maligna or acral lentiginous melanoma from SSM. The absence of a radial growth phase or any melanoma in situ distinguishes NM from SSM.
MOLECULAR AND CYTOGENETIC FINDINGS Most SSMs will have a driver mutation involving BRAF. However, NRAS or other mutations may also be seen in SSMs. Epidemiologic studies have shown that among melanomas on skin without cumulative sun damage (CSD), the probability of a BRAF mutation is significantly higher in patients younger than 40.6 In a study from Shain et al.,7 BRAF V600E melanomas were most likely to originate from an unequivocal precursor nevus in younger patients. In contrast, NRAS, BRAF V600K, or BRAF K601E mutant melanomas were more likely to occur in older patients with either a precursor melanoma in situ or a more intermediate lesion. In addition to younger age, presence in intermittently sun-damaged
skin rather than chronically sun-damaged skin and association with a precursor nevus are associated with BRAF mutations. From a diagnostic perspective, the presence of a BRAF mutation cannot differentiate dysplastic nevi from SSM but can be useful for the distinction from a spitzoid neoplasm because BRAF mutations are common in SSM but uncommon in spitzoid lesions. Although BRAF and NRAS mutations are common in both melanocytic nevi and SSM, it is the accumulation of additional genomic events over time, typically the result of UV exposure, that results in the transformation of nevi to melanoma.7 Some critical additional genomic events leading to transformation with an initiating activating mutation in BRAF or NRAS include subsequent TERT promoter mutation or amplification, homozygous deletion or mutation in CDKN2A, or PTEN deletions or mutations.8,9
Fluorescence In Situ Hybridization for the Diagnosis of Superficial Spreading Melanoma In one study of invasive SSMs with a mixture of radial and vertical growth phase lesions, fluorescence in situ hybridization (FISH) using the standard four-probe assay targeting 6p25, 6q23, CEP6, and 11q13 had a sensitivity of 81%.10 The most common aberration was clonal segmental gains in 6p25. The addition of 8q24, particularly for amelanotic cases, and 9p21 can improve the sensitivity of the test.11 In general, copy number gains detected by FISH are diagnostically more suitable and relevant when found in cell aggregates as evidence of clonal expansion. In small and thin lesions of SSM, FISH may be preferable to comparative genomic hybridization (CGH) due to limited tumor volume and purity. Pitfalls exist for false-positive (e.g., tetraploidy) or falsenegative results.
Gene Expression Profiling A qualitative reverse transcription polymerase chain reaction (qRT-PCR) assay–based gene expression test has been developed that assesses mRNA expression levels of 23 distinct genes from formalin-fixed paraffinembedded tissue as a molecular technique to differentiate melanoma from nevi.12 The 23 genes include preferentially expressed antigen in melanoma (PRAME), which is also a known melanoma tumor antigen; 5 S100A genes known as the S100A9 component; and 8 immune-related genes, as well as 9 housekeeping genes. In a validation set of 1400 melanocytic lesions, the test performed with a sensitivity of 91.5% and specificity of 92.5%.13 Advantages of this assay are that it can be performed on relatively paucicellular lesions and that it has been studied in relatively large validation cohorts. However, there are limited data on the value of the test for ambiguous cases with long-term follow-up. Although we know of anecdotal cases in which the test has been helpful to establish the correct diagnosis, we also know of cases in which the test result was misleading. Thus further studies are needed to determine the clinical value of this assay.
REFERENCES 1. Bay C, et al. Incidence and survival in patients with cutaneous melanoma by morphology, anatomical site and TNM stage: a Danish Population-based Register Study 1989-2011. Cancer Epidemiol. 2015;39(1):1–7. 2. Naldi L, et al. Pigmentary traits, modalities of sun reaction, history of sunburns, and melanocytic nevi as risk factors for cutaneous malignant melanoma in the Italian population: results of a collaborative case-control study. Cancer. 2000;88(12):2703–2710. 3. Rigel DS, et al. ABCDE–an evolving concept in the early detection of melanoma. Arch Dermatol. 2005;141(8):1032–1034. 4. Shitara D, et al. Dermoscopy of naevus-associated melanomas. Acta Derm Venereol. 2015;95(6):671–675.
CHAPTER 13 Superficial Spreading Melanoma 5. Lallas A, et al. Update on dermoscopy of Spitz/Reed naevi and management guidelines by the International Dermoscopy Society. Br J Dermatol. 2017. 6. Long GV, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–1246. 7. Shain AH, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926–1936. 8. Huang FW, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339(6122):957–959. 9. Dankort D, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41(5):544–552.
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10. Gerami P, et al. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes. Arch Dermatol. 2010;146(3):273–278. 11. Pouryazdanparast P, et al. The role of 8q24 copy number gains and c-MYC expression in amelanotic cutaneous melanoma. Mod Pathol. 2012;25(9):1221–1226. 12. Clarke LE, et al. Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma. J Cutan Pathol. 2015;42(4):244–252. 13. Clarke LE, et al. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. Cancer. 2016.
OUTLINE Clinical Findings, 158 Histopathologic Findings, 158 Differential Diagnosis, 165 Superficial Spreading Melanoma Versus Dysplastic Nevus, 165 Distinction of Superficial Spreading Melanoma From Superficial Spitz Nevi, 165
Distinction of Superficial Spreading Melanoma Versus Other Melanomas, 166 Molecular and Cytogenetic Findings, 166 Fluorescence In Situ Hybridization for the Diagnosis of Superficial Spreading Melanoma, 166 Gene Expression Profiling, 166
The term superficial spreading melanoma (SSM) is commonly used to refer to melanomas characterized by a combination of clinical and histopathologic findings. They usually occur at intermittently sun-exposed sites, manifest as peripherally spreading surface lesions, and display an intraepidermal growth of melanocytes characterized by the presence of nests and/or pagetoid melanocytes. SSM is the most common melanoma variant among adolescents and young to middle-aged adults. In prepubertal children, nodular melanoma (NM) predominates. In adolescence the ratio of SSM to NM is approximately 2 : 1, and in adults the ratio is closer to 5 : 1, with SSM constituting approximately 60% to 70% of all melanomas in mid adulthood.1 SSM may occur in all areas of the body but are most frequent on the trunk and extremities. Ultraviolet (UV) light plays a role in the risk for developing an SSM. The odds ratio for developing an SSM is nearly 2 : 1 for individuals with a tendency to burn to those who never burn, when controlled for phototype. The odds ratio is nearly 2 : 1 for patients with their first burn before 15 to those with their first burn after age 15, also controlled for phototype.2 Another related risk factor for SSM is an elevated total body nevus count. From a pathomechanistic and epidemiologic perspective descriptive reporting of melanoma growth pattern as SSM versus lentigo maligna or acral melanoma has some value and follows tradition. However, for most clinical purposes this classification is of limited or no relevance. What clinically matters in a melanoma pathology report is the correct diagnosis of a tumor as melanoma and key prognostic parameters for American Joint Committee on Cancer (AJCC) tumor staging. In this textbook, melanoma subclassification mainly serves didactic purposes. The chapter on SSM is an opportunity to discuss diagnostic issues related to nested and pagetoid growth of melanocytes in the epidermis.
includes atypical pigment network, streaks, irregular blotches, and peripheral brown structureless areas (Table 13.1). The other structures such as negative pigment network, chrysalis, atypical dots and globules, blue white structures, and atypical vascular structures may be seen in SSM but are also frequent in other subtypes of melanoma (Figs. 13.2–13.4, see also Fig. 13.1). Most lesions of SSM arise de novo, but approximately 30% to 40% may develop in association with a precursor melanocytic nevus. There is currently no way to determine which nevi are most likely to be associated with a subsequent melanoma. The probability of a melanoma to arise in association with any given nevus, whether a common nevus, dysplastic, or other nevus, is extremely low. There are approximately 90,000 new cases of melanoma in the United States per year, of which 30% may have developed in association with a nevus (0.3 × 90,000 = 27,000 nevus-associated melanomas per year). If one considers 27,000 as the number of nevus-associated melanomas in the numerator of a fraction and the total number of dysplastic nevi in the United States (a number difficult to estimate) in the denominator, it is apparent that the fraction of dysplastic nevi with subsequent development of melanoma per year is a rare event.
CLINICAL FINDINGS SSM is the type of melanoma for which the ABCD rule for clinical melanoma diagnosis is most useful. Asymmetry, with irregular border, multiple colors, and diameter greater than 6 mm are clinical features that suggest melanoma (Fig. 13.1).3 Many of the 10 melanoma-specific dermoscopic structures are most relevant to identification of SSM. This
158
HISTOPATHOLOGIC FINDINGS Histopathologically, SSM is distinguished from other melanoma types by the features of its in situ component. In SSM the intraepidermal tumor cells typically form nests and solitary units of atypical epithelioid melanocytes which are seen in the spinous cell layer in a pattern often referred to as “pagetoid” (e.g., similar to what is seen in Paget disease). The proportion of nests and solitary units may vary (Figs. 13.5–13.10). In some lesions, melanoma cells distributed in a pagetoid pattern constitute most of the intraepidermal tumor cell population. In others, nests may predominate. In most lesions, there is a mix of nests and solitary units. As with other melanoma variants, its silhouette is often asymmetric and its peripheral margin(s) ill defined. The asymmetry in the distribution of melanocytes may be accompanied by irregular melanization. Often SSMs will have effacement of the epidermis in focal areas. This may be seen in either the center of the lesion or at one lateral edge. Text continued on p. 165
CHAPTER 13 Superficial Spreading Melanoma
Keywords superficial spreading melanoma FISH gene expression profiling
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CHAPTER 13 Superficial Spreading Melanoma
A
B
C
D
E Fig. 13.1 Pigmented Superficial Spreading Melanoma. (A) Non-polarized dermoscopy. Clinical appearance: asymmetric pigmented lesion with irregular borders and variations in color. (B) Polarized Dermoscopy. (C) Histopathology: asymmetric silhouette of a broad proliferation of melanocytes associated with inflammation. (D) Large junctional nests of atypical melanocytes are present at the dermoepidermal junction, varying in size and shape. Solitary units of melanocytes are scattered in the spinous cell layer. There is irregular distribution of melanin pigment, with melanophages associated with invasive melanoma. (E) There is discohesion of melanocytes within nests. The melanocytes display nuclear atypia and contain dusty cytoplasmic melanin pigment.
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TABLE 13.1 Distinguishing Features of Superficial Spreading Melanoma, Dysplastic Nevi, and
Spitz Nevi
Dermoscopic Features
Histologic Features
Molecular Features
Superficial Spreading Melanoma
Favors melanoma: • Atypical pigment network • Asymmetric streaks • Irregular blotches • Peripheral brown structureless area • Atypical vasculature • Inverse pigment pattern • Chrysalis • Blue gray veil • Regression structures • Atypical dots and globules
• Often has predominant growth pattern of single cells over nests with lentiginous or pagetoid growth pattern. Lesion maybe poorly circumscribed laterally. • Destructive features of the epidermis such as effacement or epidermal consumption favor melanoma, though recurrent or traumatized nevus needs to also be considered • Nested patterns should have quite notable nuclear atypia and often closely opposed nests along the rete ridges, which often expand the interretial space.
• Majority have driver mutations in BRAF, although NRAS driver mutations may also be seen. Subsequent genetic alterations include TERT promoter mutation or amplification, homozygous deletions or mutations of CDKN2A, and/or deletions or mutations in PTEN. • FISH positivity such as clonal gains in 6p25, 11q23, 8q24 or homozygous deletions in 9p21 all favor a diagnosis of melanoma.
Dysplastic Nevus
• May have 1 or 2 of the dermoscopic structures typical of melanoma, such as focal chrysalis or atypical network, irregular dots, or globules. • Typically will maintain some symmetry of dermoscopic structures at least in one axis.
• Typically have a predominantly nested pattern. • May have focal upward migration of melanocytes, typically toward the center of the lesion or around follicular units. • Some level of lateral circumscription is maintained.
• May have driver mutations in NRAS or BRAF and can have heterozygous deletions in CDKN2A but lack many of the other mutations typically of fully transformed lesions.
Spitz Nevus
• Dermoscopic symmetry is a key factor. • Frequent patterns include symmetric inverse pigment pattern with or without chrysalis, symmetric starburst pattern, and symmetric tiered globular pattern.
• Histomorphology can vary depending on the subtype, but generally some level of symmetry at the histologic level, as well as some level of lateral circumscription, should be present. • Epidermal hyperplasia is frequent and Kamino bodies are characteristic. • Clefted spaces between the epidermis and junctional melanocytes is frequent. • Single cells or nests can predominate in the epidermis but again some lateral circumscription should be present. Focal effacement of the epidermis may occur but broad effacement with epidermal consumption would raise concern for melanoma.
• HRAS mutations and/or HRAS copy number gains or fusions in ALK, NTRK, ROS, BRAF, or RET, NTRK3, and MET.
CHAPTER 13 Superficial Spreading Melanoma
A B
C
D Fig. 13.2 Superficial Spreading Melanoma. (A) Clinical appearance: postauricular pigmented lesion from a man with CDKN2A germline mutation. (B) Dermoscopy shows some residual network. There is a broad structureless area as well with a vascular blush. Some small irregular dots, some of which are black in color, are seen within the structureless area. In addition, superiorly, there is an area of peripheral brown structureless changes. (C) Histopathology: the melanocytic neoplasm shows flattening of the rete ridges, more confluent growth of atypical melanocytes, and pagetoid changes, likely corresponding to the structureless area. (D) Lesional area with complex melanocytic growth, including pagetoid spread of atypical melanocytes.
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E Fig. 13.3 Amelanotic Superficial Spreading Melanoma. (A) Clinical findings: irregular erythematous lesion. (B) Dermoscopy reveals shiny white structures. (C) Histopathology: asymmetric silhouette and complex growth of melanocytes in the epidermis and dermis, with a predominance of junctional nests at the dermoepidermal junction. No melanin pigment is seen. (D) Architectural disorder of melanocytes in the epidermis and dermis associated with dense inflammation. (E) At the periphery of the lesion, there is prominent pagetoid spread of melanocytes with nuclear atypia.
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Fig. 13.5 Superficial Spreading Melanoma With Dominant Pagetoid Spread of Single Tumor Cells. Large atypical melanocytes are predominantly distributed as solitary units at all layers of the epidermis.
A
Fig. 13.6 Superficial Spreading Melanoma With Dominant Nested Pattern. Melanoma cells are predominantly arranged in nests in the epidermis and dermis. A few pagetoid melanocytes are also seen.
B Fig. 13.4 Melanoma of Small Clinical Diameter. (A) Dermoscopy of a 2-mm macule reveals globules highly variable in size, shape, and color. (B) Histopathology: there is prominent pagetoid spread of atypical epithelioid melanocytes in the epidermis. There is associated inflammation and fibrosis in the dermis, and tiers of parakeratosis are present. A small nevus remnant is present underneath the fibrosis.
Fig. 13.7 Paucicellular Melanoma In Situ. A paucicellular proliferation of melanocytes distributed as solitary units at all layers of the epidermis is present. A similar picture was present throughout a broad area of the entire lesion.
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A
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C Fig. 13.8 Melanoma With Sharp Circumscription and Minor Spitzoid Features. (A) Silhouette of the lesion. Large irregular nests are present in association with epidermal hyperplasia. (B) Cytologic atypia and mitoses are seen, as well as pagetoid spread. (C) Atypical intradermal melanocytes, some in mitosis. FISH studies of this tumor (not shown) revealed greater than 70% of melanocytes with clonal copy number gains at 6p25 (RREB1).
D Fig. 13.9 Melanoma With Nested Growth. (A) Clinical findings: large irregular and darkly pigmented papuled on the left flank. (B) Dermoscopy shows a peripheral ring of globules in combination with and area of blue gray veil towards the center of the lesion. There are also areas of atypical network. (C) Pathology: silhouette of a broad junctional melanocytic proliferation with nested growth. (D) Expansile and oddly shaped nests of melanocytes with abnormal melanin pigment distribution and nuclear atypia.
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Fig. 13.10 Melanoma With Predominant Nested Growth Pattern. (A) Asymmetric silhouette and complex growth of nests of various size and shapes at the dermoepidermal junction. The melanocytes are cytologically atypical and mitotically active. (B) FISH studies targeting 6p25 (RREB1) showed clonal copy number gains consistent with melanoma.
Most lesions measure more than 4 mm in diameter, but on occasion an SSM may present as a small macule (see Fig. 13.4). The cell density of most SSMs is high, but some early lesions may be paucicellular (see Fig. 13.7). Associated inflammation and/or fibrosis are common stromal changes. Secondary epidermal changes include epidermal hyperplasia, effacement of rete ridges (aka “consumption of the epidermis”), and ulceration. Some lesions of SMM are associated with a nevus remnant. The presence of a banal nevus remnant facilitates recognition of the melanoma because of the contrast in cytology and/or growth pattern.
DIFFERENTIAL DIAGNOSIS Superficial Spreading Melanoma Versus Dysplastic Nevus A common diagnostic challenge is the distinction of early SMM (de novo or in association with a melanocytic nevus) from a melanocytic nevus with atypical features, in particular a dysplastic nevus. This distinction can be difficult and arbitrary with regard to how many pagetoid melanocytes may be necessary to designate a lesion as “early melanoma in situ” versus “junctional nevus with atypical features.” A rare suprabasilar melanocyte, especially around follicular ostia or associated with features of irritation/trauma (parakeratosis, subepidermal fibrosis, hemorrhage) in the center of a junctional melanocytic proliferation, should not lead to a diagnosis of melanoma in situ when the remainder of the lesion shows features typical of a junctional dysplastic nevus. Florid pagetoid spread, or pagetoid spread in combination with other features associated with melanoma (lesional asymmetry, consumption of the epidermis, pagetoid spread located at the edge of the lesion), would favor a diagnosis of melanoma. However, it needs to be emphasized that pagetoid spread per se does not constitute proof of melanoma in situ because it can also be seen in traumatized nevi or in congenital nevi of children. When the histopathologic findings seem too subtle for unequivocal melanoma but too atypical for a simple designation of the lesion as a “nevus,” one may use such terms as “atypical intraepidermal melanocytic proliferation,” “junctional melanocytic proliferation insufficient for a
diagnosis of melanoma in situ,” or “de novo melanocytic dysplasia” to report such atypical junctional melanocytic proliferations (see Fig. 13.7). Although pagetoid melanocytes do not necessarily reflect melanoma in situ, their absence does not ensure the presence of a nevus. Some cases of SSM may have a predominantly nested pattern with little or no pagetoid spread (see Figs. 13.9 and 13.10). In such cases, attention to the overall symmetry of the lesion, the presence of expansile nests with mitotic activity, coalescence of large melanocytic nests with consumption of the epidermis, or marked nuclear atypia are helpful clues to the diagnosis of melanoma. Clinical and dermoscopic information may also provide another category of evidence to support one diagnosis over the other. For example, a clinical history of a previously stable lesion that has more recently been continually changing may be significant. Not all types of change are of equal value, and as a whole the parameter of change has a specificity of only approximately 20% for melanoma. The presence of melanoma-specific structures on dermoscopy is important and should be taken into account for histopathologically ambiguous or borderline lesions. For example, a melanocytic neoplasm with a histomorphologic differential diagnosis of dysplastic nevus with severe atypia versus early radial growth phase SSM is more likely to be SSM, if dermoscopic exam shows the presence of asymmetric streaks (either in the form of radial streaming or pseudopods), a notable peripheral brown structureless area, or a peripheral black blotch occupying more than 10% of the lesion or gray blue veil. The presence of a nevus remnant with a malignant melanoma growing from one lateral component is what often results in the asymmetry both at the gross and dermoscopic level.4 Alternatively, dermoscopically symmetric lesions or lesions matching one of the recognized benign nevus categories with a history of being clinically stable would clearly favor a diagnosis of dysplastic nevus.
Distinction of Superficial Spreading Melanoma From Superficial Spitz Nevi De novo SSM in situ needs to be distinguished from a pagetoid Spitz nevus. In a pagetoid Spitz nevus, the lesion may consist entirely of single melanocytes, but the cells should have a spitzoid cytology, with
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abundant eosinophilic cytoplasm, open nuclear chromatin, and lack of severe nuclear atypia. The cells should be somewhat evenly spaced out across the lower part of the epidermis, often clustered in the rete pegs and have somewhat of a well-defined start and stop. Some lesions of invasive SSM cases may also display minor spitzoid features (see Fig. 13.10). If the clinical and dermoscopic findings favor melanoma, the histopathologic silhouette is asymmetric, prominent irregular pagetoid spread is noted, and the advancing edge of the lesion is ill-defined, a diagnosis of melanoma can be established irrespective of the presence of spitzoid cytologic features. The distinction is more difficult for lesions with a nevoid silhouette with relatively sharp lateral borders. In those cases, ancillary studies, in particular cytogenetic studies, may be helpful to establish a diagnosis of melanoma. Dermoscopy can also assist in the distinction of spitzoid SSM from Spitz nevi. Asymmetric presence of streaks, peripheral blotches occupying greater than 10% of the lesion, peripheral brown structureless areas, or gray blue veil all favor a diagnosis of melanoma. Conversely, the presence of a symmetric inverse pigment pattern with or without chrysalis or a symmetric starburst pattern are acceptable patterns in benign spitzoid neoplasm.5 Demographic features also merit consideration to assess the odds of melanoma versus nevus. If a spitzoid lesion is located on the extremity of a young patient, it is more likely benign compared with a truncal location of an older individual or in an area of skin with notable solar damage. Because Spitz nevi can go through very rapid proliferative phases and not uncommonly have a history of scaling, scabbing, or bleeding, the presence of such features does not imply malignancy and limits the use of these findings for diagnostic purposes.
Distinction of Superficial Spreading Melanoma Versus Other Melanomas Not all melanomas of low to intermittently sun-damaged skin display histopathologically prominent intraepidermal nested or pagetoid growth. Their in situ component may show a predominant lentiginous junctional distribution of tumor cells. These melanocytic neoplasms can be recognized as melanomas in spite of the absence of pagetoid spread, because of marked variations in the density and pattern of lentiginous junctional growth, irregular distribution of melanin pigment, and/or associated stromal (fibrosis, inflammation) or epidermal (consumption of the rete ridges) changes conveying asymmetry. Ill-defined lentiginous junctional growth of melanocytes at the periphery of the lesion contributes to poor circumscription, which also raises the suspicion for melanoma. Clinical context, in particular dermoscopic findings, are helpful for the diagnosis of these lesions. Furthermore, not all melanomas with pagetoid or nested growth are SSM. Nests and pagetoid melanocytes can also be found in lentigo maligna, acral melanomas, and focally in NMs. Attention to anatomic site, extent of solar elastosis, and/or the predominant lentiginous growth pattern of the remainder of the lesion facilitate the distinction of lentigo maligna or acral lentiginous melanoma from SSM. The absence of a radial growth phase or any melanoma in situ distinguishes NM from SSM.
MOLECULAR AND CYTOGENETIC FINDINGS Most SSMs will have a driver mutation involving BRAF. However, NRAS or other mutations may also be seen in SSMs. Epidemiologic studies have shown that among melanomas on skin without cumulative sun damage (CSD), the probability of a BRAF mutation is significantly higher in patients younger than 40.6 In a study from Shain et al.,7 BRAF V600E melanomas were most likely to originate from an unequivocal precursor nevus in younger patients. In contrast, NRAS, BRAF V600K, or BRAF K601E mutant melanomas were more likely to occur in older patients with either a precursor melanoma in situ or a more intermediate lesion. In addition to younger age, presence in intermittently sun-damaged
skin rather than chronically sun-damaged skin and association with a precursor nevus are associated with BRAF mutations. From a diagnostic perspective, the presence of a BRAF mutation cannot differentiate dysplastic nevi from SSM but can be useful for the distinction from a spitzoid neoplasm because BRAF mutations are common in SSM but uncommon in spitzoid lesions. Although BRAF and NRAS mutations are common in both melanocytic nevi and SSM, it is the accumulation of additional genomic events over time, typically the result of UV exposure, that results in the transformation of nevi to melanoma.7 Some critical additional genomic events leading to transformation with an initiating activating mutation in BRAF or NRAS include subsequent TERT promoter mutation or amplification, homozygous deletion or mutation in CDKN2A, or PTEN deletions or mutations.8,9
Fluorescence In Situ Hybridization for the Diagnosis of Superficial Spreading Melanoma In one study of invasive SSMs with a mixture of radial and vertical growth phase lesions, fluorescence in situ hybridization (FISH) using the standard four-probe assay targeting 6p25, 6q23, CEP6, and 11q13 had a sensitivity of 81%.10 The most common aberration was clonal segmental gains in 6p25. The addition of 8q24, particularly for amelanotic cases, and 9p21 can improve the sensitivity of the test.11 In general, copy number gains detected by FISH are diagnostically more suitable and relevant when found in cell aggregates as evidence of clonal expansion. In small and thin lesions of SSM, FISH may be preferable to comparative genomic hybridization (CGH) due to limited tumor volume and purity. Pitfalls exist for false-positive (e.g., tetraploidy) or falsenegative results.
Gene Expression Profiling A qualitative reverse transcription polymerase chain reaction (qRT-PCR) assay–based gene expression test has been developed that assesses mRNA expression levels of 23 distinct genes from formalin-fixed paraffinembedded tissue as a molecular technique to differentiate melanoma from nevi.12 The 23 genes include preferentially expressed antigen in melanoma (PRAME), which is also a known melanoma tumor antigen; 5 S100A genes known as the S100A9 component; and 8 immune-related genes, as well as 9 housekeeping genes. In a validation set of 1400 melanocytic lesions, the test performed with a sensitivity of 91.5% and specificity of 92.5%.13 Advantages of this assay are that it can be performed on relatively paucicellular lesions and that it has been studied in relatively large validation cohorts. However, there are limited data on the value of the test for ambiguous cases with long-term follow-up. Although we know of anecdotal cases in which the test has been helpful to establish the correct diagnosis, we also know of cases in which the test result was misleading. Thus further studies are needed to determine the clinical value of this assay.
REFERENCES 1. Bay C, et al. Incidence and survival in patients with cutaneous melanoma by morphology, anatomical site and TNM stage: a Danish Population-based Register Study 1989-2011. Cancer Epidemiol. 2015;39(1):1–7. 2. Naldi L, et al. Pigmentary traits, modalities of sun reaction, history of sunburns, and melanocytic nevi as risk factors for cutaneous malignant melanoma in the Italian population: results of a collaborative case-control study. Cancer. 2000;88(12):2703–2710. 3. Rigel DS, et al. ABCDE–an evolving concept in the early detection of melanoma. Arch Dermatol. 2005;141(8):1032–1034. 4. Shitara D, et al. Dermoscopy of naevus-associated melanomas. Acta Derm Venereol. 2015;95(6):671–675.
CHAPTER 13 Superficial Spreading Melanoma 5. Lallas A, et al. Update on dermoscopy of Spitz/Reed naevi and management guidelines by the International Dermoscopy Society. Br J Dermatol. 2017. 6. Long GV, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–1246. 7. Shain AH, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926–1936. 8. Huang FW, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339(6122):957–959. 9. Dankort D, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41(5):544–552.
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10. Gerami P, et al. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes. Arch Dermatol. 2010;146(3):273–278. 11. Pouryazdanparast P, et al. The role of 8q24 copy number gains and c-MYC expression in amelanotic cutaneous melanoma. Mod Pathol. 2012;25(9):1221–1226. 12. Clarke LE, et al. Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma. J Cutan Pathol. 2015;42(4):244–252. 13. Clarke LE, et al. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. Cancer. 2016.