Pathology of David E. Elder

Abstract The purposes of pathologic examination of a lesion suspected of being a malignant melanoma are to provide an accurate diagnosis of melanoma (or not), and to provide prognostic information use- ful in the clinical management of the patient. In the near future, pathologic attributes will also likely be used to predict responses to therapy, as a guide to the selection of specific therapeutic agents such as ‘‘small molecule’’ inhibitors of signaling pathways.

Accurate Diagnosis of Melanoma invasive melanoma cannot be ruled out, we may use a descriptive term such as ‘‘superficial (or intraepithelial) Like other cancers, most malignant evolve atypical melanocytic proliferation of uncertain significance,’’ through stages of tumor progression. Clinically, many mela- with a statement as to the differential diagnosis. Treatment nomas begin as a pigmented patch of skin which evolves of these lesions should be based on excision with, at a to become a palpable plaque, and enlarges as if it were minimum, a pathologically confirmed clear margin around along the radii of an imperfect circle. This stage or ‘‘phase’’ of the scar of the procedure and any residual lesion. Tumorigenic progression has been termed the ‘‘radial growth phase’’ (RGP) lesions that may simulate melanomas include Spitz nevi, based on this clinical analogy (1, 2). Many melanomas, at the cellular nodules in congenital nevi, deep penetrating nevi, time of diagnosis, have progressed to the next phase of cellular blue nevi, pigmented epithelioid melanocytomas, and progression or ‘‘vertical growth phase’’ (VGP), in which a others (8). In such cases, we may use a descriptive diagnosis tumor papule appears, often within the confines of a pre- such as ‘‘melanocytic tumor of uncertain potential,’’ again existing RGP or sometimes de novo in clinically normal skin. with a statement as to the differential diagnosis that includes This papule enlarges to become a nodule and may become information as to the microstaging factors that might be ulcerated. Histologically, as well as clinically, melanomas can applicable if the lesion is a melanoma. Treatment may include be categorized as ‘‘nontumorigenic’’ or ‘‘tumorigenic.’’ Metas- a consideration of sentinel lymph node (SLN) sampling and, tasis is very rare in nontumorigenic melanomas, whereas possibly, adjuvant therapy. melanomas with a tumorigenic compartment may have competence for metastasis (3–5). Tumorigenic and Mitogenic (VGP) Melanoma Whereas most melanomas are diagnosed rapidly, repro- ducibly, and accurately by routine pathology, there are The original observations that melanomas commonly troublesome subsets of cases in which an accurate, agreed progress from a nontumorigenic ‘‘RGP’’ to a tumorigenic on diagnosis may be impossible to achieve (6, 7). We believe ‘‘VGP’’ are supported by many observations. First, the excellent that in such cases, it is best to express uncertainty directly, survival of patients whose melanomas lacked VGP has been rather than sweeping all doubt ‘‘under the rug.’’ Patients documented (3, 9). The metastasis rate in patients with mela- deserve to understand their differential diagnosis, and nomas that are confined to the RGP is of the order of 1% to therapy should be designed with that differential diagnosis 2%, and in our experience, and that of others, virtually all taken into consideration, usually based on the ‘‘worst case’’ such cases have had regression within the RGP lesion (10). It is scenario. likely that this regression may have incorporated a small focus These problematic lesions can be considered in two major of melanoma with competence for metastasis, which metasta- categories. Lesions that are nontumorigenic may have locally sized prior to the occurrence of the regression in the primary recurring potential, whereas lesions that are tumorigenic may tumor. have metastatic as well as locally recurring potential. Examples Biological evidence for progression from RGP to VGP of nontumorigenic simulants of melanoma include recurrent includes differences in cell culture behavior between the two nevi or ‘‘,’’ pigmented spindle nevi, some compartments. The success rate of establishing permanent cell nevi of special sites, and most importantly, dysplastic nevi (8). lines from RGP lesions is only 10% of that for biologically late When the differential diagnosis of in situ or nontumorigenic primary or metastatic melanomas, and in consequence, only a few cell lines are available. The cells are immortal but show reduced or no proliferation in soft agar and immunodeficient Author’s Affiliation: Department of Pathologyand LaboratoryMedicine, mice when compared with the VGP (11). Additional evidence University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania has come from molecular studies; for example, by comparative Received 11/15/05; revised 1/5/06; accepted 1/13/06. genomic hybridization, there are shared chromosomal abnor- Presented at the First International Conference on Innovations and Challenges in Melanoma, July15-16, 2005, Cambridge, Massachusetts. malities between the RGP and the VGP compartments F 2006 American Association for Cancer Research. (11–13). In addition, it has been shown by microdissection doi:10.1158/1078-0432.CCR-05-2504 and sequencing studies that the same mutated oncogenes are

ClinCancerRes2006;12(7Suppl)April1,2006 2308s www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Pathology of Melanoma shared by the VGP, RGP, and associated compartments (0-1.2%; n = 411). Survival curves differed significantly among of a primary melanoma (14). the four groups (P < 0.001; ref. 17). The working definition of the VGP that was established in In addition to its role as a predictor of metastasis-free early studies includes the properties of ‘‘tumorigenicity’’ and survival, it has also been recently shown that the property of ‘‘mitogenicity.’’ Thus, early VGP was defined as: first, the mitogenicity is useful as a predictor of the likelihood of SLN presence of a cluster of cells in the dermis that is larger than the involvement in patients with AJCC stage I melanomas. Among largest cluster in the epidermis (tumorigenicity, Fig. 1), and/or 181 patients with thin melanomas who underwent lymphatic second, the presence of any dermal mitoses (mitogenicity). mapping and sentinel lymphadenectomy, the overall SLN Either of these two properties suggests that the melanoma has positivity rate was 5%. All patients with a positive SLN had now acquired the capacity for growth not only in the epidermis an MR of >0, i.e., were ‘‘mitogenic.’’ On the basis of a classi- but also in the dermis (4, 9). Prognosis has long been known to fication tree, patients with an MR >0 and tumor thickness correlate with melanoma thickness as measured microscopi- z0.76 mm were identified as a higher-risk group, with an cally, which forms the basis of the American Joint Committee SLN positivity rate of 12.3% (18). Thus, in patients with on Cancer (AJCC) staging system that is currently in use (15). thin melanomas, mitogenicity was a significant predictor of In a recent study of expression of the proliferation marker Ki-67 SLN positivity that may be used to risk-stratify and select in 402 AJCC stage I ‘‘thin’’ invasive melanomas, it was shown patients, supporting findings from a similar study by Sondak that proliferation of melanoma cells in RGP melanomas slows et al. (19). as they enter the dermis, and then increases with the onset of These findings show that two major properties of melanoma, tumorigenic VGP (16). The mean dermal Ki-67 expression in i.e., tumorigenicity and proliferation rate, as judged by mitotic 171 invasive RGP tumors was 3.5%, whereas in 199 tumori- rate or Ki-67 expression, are critical determinants of prognosis genic VGP melanomas, the expression was 13%. Similar in thin melanomas. In particular, the property of mitotic rate findings were shown in terms of mitoses. These were absent (determined as the number of mitoses per square millimeter in all of the invasive RGP melanomas by definition, whereas usually from a ‘‘hotspot’’ if any is present on the sides of the they were present in 54% of the tumorigenic VGP melanomas. lesion) has been reported in multiple studies from many Thus, in the evolution of primary melanomas, there is a shift in institutions (16, 17, 19–32) and is a simple attribute that can the pattern of proliferation from a predominantly epidermal be readily and reproducibly determined by any pathologist pattern in the RGP to an epidermal and dermal pattern of using standard equipment (25). This attribute, therefore, proliferation in the VGP (16). should be recorded in pathology reports, and in particular, In another study of prognosis in thin melanomas, which are the simple property of mitogenicity, i.e., the presence of any considered to have a good prognosis, a tree-structured analysis mitoses in the dermis, should, in the opinion of this author, of 10-year metastasis defined four risk groups: high risk, men be taken into consideration as a modifying attribute for AJCC with VGP lesions that had a mitotic rate (MR) >0, and for stage 1 and used in making decisions regarding indications for whom the 10-year metastasis rate was 31% (c.i. 22-42%; n = lymphatic mapping and sentinel lymphadenectomy. 90); moderate risk, women with VGP lesions that had an MR >0 and for whom the rate was 13% (9-18%; n = 136); low risk, patients with VGP lesions that had MR of 0 and for whom the Microscopic Morphology and Clinicopathologic n rate was 4% (2-7%; = 247); and minimal risk, patients with Subtypes of the RGP invasive lesions without VGP for whom the rate was 0.5% The microscopic features of the RGP or ‘‘nontumorigenic compartment’’ of the melanoma are confined to the epidermis and the papillary dermis. Any lesional cells that are present in the dermis are, by definition, ‘‘nonmitogenic’’ and ‘‘non- tumorigenic.’’ There are often two, but not necessarily mutually exclusive, major patterns of proliferation of melanoma cells in the epidermis—a pattern of extensive, high-level ‘‘pagetoid’’ proliferation of uniformly atypical melanocytes, extending throughout the layers of the epidermis seen in the common melanomas of the superficial spreading type (Fig. 1), and a ‘‘lentiginous’’ pattern of continuous basal proliferation of uniformly atypical melanocytes, seen in maligna and acral-lentiginous melanomas. These patterns correlate broadly with site, with chronic versus intermittent sun exposure, and with molecular findings that likely reflect differences in pathogenesis of the lesions (1, 13, 33–36). Molecular studies in melanoma. High throughput molecular studies in melanoma have been done by comparative genomic hybridization (CGH), fluorescent in situ hybridization, and by RNA expression profiling. Comparative genomic hybridization Fig. 1. EarlytumorigenicVGP in a superficial spreading melanoma.Variablysized is a technique in which DNA copy numbers from tumors are and shaped nests and single melanocytes are present in the epidermis in a pagetoid pattern characteristic of melanoma of the superficial spreading type.There is a nest compared with standard controls. Amplifications and deletions in the dermis that is larger than the largest intraepidermal nest. of individual genes can then be confirmed by fluorescent in situ

www.aacrjournals.org 2309s Clin Cancer Res 2006;12(7 Suppl) April 1, 2006 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. hybridization done on sections of the tumors. The comparative defy diagnosis. How should age be factored into the threshold genomic hybridization technique was first used in melanoma for diagnosis of melanoma, especially in the spitzoid lesions by Trent’s group at the University of Michigan, in a study that that plague us increasingly? Why would cellularly identical showed clonal derivation of the VGP from the RGP compo- lesions in a 2-year-old and a 30-year-old only be called nents of three tumors (12). In more recent studies using array- melanoma in the 30-year-old? based comparative genomic hybridization, the use of this Dr. Elder: If it’s strictly identical, it should probably be called technique has been shown for helping to make the diagnos- melanoma in both. But in lesions where there is really a tically important distinction between atypical Spitz nevi and diagnostic dilemma, age certainly factors in. There’s a nice ‘‘spitzean’’ melanomas (37–39). These studies have also shown paper by Vollmer that gives a table of the probability of a important genomic alterations common to the various subsets diagnosis based on age, with a certain prior probability of of melanomas, including cyclin D amplification, which is most diagnosis. If it’s a 50/50 call, the table will take you down a frequent in acral melanomas (40, 41), and BRAF amplification, curve. If it’s a 2-year-old, then it’s 90% benign; if it’s a 40-year- which seems to be most important in melanomas on inter- old, it’s 90% malignant, just based on the prior probabilities of mittently sun-exposed skin (superficial spreading melanomas; knowing the patient’s age (47). refs. 36, 42, 43). Dr. Kirkwood: We have a 2-year-old coming in next week for Various techniques have been used for profiling the a sentinel node biopsy. We now think that the morbidity expression of genes at the mRNA level. At present, the most caused by sentinel node biopsy is so low that the chance to common of these is the use of high-density oligonucleotide illuminate the lesion makes the process worth it. arrays. In an early microarray study, a cluster of aggressive Dr. Sondak: We are in the process of reviewing our results melanomas was identified and confirmed by correlating the with over 60 children with melanoma treated over the past cluster with reduced motility, invasive ability, and vasculogenic decade or so. Our youngest child with a sporadic melanoma is in vitro 1 mimicry potential (44). More recently, RNA expression 4 2 years old. At 2 years, I would be suspicious of that diagnosis profiling and hierarchical cluster analyses were used to separate if the patient didn’t have a congenital nevus. There’s so much desmoplastic from nondesmoplastic melanomas. Various we don’t know. Our biggest enemy is the fear of expressing neurotrophic factors and genes involved in extracellular matrix uncertainty—if pathologists aren’t sure what the lesion is, they production were up-regulated in desmoplastic melanomas and should tell us and let us help the patient and their family make confirmed with immunohistochemical results (45). In another an informed decision. recent study, the gene expression profiles of a series of nevi, Dr. Atkins: What is the role of gender? It’s surprising that it primary melanomas, and metastases were compared (46). came out so powerful in your database, when it didn’t come out Unsupervised hierarchical clustering accurately separated nevi in the AJCC database as being that important. Is it different for from primary melanomas. The metastatic melanomas different types of melanoma? Is there some component of exhibited two dichotomous patterns of gene expression that either testosterone or estrogen that’s important here? unexpectedly reflected gene expression differences that were Dr. Elder: Gender has been an important prognostic apparent after comparing the radial and vertical phases of attribute in our model since the first complete model we did a large primary melanoma. Further analysis of the genes back in 1989. It’s not surprising that it is apparent again in the involved in these differences will lead to an improved same, although much greatly expanded, basic data set. The molecular understanding of the pathogenesis of melanoma attributes that we look at are vastly different from the attributes and to new approaches to diagnosis. However, at the present that were looked at in the AJCC model. time, histopathology remains the gold standard for diagnosis Dr. Ross: In the AJCC model, the incidence of ulceration in and prognosis. thin melanomas was 6% or 8%, whereas in the University of Pennsylvania database, it is only 1.6%. It’s probably a dif- Open Discussion ferent group of patients. Gender may be relatively more important than other factors, but it may get trumped by other Dr. Slingluff: The father of one of the 20-year-olds I treated important factors such as tumor thickness or sentinel node called me with a concern about his insurance rates. One positivity. pathologist had called the lesion a primary melanoma and one Dr. Elder: But gender still plays a role, and we don’t know had called it a . We performed a sentinel node why. It’s certainly not just based on the fact that women have biopsy. Some melanocytic cells were apparent in the sentinel their melanomas on the leg, which is a prognostically more node, but there was disagreement about whether they favorable site. represented a melanoma metastasis or a cell rest. The father Dr. Sondak: You implied that we understand some of these asked for a note saying that this was not melanoma? How do survival factors that promote tumors progressing from radial you suggest dealing with that when there’s a record that says to vertical growth phase. What are some examples of those melanoma at some institutions and not at others? survival factors? Dr. Elder: Obviously, if the patient has a diagnosis of Dr. Elder: There was a study performed in Meenhard melanoma, the insurance company has a right to rate him Herlyn’s lab by Mei Yu Hsu with radial growth phase–like cell based on that. You’re probably a little less likely to have an lines. They were nontumorigenic in mice and were derived insurance problem with a diagnosis of melanocyte tumor of from the radial growth phase of complex primaries. So they’re uncertain malignant potential with a note that says, ‘‘Cannot different from the usual cell lines, which would be tumorigenic rule out melanoma, treat for the worst case scenario.’’ in mice. In the skin reconstruct model, these cell lines mixed up Dr. Kirkwood: The biggest risk factor for this disease is age. nicely with the keratinocytes and they line up along the basal Increasingly, very young patients arise with spitzoid lesions that layer. They look like in situ melanomas. They don’t invade the

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dermis, or if they do, they undergo apoptosis. They are then fragment ligand in the artificial dermis, which sends protective transfected with the h3 integrin gene, which we had identified signals, to prevent apoptosis. They not only survive, but they as a marker of the transition from radial to vertical growth also invade and form tumors in the dermis. It was a great phase. The cells did not undergo apoptosis; they met a collagen experiment (48).

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David E. Elder

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