A systematic review and meta-analysis of animal-type melanoma

REVIEW

A systematic review and meta-analysis of animal-type melanoma Ritva Vyas, MBChB, FRACP, Jesse J. Keller, MD, Kord Honda, MD, Kevin D. Cooper, MD, and Meg R. Gerstenblith, MD Cleveland, Ohio Background: Animal-type melanoma is a rare subtype of melanoma with heavily pigmented dermal epithelioid and spindled melanocytes. Its classification as a subtype of melanoma versus a borderline melanocytic tumor is debated. Objectives: Our primary objective was to characterize the demographics, clinical presentation, histopathology, management, and outcomes of patients with animal-type melanoma. Methods: We performed a systematic review and meta-analysis of the English-language literature on animal-type melanoma. Results: We identified 190 cases of animal-type melanoma. They occurred equally in men and women, with Caucasians (53.7%) most commonly affected. The median Breslow depth was 3.8 mm; ulceration was reported present in 15.8%; and dermal mitoses greater than or equal to 1/mm2 was reported in 27.4%. The most common initial management was wide local excision with sentinel lymph node biopsy (55.7%). In all, 78 patients underwent sentinel lymph node biopsy with 41.0% positivity rate. A total of 32 patients underwent completion lymph node dissection with 34.4% positivity rate. Locoregional recurrence was reported in 15 patients, recurrence with distant metastases in 6 patients, and death in 5 patients. Limitations: Data were obtained from small studies with limited follow-up. There is no universally accepted definition of animal-type melanoma. Conclusion: Prospective studies with complete staging information and molecular profiling may allow further characterization of this tumor. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.08.016.) Key words: animal type melanoma; equine-type melanoma; melanoma with prominent pigment synthesis; pigment synthesizing melanoma; pigmented epithelioid melanocytoma.

n 1832, Dick1 first described heavily pigmented nodular melanomas in horses and named these ‘‘equine melanotic disease.’’ Almost 100 years later, in 1925, Darier described similar-appearing melanocytic tumors in human beings and named them ‘‘melanosarcoma.’’2 The term ‘‘animal-type melanoma’’ was first proposed by Clark and Guerry in 1990 to describe this same entity.3 Since then, the terms ‘‘animal-type melanoma,’’ ‘‘pigment

I

From the Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine. Supported in part by the Char and Chuck Fowler Family Foundation and the Dermatology Foundation Career Development Award in Medical Dermatology (M.R.G.). Conflicts of interest: None declared. Accepted for publication August 11, 2015. Reprint requests: Meg R. Gerstenblith, MD, Department of Dermatology, University Hospitals Case Medical Center, Case

Abbreviations used: CLND: EBN: SLNB:

completion lymph node dissection epithelioid blue nevus sentinel lymph node biopsy

synthesizing melanoma,’’ ‘‘melanoma with prominent pigment production,’’ ‘‘equine-type melanoma,’’ and most recently, ‘‘pigmented epithelioid Western Reserve University School of Medicine, 11100 Euclid Ave, Lakeside Third Floor, Cleveland, OH 44106. E-mail: Meg. [email protected]. Published online September 23, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.08.016

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melanocytoma’’ have been used to describe this RESULTS subtype, and some controversy exists regarding its Demographics and clinical features histologic classification. Some reports suggest There were 39 studies identified, with 190 cases animal-type melanoma is less aggressive than reported.4,5,7,13-48 Table I summarizes the democommon types of melanoma; however, animal-type graphics and clinic presentations of animal-type melanoma is not well characterized. melanoma in these cases. The median age was Our primary objective was to conduct a systematic 27 years, ranging from newborn to 92 years. Of review and meta-analysis of those studies that reported published cases of animalsex, male and female CAPSULE SUMMARY type melanoma to describe individuals were affected at the demographics, clinical equal frequency. Race was Animal-type melanoma is a rare subtype presentation, histopathoreported in 54 cases; in these, of melanoma with heavily pigmented logy, management, and animal-type melanoma most dermal epithelioid and spindled outcomes of patients with commonly presented in melanocytes. animal-type melanoma. Caucasians (53.7%), folA comprehensive literature search lowed by Hispanics (18.5%), identified 190 cases of animal-type Asians/Persians (18.5%), and METHODS melanoma; we report clinical findings, blacks (9.3%). The most Data source histology, management, and outcomes. common site of occurrence An independent literature Animal-type melanoma appears to have was an extremity (38.3%), search was conducted using different clinical, histologic, and followed by the head and the following databases: prognostic features compared with other neck (30.8%) and trunk PubMed, EMBASE, CINAHL, subtypes of melanoma. (30.8%). The most common Cochrane library, Web of presenting feature was a Science, Clinicaltrials.gov, blue-black or blue nodule. and psycINFO from inception In the 29 cases where lesion duration was noted, through May 22, 2015. The following search terms were 10 cases (34.4%) reported having preexisting lesions used: ‘‘animal-type melanoma,’’ ‘‘pigmented epithelioid present since birth or childhood that were then noted melanocytoma,’’ ‘‘pigment synthesizing melanoma,’’ to expand. The lesion duration was between 1 to ‘‘melanoma with prominent pigment synthesis,’’ and 5 years in another 9 cases (31.0%). ‘‘equine-type melanoma.’’ Several studies described the dermoscopic characteristics of animal-type melanoma, and a common feature was a homogenous blue-black or Study selection blue appearance with blue-white veil or irregular All articles reporting original cases of animal-type white areas.26,28,46,48 Satellite lesions on clinical melanoma were selected. Only English articles examination were reported in 12 patients (6.3%). were included. Meeting abstracts were excluded. Four patients had clinically palpable lymph node References of selected articles were also reviewed metastases at presentation. Two patients had distant for potential cases. Some cases were reported in the metastases at presentation: 1 with a scalp primary literature multiple times; we only counted these 4-6 had liver metastases, and 1 with an extremity primary cases once. As mucosal melanomas may have had liver and lung metastases. A 44-year-old woman distinct behavior as compared with cutaneous melhad 2 separate primary animal-type melanomas on anomas, 7 cases of mucosal animal-type melanoma 5,7-11 the shoulder and the vaginal vestibule as described were excluded. In addition, the histology of by Zembowicz et al5; the vaginal animal-type ocular melanomas can be very spindled and heavily melanoma was not included as noted above. A melanized similar to animal-type melanoma; therefamily history of melanoma was reported in 1 patient fore; 1 case of ocular animal-type melanoma was 12 with animal-type melanoma who also had a history excluded. of 2 superficial spreading melanomas.14 No other patients were reported to have multiple primary Statistical analysis melanomas. Data were derived from prospective and retrospective case series and case reports and therefore Histopathology analyzed using descriptive statistics; common statisAnimal-type melanoma is a predominantly dermal tical measures were combined for meta-analysis. melanocytic proliferation of heavily pigmented Medians were reported in preference to means. d

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Table I. Demographic, clinical, and histologic features of reported cases of animal-type melanoma Age, y (n = 71) Median Range Male: female (n = 131) Race (n = 54) Caucasian Hispanic Other Black Duration of lesion (n = 29) Congenital Since childhood \1 y 1-5 y 5-10 y [10 y Long-standing Lesion morphology (n = 60) Nodule Plaque Papule Macule Subcutaneous mass Lesion color (n = 73) Blue-black or blue Brown-black or brown Black Pigmented Other Lesion location (n = 133) Extremity Head and neck Trunk Satellite lesions* Histologic features Breslow depth, mm, range (median) (n = 45) Ulceration (n = 101) Dermal mitoses (n = 113) Not quantified $1/mm2 \1/mm2 #1/mm2 0/mm2 Precursor nevus*

27 0-92 N (%) 64 (48.9): 67 (51.1) 29 10 10 5

(53.7) (18.5) (18.5) (9.3)

7 3 2 9 3 4 1

(24.1) (10.3) (6.9) (31.0) (10.3) (13.8) (3.4)

46 5 5 3 1

(76.7) (8.3) (8.3) (5.0) (1.7)

31 17 11 8 6

(42.5) (23.3) (15.1) (11.0) (8.2)

51 41 41 12

(38.3) (30.8) (30.8) (6.3)

0.7-20 (3.8) 16 (15.8) 20 31 37 13 12 11

(17.7) (27.4) (32.7) (11.5) (10.6) (5.8)

*Clinical satellite lesions and histologic precursor nevus were only mentioned when present; therefore, the denominator used to obtain percentages in these 2 categories was 190 cases.

epithelioid and spindled melanocytes.7,14,15,17,49 The pattern of pigmentation ranges from fine, granular light-brown deposits to coarse, dark-brown deposits, and the malignant cells are often arranged in sheets or

fascicles.17 There is frequent periadnexal and perieccrine spread.17,49 Zembowicz et al5 examined the distribution of the epithelioid and spindled cells and found that the epithelioid cells occupied the central portion with 2 distinct cell populations (small epithelioid and large epithelioid), whereas the spindled cells are more numerous at the periphery. Associated epidermal hyperplasia above the dermal neoplasm is frequently seen; however, in some cases, a Grenz zone has been noted.49 Some cases have a junctional component, and 1 case was reported to be purely intraepidermal with melanoma in situ type animal-type melanoma.30 Similar to conventional melanoma, immunohistochemistry of animal-type melanoma is positive for S-100 protein, vimentin, HMB-45, and Melan-A.15 The heavy pigmentation can obscure tumor cell morphology, but bleaching of the specimen with hydrogen peroxide has been reported to be helpful in looking at nuclear features.14,17 The histologic differential diagnoses include other dermally based pigmented melanocytic proliferations comprising spindled and/or epithelioid melanocytes, including common blue nevus, cellular blue nevus, malignant blue nevus, deep penetrating nevus, pigmented Spitz nevus, and regressed melanoma (tumoral melanosis) with prominent melanophages (Fig 1).14,49 The reported histologic findings in animal-type melanoma are summarized in Table I. In the 190 reported cases, histologic features that prognosticate conventional melanoma were not well reported. There was 1 case of melanoma in situ.30 Of the invasive melanomas, Breslow depth was reported in only 45 patients, and ranged from 0.7 to 20 mm, with a median of 3.8 mm. Although Zembowicz et al5 and Magro et al16 reported on mean Breslow depth and Ludgate et al7 on median Breslow depth, individual depths were not published, so we could not include them in our calculation of the median Breslow depth. Ulceration status (absent/present) was reported in 101 cases: ulceration was reported as present in 16 cases (15.8%) and absent in 85 cases (84.2%). Dermal mitoses were reported in 113 patients. Of these, dermal mitoses were reported as present but not quantified in 20 patients (17.7%); in the remaining, dermal mitoses greater than or equal to 1/mm2 were reported in 31 patients (27.4%), dermal mitoses less than 1/mm2 were reported in 37 patients (32.7%), dermal mitoses less than or equal to 1/mm2 were reported in 13 patients (11.5%), and dermal mitoses 0/mm2 were reported in 12 patients (10.6%). Underlying nevi were noted in 11 patients (5.8%). Table II summarizes the immunohistochemical, ultrastructural, and molecular studies on animal-type melanoma.

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Fig 1. The histologic differential diagnosis of animal-type melanoma includes other dermally based pigmented melanocytic proliferations comprising spindled and/or epithelioid melanocytes, including common blue nevus, cellular blue nevus, deep penetrating nevus, pigmented Spitz nevus, malignant blue nevus, and regressed melanoma (tumoral melanosis) with prominent melanophages.

Management Table III summarizes management and outcomes of patients with animal-type melanoma. There were 140 cases where surgical management was reported. Most patients (n = 78, 55.7%) had wide local excision and sentinel lymph node biopsy (SLNB) as their initial postbiopsy surgical management. In all, 51 patients (36.4%) were reported to have wide local excision alone; 7 (5.0%) had simple excision; 3 (2.1%) had wide local excision and completion lymph node dissection (CLND), 2 for lymphoscintigraphy-detected sentinel lymph nodes and 1 for radiologically detected enlarged nodes; and 1 (0.7%) had Mohs micrographic surgery. Nine patients had adjuvant treatments postsurgery; 8 had postoperative interferon, and 1 had both postoperative radiation and interferon. Outcomes Of the 78 patients who underwent SLNB, 32 (41.0%) had positive sentinel lymph nodes for metastatic melanoma. Two patients who had positive SLNB did not go on to have CLND, and 1 patient declined CLND. Three patients underwent CLND without prior SLNB. Eleven of 32 patients (34.4%) who underwent CLND had 1 or more lymph nodes

positive for metastatic melanoma. Fifteen patients (7.6%) had locoregional recurrence at follow-up, and 6 patients (3.0%) developed distant metastases at follow-up. There were 5 reported deaths (2.5%); however, 1 was caused by cardiovascular disease and thought to be unrelated to the melanoma. In the 9 patients who had adjuvant treatments postsurgery, no locoregional recurrence, distant metastases, or deaths were reported. Median follow-up was available for 47 patients and was 36 months (3 years), ranging from 3 to 348 months. Two case series with 40 patients combined reported median follow-up of at least 5 years; 7 patients (17.5%) had locoregional recurrence at follow-up, and 1 (2.5%) had distant metastases with no reported deaths.4,14

DISCUSSION Animal-type melanoma appears to have different clinical, histologic, and prognostic features compared with other subtypes of melanoma. Clinically, many patients reported a lesion present since birth or childhood that in later years began to grow; this is not usually a feature of other subtypes of melanoma. Animal-type melanoma often occurred as a blue-black or blue nodule growing over a few years’ time. In addition, satellitosis was frequently

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Zembowicz et al (n = 40)

Zembowicz et al50 (n = 32)

Study description

- Blinded comparison of histology of ATM and EBN associated with Carney complex - PRKAR1A gene is mutated in Carney complex - PRKAR1A gene codes for R1a protein that regulates cyclic AMP and protein kinase A signaling, important for melanocyte function - R1a antibody test and PRKAR1A mutation analysis

Orlandi et al15 (n = 7)

- GST family of proteins implicated in tumor progression - Nuclear expression of GST-p and EM studies performed

Urso et al45 (n = 5)

- FISH analysis for chromosomal aberrations in RREB1, MYB, CCND1, CEP6 - BRAF mutation testing - FISH analysis for chromosomal aberrations in RREB1, MYB, CCND1, CEP6 - IHC profile of tumor infiltrating histiocytes

Battistella et al18 (n = 2)

Sadayasu et al35 (n = 1)

Kazakov et al32 (n = 1)

- Ultrastructural studies

Findings

- ATM and EBN were histologically indistinguishable - No PRKAR1A mutations identified in conventional melanomas (0/60), rate of LOH for 17q22-24 \7% - No PRKAR1A mutations in ATM/EBN (0/7); however, extensive LOH for 17q22-24 (71%) - 82% (28/32) of ATM and 100% (8/8) of EBN had loss of expression of R1a compared with 0.34% (1/297) of other benign and malignant melanocytic tumors - Low nuclear expression of GST-p in ATM compared with conventional melanomas - EM studies: large indented nuclei, abundant cytoplasm, numerous single melanosomes varying in size, mainly in the early stage of maturation sometimes with a pleomorphic appearance - FISH analysis negative in all 4 cases

Conclusions

- Proposed term ‘‘pigmented epithelioid melanocytoma’’ to encompass these 2 entities - Loss of expression of R1a useful diagnostic test to distinguish ATM/EBN from lesions that mimic it histologically

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Table II. Summary of immunohistochemical, ultrastructural, and molecular testing on animal type melanoma

- Low nuclear expression of GST-p may be blocking tumor progression in ATM - EM findings in accordance with previously reported findings by Kazakov et al32

- Too few cases to establish validity of FISH testing in ATM

- No BRAF mutation found - FISH analysis showed an extra copy of chromosome 6 in 1 of the 2 cases

- Four-color FISH may be a useful to assess the prognosis of ATM

- Majority of tumor infiltrating histiocytes were CD681CD163 MMP9 and few Foxp3HIGH1 Tregs were observed - Abundant cytoplasm, numerous single melanosomes in stages II-IV of maturation - Predominance of early-stage melanosomes, high no. of aberrant melanosomes - Melanophages a minor component

- Absence of these cells might be responsible for a more favorable prognosis of pigmented epithelioid melanocytoma/ATM - ATM is a neoplasm of melanosome producing cells with most melanosomes in the early stages of maturation

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AMP, Adenosine monophosphate; ATM, animal-type melanoma; CD, cluster of differentiation; EBN, epithelioid blue nevus; EM, electron microscopy; FISH, fluorescent in situ hybridization; GST, glutathione S-transferase; IHC, immunohistochemistry; LOH, loss of heterozygosity; MMP, matrix metallopeptidase; PRKAR1A, protein kinase A regulatory subunit type 1a; R1, regulatory subunit 1; Tregs, T regulatory cells.

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Table III. Management and outcomes in animaltype melanoma N (%)

Surgical management (n = 140) WLE with SLNB WLE Simple excision WLE with CLND Mohs micrographic surgery Adjuvant treatments (n = 9) Interferon alfa Interferon alfa and radiation Lymph node metastases at presentation Palpable lymph nodes* SLNB positivity (n = 78) CLND positivity (n = 32) Distant metastases at presentation*y Recurrence* Locoregional recurrencez Distant metastases Death* Duration of follow-up (n = 47) Median Range

78 51 7 3 1

(55.7) (36.4) (5.0) (2.1) (0.7)

8 (88.9) 1 (11.1) 4 32 11 2

(2.1) (41.0) (34.4) (1.1)

15 (7.6) 6 (3.0) 5 (2.5) Months 36 3-348

CLND, Completion lymph node dissection; SLNB, sentinel lymph node biopsy; WLE, wide local excision. *In these categories the denominator used to calculate the percentages was the total of 190 cases. y One patient with a primary animal-type melanoma on the scalp had metastases to the liver, 1 patient with a primary animal-type melanoma on a limb had metastases to the lung and liver. z Locoregional recurrence was defined as recurrence at the primary site, in-transit metastases, or metastases to regional lymph nodes.

present on examination. In this series, we found that animal-type melanoma affects men and women equally; this is different from the more common types of melanoma where the incidence is higher in men compared with women.51 Because race was only reported in 54 of 190 cases of animal-type melanoma, it is difficult to draw conclusions on differences in incidence of animal-type melanoma by race. However, compared with the race/ethnicity distribution reported by the National Cancer Database in 77,347 cases of cutaneous melanoma, there was a lower percentage of cases in Caucasians and a higher percentage in other racial groups for animal-type melanomas in this series (Table IV).52 The apparent differences in the increased proportions of non-Caucasian cases could be a result of reporting bias given the low number of published cases that reported race. The histopathological diagnosis of animal-type melanoma is challenging because of overlapping features with several other dermal melanocytic

proliferations and a lack of universally accepted histologic diagnostic criteria. Zembowicz et al5 found animal-type melanoma to be histologically indistinguishable from epithelioid blue nevus (EBN) associated with Carney complex and proposed a unifying term of ‘‘pigmented epithelioid melanocytoma’’ and classification of this entity under borderline melanocytic tumors rather than true melanoma. In another study by the same group, animal-type melanoma had loss of expression of cyclic adenosine monophosphateedependent protein kinase A regulatory subunit 1a, a feature also seen in EBN.50 On this basis, the term ‘‘pigmented epithelioid melanocytoma’’ was suggested to encompass animal-type melanoma and EBN, although this term is not universally accepted, and studies replicating these findings are needed.53,54 Despite histologic and genetic similarities, EBN associated with Carney complex is not reported to metastasize to lymph nodes or to distant sites, unlike animal-type melanoma. Magro et al16 proposed that these tumors be classified under the term ‘‘dermalbased borderline melanocytic tumors.’’ Additional molecular characterization of animal-type melanoma has not been undertaken extensively. It is unknown at the present time whether the mutations that occur commonly in melanoma, such as BRAF, NRAS, and ckit, are also present in animal-type melanoma. In addition, there could be yet undiscovered molecular differences, which may only become apparent with whole genome or exome sequencing of these tumors. Some authors have claimed the SLNB positivity rates for animal-type melanoma are higher than for more common melanoma subtypes. Several studies have reported an approximately 20% SLNB positivity rate for cutaneous melanomas, with positivity rates increasing with the tumor stage.55-57 The SLNB positivity rate in 78 animal-type melanoma cases in our analysis was higher than this, at 41.0%. Only 23 animal-type melanoma cases reported on both the tumor stage and the SLNB result, and most of these were T3 or T4 tumor stage; therefore, it is difficult to make comparisons regarding SLNB positivity rates stratified by tumor stage. The CLND positivity rate was slightly higher at 34.4% (11/32) in our series of animal-type melanomas compared with reported cutaneous melanoma CLND positivity rates of 23% to 26.1%, but the low numbers prohibit definitive conclusions to be drawn regarding differences.55,58 The prognosis of animal-type melanoma as reported seems to be better than conventional melanoma with only 5 reported deaths of 190; however, median follow-up was only 36 months.

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Table IV. Race distribution of animal-type melanoma compared with race/ethnicity distribution of cutaneous melanomas reported by the National Cancer Database report ATM cases (%) (n = 54)

Caucasian Hispanic Other* Black

29 10 10 5

(53.7) (18.5) (18.5) (9.3)

NCDB cutaneous melanoma (%) (n = 77,347)

White non-Hispanic Hispanic (any race) Other/unknown African American non-Hispanic

72,500 911 3346 590

(93.7) (1.2) (4.3) (0.8)

ATM, Animal-type melanoma; NCDB, National Cancer Database. *Nine Asian patients and 1 patient reported to be Persian.

In the 2 case series of animal-type melanoma with 5-year follow-up with a total of 40 patients, survival was 100%.4,14 Given the small number of cases with long-term follow-up data, we are unable to draw conclusions regarding differences between the prognosis of individuals with animal-type melanoma and those with conventional melanoma subtypes. Limitations There are a number of limitations to this study. The data for animal-type melanoma are derived from retrospective and prospective case series and case reports, with small numbers of patients, limited duration of follow-up, and no control group that can be used for direct comparison. In addition, there is no universally accepted definition of animal-type melanoma; therefore, this cohort may be heterogeneous. These limitations may be resolved with molecular profiling of animal-type melanoma cases, with comparison with its histologic differentials and other subtypes of cutaneous melanoma. Long-term prospective studies with complete staging information and 5- and 10-year follow-up may also provide a more accurate assessment of outcomes. Given the rare nature of animal-type melanoma, this may require multicenter collaboration. Conclusion In conclusion, we identified 190 reported cases of animal-type melanoma and characterized the clinical and histologic features of these tumors along with the management and outcomes of affected patients with this rare melanoma subtype. Currently, management as per conventional melanoma guidelines is recommended. Molecular profiling might help further characterize and classify animaltype melanoma. REFERENCES 1. Dick W. Melanosis in men and horses [letter]. Lancet. 1832; 192:8. 2. Darier J. Le melanome malin mesenchymateux ou melanosarcome. Bull Assoc Fr Cancer. 1925;14:221-249.

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