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. Author manuscript; available in PMC: 2015 Jun 1.
Published in final edited form as: J Am Acad Dermatol. 2014 May 17;71(2):229–236. doi: 10.1016/j.jaad.2014.03.033

Oncogenic mutations in melanomas and benign melanocytic nevi of the female genital tract

Diane Tseng a,b, Julie Kim c, Andrea Warrick d, Dylan Nelson d, Marina Pukay d, Carol Beadling d, Michael Heinrich e, Maria Angelica Selim c, Christopher L Corless d, Kelly Nelson c
PMCID: PMC4450888  NIHMSID: NIHMS692974  PMID: 24842760

Abstract

Background

The genetic heterogeneity of melanomas and melanocytic nevi of the female genital tract is poorly understood.

Objective

We aim to characterize the frequency of mutations of the following genes: BRAF, NRAS, KIT, GNA11, and GNAQ in female genital tract melanomas. We also characterize the frequency of BRAF mutations in female genital tract melanomas compared with melanocytic nevi.

Methods

Mutational screening was performed on the following female genital tract melanocytic neoplasms: 25 melanomas, 7 benign melanocytic nevi, and 4 atypical melanocytic nevi.

Results

Of the 25 female genital tract melanoma specimens queried, KIT mutations were detected in 4 (16.0%), NRAS mutations in 4 (16.0%), and BRAF mutations in 2 (8.0%) samples. Two of the tumors with KIT mutations harbored double mutations in the same exon. No GNAQ or GNA11 mutations were identified among 11 melanomas screened. BRAF V600E mutations were detected in 7 of 7 benign melanocytic genital nevi (100%) and 3 of 4 atypical genital nevi (75%).

Limitations

Our study is limited by the small sample size of this rare subset of melanomas.

Conclusion

KIT, NRAS, and BRAF mutations are found in a subset of female genital tract melanomas. Screening for oncogenic mutations is important for developing and applying clinical therapies for melanomas of the female genital tract.

Keywords: BRAF, female genital melanomas, female genital nevi, KIT, NRAS, oncogenic mutations

Over the past decade, the development of targeted therapies has significantly changed the clinical approach to patients with advanced melanoma. Improvements in targeted therapies rely on a fundamental understanding of the genetic heterogeneity of cancer. Recent studies have revealed different patterns of genetic mutations in known melanoma oncogenes depending on anatomic site1 (ie, chronic sun-damaged skin vs nonchronic sun-damaged skin vs acral vs mucosal). We hypothesize that additional genetic heterogeneity can be appreciated even within this classification. For example, of melanomas arising in mucosal sites, previous studies have suggested that the frequency of KIT gene mutations may be higher in melanomas of the reproductive mucosal sites compared to melanomas of the sinonasal mucosa.2,3 These studies have generally been performed as single-institution studies and on a small number of clinical samples. Our current understanding of the genetic characteristics of subtypes of mucosal melanomas is limited and warrants additional investigation.

In particular, melanomas of the female genital tract present many unique clinical challenges. The lack of effective screening methodologies results in tumors that are frequently diagnosed at advanced stages and are associated with poor outcomes.4,5 The desire to temper aggressive, potentially noncurative surgical interventions with more conservative approaches may narrow therapeutic margins. The complex pelvic lymphatic drainage patterns, particularly for women with multifocal mucosal disease, may blunt the diagnostic accuracy of sentinel lymph node biopsy. The rare nature of these cancers (0.23% of all melanomas and 18% of mucosal melanomas6) has challenged rigorous query into the associated oncogene patterns.

The current standard of care for managing melanoma of the female genital tract involves local excision using margins based upon the measured depth of invasion or Breslow thickness. Sentinel lymph node biopsy, nodal dissection, radiotherapy, and chemotherapy are also considered in the patient-specific context. However, in recent years, kinase inhibitors have proven effective for some patients with advanced disease. For example, vemurafenib and dabrafenib are drugs that have been shown to be effective for BRAF-mutant melanomas (V600E/K substitutions).7–9 KIT kinase inhibitors, such as imatinib, sunitinib, and sorafenib, have yielded responses in KIT-mutant melanomas, and NRAS-mutant melanomas are being targeted with mitogen-activated protein kinase kinase inhibitors in ongoing clinical trials.10–15 In a recent report, a patient with vulvar melanoma that experienced progression to lymph node metastasis after interferon-alpha therapy achieved disease stabilization for 8 months on imatinib.16 As shown in these clinical experiences, genetic alterations in melanoma subtypes may have both prognostic and therapeutic significance.17 Mucosal melanomas have been previously described to exhibit heterogeneity in their oncogenic aberrations,2,3,18–29 but the extent to which anatomic location correlates with this genetic diversity remains largely unexplored. To our knowledge, there are no studies focused specifically on oncogenic mutations in melanomas of the female genital tract. Therefore, we screened for such oncogenic mutations in BRAF, NRAS, KIT, GNA11, and GNAQ.

In addition to the therapeutic challenge of treating female genital tract melanomas, there is also the challenge of clinical screening for their precursor lesions. While genital nevi are not uncommon, cytologic and architectural atypia challenges accurate histopathologic characterization and leads to confusion of their identity as possible precursors of melanoma. As such, we sought to clarify whether benign melanocytic nevi (with and without atypia) might be precursor lesions for invasive melanoma by comparing their BRAF mutation pattern to female genital tract melanomas. This investigative focus seeks to guide the clinical management of atypical genital nevi, which are an overall poorly understood group of melanocytic lesions in the spectrum of nevi of special sites.

METHODS

After obtaining institutional review board approval for this retrospective study, 11 cases of melanoma arising from the female genital tract with retrievable tumor material and 11 control cases of benign gynecologic melanocytic lesions were identified from the Duke Melanoma Database and the Duke University Tumor Registry. Fourteen additional cases of melanoma arising in the female genital tract that have not been previously published were obtained from the pathology archives of Oregon Health and Science University. Deidentified clinical information was obtained for each subject, including patient demographic information (eg, age and race) and clinical features (eg, ulceration, anatomic location, immunosuppressed status, and nodal positivity).

All cases were reviewed microscopically by a pathologist to confirm the diagnosis and to identify areas rich in lesional cells (ie, nevoid cells or melanoma, depending on the case). Tumor-rich areas were then isolated by macrodissection from parallel unstained sections (minimum 60% tumor cellularity), and DNA was prepared as previously described.30 Eleven of the melanomas were screened for mutations in BRAF, NRAS, KIT, GNA11, and GNAQ using a combination of multiplex polymerase chain reaction studies and mass spectroscopy (Sequenom; San Diego, CA).30 The complete list of mutations screened by this approach was previously published as a supplemental table in reference 30. This approach covers all hotspot regions of these genes, but does not cover some known KIT exon 11 insertions and deletions. Therefore, additional screening of this exon was carried out with high-resolution melting curve analysis using an LC480 LightCycler (Roche, Mannheim, Germany). The remaining 14 melanoma cases were screened for mutations in BRAF (exon 15), NRAS (exons 1 and 2), and KIT (exons 11, 13, and 17) using standard, bidirectional Sanger sequencing. All mutations identified on the Sequenom system were also confirmed by Sanger sequencing. All melanocytic nevi were screened for BRAF using Sanger sequencing.

Two melanomas were found to harbor dual KIT gene mutations. To determine whether these mutations were on the same allele, we used a combination of an amplicon-based library preparation and semiconductor-based next generation DNA sequencing (Ion Torrent Personal Genome Machine; ThermoFisher Scientific, Waltham, MA), as previously described.31 It should be noted that this type of sequencing was not available when the study was initiated, and was only used to examine the 2 tumors with dual mutations.

A systematic review of the literature surrounding benign nevi and melanoma of the female genital tract was performed. The search was performed on April 7, 2013 using the PubMed database. Search terms included the following MeSH terms: “nevi and melanomas,” “genitalia, female,” “mucous membrane,” “tumor markers, biological,” “genetics,” and “genetic phenomena.” The search algorithm was also inclusive of any literature containing the following key terms in either the title or abstract: “pigmented lesion(s),” “mole(s),” “nevus,” “nevi,” “melanoma(s),” “vulva(r),” vagina(l),” “labia(l),” “clitoral,” “clitoris,” “gynecologic,” “mucosal,” “KIT,” “oncogene,” and “genetic(s).” This comprehensive search yielded 498 articles, with 19 articles (3.8%) containing subject matter relevant to this study. To be included, articles were required to be written in English and to illustrate oncogene or mutational analysis of benign nevi, atypical nevi, or melanomas localized to the female genital tract. Articles with questionable relevance were reviewed. In addition, the reference sections of selected studies were reviewed for potentially inclusive articles missed during the initial search. Included articles were reviewed independently by the first (D.T.), second (J.K.), and senior authors (K.N.; Table I).

Table I.

Literature review summarizing oncogenic mutation frequency in female genital melanomas

Authors No. of cases/anatomic site BRAF
NRAS
KIT
Methods
N (%) [site] Mutations No. (%) [site] Mutations No. (%) [site] Mutations Mutations
Carvajal et al10 13/Vulva and vagina 0/13 (0%) NA 3/13 (23.1%) [vulvovaginal] Exon 2 Q61L (1/13), exon 1 G12D (1/13), and exon 1 G13V (1/13) 7/13 (53.8%) [vulvovaginal] Exon 11 L576 P (5/13), exon 11 Y553C (1/13), exon 18 V852I (1/13), and exon 13 K642E (1/13) PCR, followed by Sanger sequencing, KIT exons 9, 11, 13, 17, 18; NRAS exons 1 and 2; BRAF exon 15
Cohen et al22 8/Vulva 0/8 (0%) NA Not tested Not tested Not tested Not tested PCR, followed by sequencing of BRAF exon 15; Mutector assay
Edwards et al23 8/Vulva 0/8 (0%) NA Not tested Not tested Not tested Not tested PCR, followed by sequencing using BRAF exon 15F; restriction length polymorphism analysis by TspRI
Handolias et al24 7/1 Vagina, 1 cervix, 4 vulva, and 1 labia Not tested Not tested Not tested Not tested 2/7 (29%) [1 vulva and 1 labia] Exon 11 L576P (1/7); exon 13 K642 (1/7) High-resolution melting-screen analysis; sequencing KIT exons 11, 13, 17
Omholt et al2 30/23 Vulva and 7 vagina 2/30 (6.7%) [both vulvar] Exon 15 V600E (2/30) 3/30 (10%) [all vaginal] Exon 1 G12D (1/30), exon 2 Q61L (1/30), and exon 2 Q61H (1/30) 8/30 (26.7%) [all vulvar] Exon 11 W557R (1/30), exon 11 V559D (1/30), exon 11 V560D (1/30), exon 11 P573L (1/30), exon 11 L576P (2/30), exon 17 D820Y (1/30), and exon 17 N822K (1/30) PCR; sequencing KIT exons 9, 11, 13, 17, 18; NRAS exon 15; BRAF exon 15
Satzger et al25 10/Female genital tract 0/5 (0%) NA Not tested Not tested 3/9 (25%) [not specified] Exon 11 579del (1/9), exon 18 184IV (1/9), and exon 11 L576P (1/9) PCR; sequencing KIT exons 9, 11, 13, 17, 18; BRAF exon 15; also fluorescent melting curve analysis for BRAF
Torres-Cabala et al21 15/11 Vulva and 4 vagina-cervix Not tested Not tested Not tested Not tested 4/15 (26.7%) [3 vulvar and 1 vaginal] Exon 11 L576P (1/15), exon 17 D816V (1/15), exon 13 K642E and exon 17 N822I (1/15), and exon 13 K642E (1/15) PCR; sequencing KIT exons 11, 13, and 17
Wong et al27 8/1 Cervix, 4 vagina, and 3 vulva 1/8 (12.5%) [vulvar] N581I 1/8 (12.5%) [vaginal] Exon 2 Q61K Not tested Not tested PCR; sequencing BRAF exons 11 and 15; NRAS exons 1 and 2
Schoenewolf et al3 16/Vulva and vagina Not tested Not tested Not tested Not tested 5/11 (45.5%) [vulvovaginal] Exon 13 K642E (1/11), exon 11 L576P (2/11), exon 11 V560D (1/11), and exon 13 L641H (1/11) PCR; sequencing KIT exons 9, 11, 13, 17, 18
Abu-Abed et al28 19/2 Vagina and 17 vulva Not tested Not tested Not tested Not tested 1/19 (5.3%) [vulvar] Exon 11 L576P PCR; sequencing KIT exons 11 and 13
Current study 25/8 Vagina, 9 vulva, 2 labia, 1 introitus, 1 cervix, 3 LN, and 1 metastasis 2/25 (8.0%) [metastasis, vagina] Exon 15 V600E (metastasis) (1/25), exon 15 K601E (vagina) (1/25) 4/25 (16.0%) [1 vaginal, 3 vulva] Exon 1 G12V (1/25), exon 1 G13D (1/25), exon 2 Q61K (1/25), and exon 2 A59T (1/25) 4/25 (16.0%) [1 vagina, 2 vulva, and 1 LN] Exon 13 K642E and Y646H (1/25), exon 11 L576P (1/25), exon 11 W557R and L576P (1/25), and exon 13 K642E (1/25) PCR and mass spectroscopy; sequencing KIT exons 11, 13, 17; NRAS exons 1 and 2; BRAF exon 15; high resolution melting curve analysis for exon 11 of KIT
Cumulative frequency (%) 5/97 (5%) 11/76 (15%) 34/129 (26%)
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BRAF, V-raf murine sarcoma viral oncogene homolog B; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CD117; LN, lymph node; NA, not available; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; PCR, polymerase chain reaction.

The frequency of BRAF, NRAS, and KIT mutations in our series of gynecologic melanomas was compared with the cumulative published frequencies of these oncogenes in primary and metastatic cutaneous melanomas.

RESULTS

Mutations in KIT or NRAS are found in a subset of melanomas arising from the female genital tract

Mutational screening of the candidate oncogenes BRAF, NRAS, KIT, GNA11, and GNAQ was performed on 25 melanomas arising from the female genital tract. Data were compiled from patient tumors at Duke University (n = 11) and Oregon Health and Science University (n = 14; Table II). Patient ages ranged from 29 to 82 years (median, 68 years of age). Primary melanomas of the female genital tract included those arising from the vagina (n = 8), vulva (n = 9), labia (n = 2), introitus (n = 1), and cervix (n = 1); metastatic locations included inguinal nodes (n = 3) and 1 cutaneous metastatic deposit. KIT mutations were detected in 4 of 25 samples (16.0%; see Table II). Interestingly, 2 of the tumors harbored double mutations in the same exon (KIT exon 13, K642E and Y646H; KIT exon 11, W557R and L576P). In both cases, next generation sequencing revealed that the mutations were on the same allele.

Table II.

Oncogenic mutations detected in female genital melanomas in this study

Case no. Melanoma site Age, y Mutations
1 Vagina 62 None detected
2 Vagina 70 None detected
3 Vagina 77 None detected
4 Vagina 75 None detected
5 Vagina 61 None detected
6 Vagina 62 KIT exon 13 K642E and Y646H (in cis)
7 Vagina 77 NRAS exon 1 G12V
8 Vagina 46 BRAF exon 15 K601E
9 Vulva 70 None detected
10 Vulva 52 None detected
11 Vulva 70 None detected
12 Vulva 75 None detected
13 Vulva 71 None detected
14 Vulva 58 NRAS exon 1 G13D
15 Vulva 29 NRAS exon 2 Q61K
16 Vulva 57 KIT exon 11 L576P
17 Vulva 67 KIT exon 11 W557R and L576P (in cis)
18 Labia 81 NRAS exon 2 A59T
19 Labia 82 None detected
20 Introitus 50 None detected
21 Cervix 39 None detected
22 Inguinal node 70 None detected
23 Inguinal node 70 None detected
24 Inguinal node 68 KIT exon 13 K642E
25 Cutaneous metastasis 57 BRAF exon 15 V600E, KRAS exon G13D, and PIK3CA exon 9 E545K
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BRAF, V-raf murine sarcoma viral oncogene homolog B; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CD117; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog.

NRAS mutations were detected in 4 of 25 samples (16.0%). These include 1 melanoma of the labia (NRAS A59T), 2 melanomas of the vulva (NRAS G13D and NRAS Q61K), and 1 melanoma of the vagina (NRAS G12V). Mutations in NRAS and KIT were mutually exclusive.

BRAF mutations were detected in 2 of 25 samples (8.0%), representing a vaginal melanoma (BRAF K601E) and a cutaneous metastasis of a primary female genital tract melanoma (BRAF V600E). Interestingly, the cutaneous metastasis also had mutations in KRAS (G13D) and PIK3CA (E545K), which were detected as part of a broader screening panel performed on this particular sample (a combination of multiplex polymerase chain reaction studies and mass spectroscopy). Fifteen tumors lacked detectable mutations in the KIT, NRAS, or BRAF oncogenes. No GNAQ or GNA11 mutations were identified among 11 melanomas that were screened.

The BRAF V600E mutation is commonly found in benign and atypical nevi of the female genital tract

We researched the frequency of BRAF mutations in 7 benign melanocytic genital nevi (3 compound nevi and 4 intradermal nevi) and 4 atypical genital nevi in parallel with the analysis of the 25 female genital melanomas. BRAF V600E mutations were detected in 7 of 7 benign melanocytic genital nevi (100%) and 3 of 4 atypical genital nevi (75%; Table III). These results indicate that BRAF V600E is common in benign and atypical genital nevi but not in invasive melanomas of the female genital tract.

Table III.

Oncogenic mutations detected in female genital nevi in this study

Path No. of samples BRAF
n/N (%) Mutations
Intradermal nevus 4 4/4 (100) V600E
Compound nevus 3 3/3 (100) V600E
Atypical nevus, genital type 4 3/4 (75) V600E
Total 11 10/11 (91)
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BRAF, V-raf murine sarcoma viral oncogene homolog B; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CD117; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog.

DISCUSSION

Mutational analysis of mucosal melanomas to date has been quite limited.18 Most mutational studies have focused on melanomas originating from various cutaneous sites, with relatively limited numbers of mucosal melanomas and even fewer of the female genital mucosa.32

Of the 25 melanoma cases in our study, 4 (16%) harbored KIT mutations, 4 (16%) had NRAS mutations, and 2 (8%) had BRAF mutations. The mutational frequencies we observed in KIT, NRAS, and BRAF in female genital melanoma are comparable to the frequencies previously reported for mucosal melanomas in general (of different anatomic sites).16,17 However, the small number of samples analyzed in our study may not provide enough resolution to distinguish true differences in mutational frequency between mucosal melanomas in general compared with female genital melanomas. In fact, mucosal and glabrous epithelia are distinct at the histologic level. No GNAQ or GNA11 mutations were identified among 11 melanomas that were screened. These genes are commonly mutated in uveal/choroidal melanomas, and rarely in cutaneous melanomas.33,34 Of note, the majority of melanoma cases lacked a detectable driver mutation in the oncogenes most commonly associated with melanoma. This suggests that other genes yet to be determined, including those downstream of the RAS–BRAF pathway, may be important in the development of genital melanomas. In addition to genetic mutations, chromosomal changes leading to copy number variation has been reported to be higher in mucosal melanomas than melanomas arising from other sites in the body. The frequency of genome-wide copy number changes in female genital melanomas is not known, but beyond the scope of the current study. Whether anatomic sub-sites, such as glabrous sites (ie, nonhair-bearing, modified mucosa, such as the labia minora and vaginal/cervical mucosa) compared with nonglabrous sites (ie, hair-bearing, such as the labia majora) might differ in oncogene mutations remains an open question.

Based on our findings and those of previous publications (Table I), BRAF mutations are uncommon in melanomas of the female genital tract. Moreover, when they do occur, they may be substitutions other than V600E (eg, K601E in our study; N581I in Wong et al27). The single V600E-mutant melanoma in our series also harbored KRAS and PIK3CA mutations. This is quite unusual, but it has previously been reported that paired primary and metastatic melanomas can have different oncogenic mutations, presumably because of metastatic outgrowths from a genetically heterogeneous primary tumor.35 Interestingly, Turajlic et al36 recently reported a BRAF V600E-mutant melanoma that showed primary resistance to a BRAF inhibitor because of coexisting GNAQ and PTEN mutations.36 Our results, together with these studies, offer mechanistic insights into why melanomas of the female genital tract may not clinically respond to BRAF V600E-targeting therapies.

For benign genital nevi, a high percentage (91%) harbored BRAF V600E. This mutation has previously been documented in genital nevi by Nguyen et al37: 6 of 20 nevi (30%), with 3 of 13 (23%) of atypical genital nevi and 3 of 7 (43%) of genital nevi without atypia, had a BRAF V600E mutation. In comparison, our results showed a considerably higher incidence of BRAF V600E, present in 75% of genital nevi with atypia and 100% of genital nevi with atypia. The difference in results may be attributable to differences in genotyping methodologies or they may be related to the relatively small numbers of cases in both studies. While it is possible that BRAF-mutant nevi may evolve into BRAF-mutant melanomas, the finding that BRAF mutations are rare in gynecologic melanomas but common in melanocytic lesions of the vulva suggests that melanocytic nevi are unlikely to be precursors for most melanomas arising in this anatomic location.

Ten of 19 (53%) articles selected for review included mutational analyses of mucosal melanomas of various sites. From these studies, data pertaining strictly to melanoma of the female genital tract were extracted to calculate the cumulative published frequencies of the oncogenes of interest (Table I). All relevant cases of primary melanomas, lymph node metastases, local recurrences, and cutaneous metastases localized to the female genital tract were included. The results of the literature review combined with results of our study show that gynecologic melanomas most frequently feature KIT mutations (26%), less frequently harbor NRAS mutations (15%), and uncommonly have BRAF mutations (5%). It is therefore possible that the frequency of KIT mutations in female genital melanomas may be higher than that estimated from our study alone (16%). In calculating the cumulative frequency among the published literature, we note that the Abu-Abed et al study28 reported a lower frequency of KIT mutations (5%) compared to other studies (range, 25–54%), which is only partially explained by their restricted sequencing of KIT exons 11 and 13. Additional limitations of combining mutational frequencies from a review of the literature include variability in sample preparation and mutation screening techniques (ie, melting curve analysis, polymerase chain reaction–based DNA sequencing, or high-throughput genotyping platforms) and limited access to quality controlled data.

As our understanding of the genetic heterogeneity of melanoma grows, investigation of the genetic subsets of melanoma becomes essential for informing targeted therapeutic options. Importantly, all of the KIT mutations identified in our study would be predicted to be sensitive to KIT kinase inhibitors, including imatinib, sunitinib, dasatinib, sorafenib, and regorafenib. The exceptions might be those tumors harboring 2 KIT mutations, because there are no preclinical data available on the drug sensitivity of these forms of doubly-mutated KIT. In addition, early clinical trial data suggest that NRAS-mutant melanomas may respond to mitogen-activated protein kinase kinase inhibitors.38 In conclusion, the high frequency of clinically targetable mutations in primary melanomas of the female genital tract indicates an important role of genotyping in the clinical management of these tumors.

CAPSULE SUMMARY.

  • Different patterns of genetic mutations may occur in melanomas arising in different anatomic sites.

  • Of 25 female genital melanomas screened, KIT mutations were detected in 4 of 25 (16.0%), NRAS mutations in 4 of 25 (16.0%), and BRAF mutations in 2 of 25 (8.0%) samples.

  • A subset of female genital melanomas may benefit clinically from targeted therapies.

Acknowledgments

Supported by a Women’s Dermatologic Society Academic Research Award (to Dr Nelson) and a Melanoma Research Foundation Medical Student Grant (to Dr Tseng).

We thank Megan Von Isenburg, Associate Director, Research and Education at Duke Medical Center Library, for assistance with literature review strategy.

Abbreviations used

BRAF

v-raf murine sarcoma viral oncogene homolog B

KIT

v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CD117

NRAS

neuroblastoma RAS viral (v-ras) oncogene homolog

Footnotes

Conflicts of interest: None declared.

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