Vulvar Part 3: Paget’s, Melanoma

Vulvar Cancer
Written By Sydney Oesch

Episode Notes

  1. Location Is Key

    1. Hart’s line: lateral border of the vestibule, the area between the labia minora and the hymen, where nonkeratinizing vaginal epithelium meets the keratinizing epithelium of the labia minora

    2. Inside Hart’s line → mucosal vulvovaginal melanoma; outside Hart’s line → cutaneous

  2. Workup

    1. H&P, full skin assessment

      1. Document clearly where the lesion was biopsied

    2. PET CT most sensitive in diagnosing distant metastases

    3. Nodal basin US and brain MRI can be considered

  3. Staging

    1. Same as cutaneous melanoma

    2. GOG study in 1990s determine AJCC TNM staging system was prognostically the most accurate staging system in vulvovaginal melanoma

    3. Briefly..

      1. T: primary thickness of the lesion

        1. ≤ 1 mm T1 disease, >4 mm T4 disease

          1. Ulceration upstages T component

      2. N: number of involved nodes

        1. N0: no regional mets; N3: ≥ 4 nodes involved

      3. M: sites of metastasis

        1. M0: no distant mets; M1a-d to skin or soft tissue, lung, non-CNS visceral sites, CNS disease, respectively

  4. Treatment Algorithm

    1. Overall less standardized than other disease sites; do not have any RCTs

    2. Is primary tumor resectable?

      1. Yes → partial vulvectomy with at least 1 cm margins

        1. Add SLNB if ≥ stage 2

        2. Consider for stage IB

      2. SLNB is standard of care

        1. MSLT-1, 2014

          1. Established efficacy and safety of SLNB in cutaneous melanoma (primary site agnostic)

        2. MSLT-2, 2017

          1. Determined that completion lymphadenectomy after positive SLNB did not improve outcomes compared to observation alone

      3. Stage 3

        1. Partial vulvectomy with margins of 1 cm + systemic therapy and/or radiation or observation

      4. Not resectable → systemic therapy w/ RT

  5. Systemic Treatment

    1. Preferred category 1

      1. Nivolumab + ipilimumab

      2. Nivolumab + relatimab

    2. Category 1

      1. Pembrolizumab monotherapy

      2. Nivolumab monotherpy

      3. Dabrafenib-trametinib for BRAF V600E tumors

  6. Vaginal Melanomas

    1. Super rare (<10% of all primary vaginal cancers, which are already rare)

    2. Most commonly distal ⅓ of vagina

    3. Staging (differs from vulvovaginal/cutaneous melanoma staging)

      1. Stage 1: clinically localized disease

      2. Stage 2: regional lymph node involvement

      3. Stage 3: distant metastases

      4. Does not consider depth of invasion

      5. Not very prognostic

    4. Treatment Algorithm

      1. Is the primary tumor resectable?

        1. Yes → wide local excision vs partial vaginectomy w/ 1 cm margins

          1. Can consider SLNB if clinically negative nodes but does not change survival

          2. Resect grossly positive nodes

          3. After excision → observation +/- brachy +/- EBRT +/- systemic therapy

        2. No → clinical trial vs RT vs systemic therapy

  7. Molecular Testing of VVM

    1. Wilhite et al. 2024

      1. Molecular analysis of 142 VVM and 3823 cutaneous melanomas

      2. “Immunogenicity” lower in VVM - 0% TMB high and 18% PD-L1 positive

      3. Worse clinical outcomes - median OS shorter for pts with VVM treated with immune checkpoint inhibitors compared to CM (17.5 mo vs 38 mo)

      4. Takeaway: molecular profiling should be done on all VVM in order to guide choice of therapy, as these tumors don’t respond as well to the traditional cutaneous melanoma therapies

  8. Vulvar Paget’s Disease

    1. Form of intraepithelial adenocarcinoma

    2. Itching is most common symptom

    3. On exam: lesions are typically multifocal, eczematous appearance, can extend into vagina

    4. 25% will have invasive AC in or beneath surface lesion; 25% with synchronous malignancy elsewhere

      1. Work up with mammogram, colonoscopy, consideration of cystoscopy

      2. Consider CT C/A/P

    5. Treatment

      1. WLE or vulvectomy w/ recommended 2 cm margin

    6. Risk of recurrence 12-58%

    7. Can consider imiquimod for noninvasive vulvar Paget’s disease

    8. Surveil with yearly exam and low threshold for biopsy

References

1. Phillips GL, Bundy BN, Okagaki T, Kucera PR, Stehman FB. Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group. Cancer. 1994;15(73):2626-2632.

2. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: Results of the NCI-MATCH trial subprotocol H. Journal of Clinical Oncology. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762

3. Wilhite AM, Wu S, Xiu J, et al. A paradigm shift in understanding vulvovaginal melanoma as a distinct tumor type compared with cutaneous melanoma. Gynecol Oncol. 2024;188:13-21. doi:10.1016/j.ygyno.2024.06.002

4. Morton DL, Thompson JF, Cochran AJ, et al. Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma. New England Journal of Medicine. 2014;370(7):599-609. doi:10.1056/NEJMOA1310460/SUPPL_FILE/NEJMOA1310460_DISCLOSURES.PDF

5. Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. New England Journal of Medicine. 2017;376(23):2211-2222. doi:10.1056/NEJMOA1613210/SUPPL_FILE/NEJMOA1613210_DISCLOSURES.PDF

6. Wagar MK, Zhang RC, Weisman P, Spencer RJ, Kushner DM. Fluorescein Mapping in Vulvar Paget Disease. Obstetrics and gynecology. 2023;141(3):608-612. doi:10.1097/AOG.0000000000005084


Sydney Oesch
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Chemotherapy: IO
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Vulvar Part 2: Advanced