Vulvar Part 1: Early Stage

Vulvar Cancer
Written By Sydney Oesch

Episode Notes

  1. Epidemiology

    1. Only 0.3% of all cancer

    2. Vast majority are squamous cell carcinoma (SCC)

    3. Less common: melanoma, basal cell carcinoma, Bartholin gland adenocarcinoma, sarcoma, invasive Paget’s disease

    4. 5-year overall survival (OS) 69.6%

    5. At time of diagnosis, 60% localized, 27% regional spread, 14% distant or unknown stage

    6. Median age at diagnosis 69; <20% diagnosed at age <55

  2. Pathogenesis

    1. SCC

      1. HPV infection → vulvar intraepithelial neoplasia (VIN)/dysplasia: better prognosis

        1. Stains p16 pos and p53 pos

      2. Inflammatory conditions (i.e. lichen sclerosis) → differentiated VIN: poorer prognosis

        1. P16 neg and p53 WT

        2. P16 neg and p53 mut: worst prognosis of all

  3. Diagnosis

    1. Physical exam: measure and biopsy, document location

    2. Imaging depends on extent of disease

      1. If tumor stage ≥ 2 or mets suspected → PET CT or CT C/A/P

  4. Staging

    1. Updated in 2021

      1. Stage 3 includes upper ⅔ vaginal, bladder, and/or anal involvement

        1. Emphasizes that local disease is often salvageable, whereas groin involvement has a much worse outcome

      2. Depth of invasion (DOI) now measured from basement membrane of the deepest adjacent dysplastic/noninvasive rete ridge to the deepest point of invasion

    2. Early stage: stage I and select stage 2 disease (where disease is resectable without removing the proximal urethra, bladder, or anus)

  5. Prognostic Factors

    1. HPV dependent > HPV independent

    2. Stage (5-year relative survival 86% for localized, 22% for distant)

    3. LN status

      1. Negative: 5-yr OS 80%

      2. 1 pos: 60%

      3. 2 pos: 30%

      4. 3 pos: 20%

  6. Surgical Management

    1. Stage IA: ≤ 1 mm invasion on biopsy → simple partial vulvectomy

      1. If margins negative → observation

      2. If margins positive → re-excision

      3. If re-excision margins negative → obs or EBRT

      4. If re-excision margins positive → EBRT

    2. Stage IB and “select stage II”

      1. Lesion ≥ 2 cm from midline → radical partial vulvectomy + ipsilateral inguinofemoral lymph node biopsy (IFLNB)

        1. Full IFLND vs SLNB (only if tumor < 4 cm)

      2. Central lesion → radical partial vulvectomy + bilateral IFLNB

  7. Literature Behind Surgical Management

    1. GOG 36, Sedlis 1987

      1. Predictors of lymph node metastases in superficial vulvar cancer

      2. N = 558 w/ primary vulvar SCC underwent radical vulvectomy and bilateral groin node dissection

        1. 252 with superficial (<=5 mm invasion)

        2. 21% w/ positive nodes, 10.3% with 2+ pos nodes

      3. Tumor thickness, grade, capillary-like space involvement, clitoral or perineal location, clinically suspicious LN predicted LN involvement

    2. Homesley et al., 1993

      1. Reanalyzed above paper

      2. LN involvement 19% in lesions <=2 cm and 42% if > 2 cm

      3. 24% of patients w/ clinically unsuspicious nodes had surgically positive nodes

      4. Risk factors in order of importance: higher grade, suspicious/fixed/ulcerated nodes, LVSI, older age, depth of invasion

    3. GOG 74, 1992

      1. N = 155; clinical stage I disease, tumors ≤ 2 cm, unsuspicious nodes, DOI ≤ 5 mm

      2. Underwent modified radical hemivulvectomy and superficial inguinal LND

      3. Surgical morbidity improved

      4. Risk of death not increased compared to historic controls

      5. Higher rates of groin recurrences may have been due to only performing superficial nodal dissection; Takeaway: thus, IFLND today involves superficial inguinal and deep femoral lymph nodes

    4. GOG 88, 1992

      1. N = 58, stage I-II disease

      2. Randomized to radical vulvectomy + groin dissection vs radical vulvectomy + groin irradiation

      3. Closed prematurely due to increased relapses in the radiation arm - 18.5% rate of relapse in radiation group vs none in surgery

      4. Takeaway: nodes need to be surgically assessed if > stage IA disease, and radiation alone is not sufficient

  8. Literature About Lymph Node Evaluation

    1. GROINSS-V-1, 2008

      1. N = 403 w/ 623 groin dissection sites in total

      2. Included if lesions < 4 cm, DOI > 1 mm, clinically negative LN

      3. Underwent SLN detection with radioactive tracer and blue dye

        1. If SLNB neg on ultrastating → observation x 2 years

        2. If SLNB pos → full IFLND

        3. If >1 intranodal met or extranodal growth detected → EBRT

      4. 259 pts w/ unifocal disease and neg SLNB: groin recurrence rate 2.3% and 3-yr OS 97%

      5. Morbidity improved in short-term and long-term (wound breakdown, cellulitis, lymphedema)

    2. Oonk et al., 2010

      1. Follow up study of above

      2. Risk of non-sentinel node metastases higher when SLN detected by routine pathology vs ultrastaging

      3. Disease-specific survival for pts w/ SLN mets > 2 mm poorer than those w/ micrometastases

    3. GOG 173, 2012

      1. N = 452, vulvar-limited SCC, DOI > 1 mm, tumor 2-6 cm, clinically negative LN

      2. Underwent lymphatic mapping with isosulfan blue dye and radioactive tracer, SLNB, and IFLND

      3. False negative predictive value of SLNB 3.7%, but if limited to tumors < 4 cm, rate dropped to 2.9%

      4. Takeaway: established 4 cm as the cutoff for SLNB candidacy

    4. GOG 270/GROINSS-V2, 2021

      1. N = 1535, Prospective, single-arm, phase II study

      2. Vulvar cancer < 4 cm without positive lymph nodes on imaging

      3. At the time, SOC w/ mets to SLN was interval LND w/ adjuvant radiation for patients w/ extracapsular spread or >1 met LN detected on interval LND

      4. Protocol: local excision w/ SLNB

        1. If > 1 cm from midline → unilateral

        2. If < 1 cm from midline → bilateral

        3. If < 1 cm midline but lymphoscintigram only w unilateral drainage → unilateral

        1. If SLNB positive → EBRT 50 Gy to lymph node bed

      5. Results

        1. SLNB pos 21%

          1. 50% only w/ micrometastatic disease (>0.2 mm to <2 mm)

            1. In those receiving radiation per protocol, 1.6% had isolated ipsilateral groin recurrences

              1. Among the 18 patients who received no further treatment, ipsilateral groin recurrence rate was 11.8%

          2. 50% w/ macrometastatic disease

            1. Rate of groin recurrence at 2 years ws 22% in those who received radiation alone vs 6.9% in those who had interval lymphadenectomy +/- radiotherapy

            2. No recurrences in 7 patients who received chemoradiation

        2. SLNB neg

          1. 2.7% w/ isolated groin recurrences

        3. 2-yr OS

          1. SLNB neg: 95%

          2. Micromets: 88%

          3. Macromets: 69%

        4. Estimated risk for disease-specific death at 2 years for patients with macromets not different between those who underwent interval IFLND +/- radiation vs radiation alone

      6. Takeaways

        1. Interesting that many patients did not receive the treatment per outlined protocol

        2. Radiation alone inferior for recurrence rate, but OS may not be different

        3. Radiation alone after positive SLNB showing micromets has a very low isolated groin recurrence rate

        4. Radiation alone after positive SLNB showing macromets is not sufficient, given high recurrence rate in absence of full IFLND

  9. Literature About Chemoradiation

    1. GROINS-V III/NRG-GY024

      1. Ongoing, single-arm, phase II trial investigating whether IFLND can be replaced by chemoradiation in patients with early stage vulvar disease and macrometastases on SLNB

      2. Results expected in 2029

    2. AGO-CaRE-1, Mahner et al., 2015

      1. Retrospective

      2. N = 1249, vulvar SCC w/ surgical groin staging

      3. Pos vs neg nodes

        1. 3-year PFS: 35.3% vs 75%

        2. 3-year OS: 56% vs 90%

      4. 55% of patients w/ positive nodes received adjuvant therapy; outcomes improved if they received adjuvant treatment

        1. 84% adjuvant radiation and 13.5% chemoradiation

      5. Benefit of adjuvant treatment exaggerated in patients who had 2 or more positive lymph nodes

    3. Gill et al., 2015

      1. Retrospective study of NCDB

      2. Adjuvant chemotherapy in addition to RT associated with improvement in OS from 29.7 mo w/ radiation alone to 44 months

        1. 38% reduction in risk of death

    4. NCCN statement regarding chemoradiation: strongly recommended for patients with 2 or more positive IFLN or single IFLN w/ a macromet

  10. Special Considerations

    1. Adjuvant therapy for completely resected, node negative disease?

      1. Some experts suggest adjuvant therapy should be given if primary tumor is > 4 cm or positive or close (<8 mm) margins

        1. Also reasonable to re-excise or closely surveil

    2. Unilateral node dissection which is positive?

      1. Risk of positive contralateral nodes is 15%

      2. NCCN: “in select cases of a single, small-volume, unilateral positive inguinal node with a well-lateralized small primary tumor and a DOI <= 5 mm with a clinically negative contralateral groin examination, a contralateral groin LND or radiation may be omitted”

      3. Risk/benefit conversation with patient, most providers would recommend surgical evaluation of contralateral groin

  11. Literature on Close Margins

    1. Grootenhuis et al., 2019

      1. Retrospective

      2. Negative margins of any distance did not impact the rate of recurrence using cutoff of 8, 5, and 3 mm

    2. AGO-CaRE-1, Mahner et al., 2015

      1. No margin level from 2-8 mm significantly related to recurrence

    3. 2016 Meta-analysis

      1. Relative risk for recurrence of 2 if margin < 8

    4. NCCN: observation with regular close follow-up is reasonable, that re-excision should be considered for positive margins, adjuvant RT is another alternative to re-excision, and the survival advantage of re-excision and adjuvant vulvar radiation remains to be determined”.

  12. Adjuvant Therapy for Close Margins?

    1. Viswanathan et al., 2013

      1. Retrospective study

      2. 4-yr recurrence rate for negative, close, pos margins: 82% vs 63% vs 37%

      3. Margins < 5 mm had highest risk of recurrence

      4. Higher dose of adjuvant RT had lower rate of recurrence

    2. Ignatov et al.

      1. Retrospective study

      2. 5-year OS improved by addition of RT for pts w/ close or positive margins: 67.6% vs 29%

        1. Similar OS for pts receiving RT w/ close or positive margins to those with negative margins

References

1. Sedlis A, Homesley H, Bundy BN, et al. Positive groin lymph nodes in superficial squamous cell vulvar cancer: A gynecologic oncology group study. Am J Obstet Gynecol. 1987;156(5):1159-1164. doi:10.5555/URI:PII:0002937887901323

2. Homesley HD, Bundy BN, Sedlis A, et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecol Oncol. 1993;49(3):279-283. doi:10.1006/GYNO.1993.1127

3. Homesley HD, Bundy BN, Sedlis A, et al. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (A Gynecologic Oncology Group Study). Am J Obstet Gynecol. 1991;164(4):997-1004. doi:10.1016/0002-9378(91)90573-A

4. Stehman F, Bundy B, Dvoretsky P, Creasman W. Early Stage I Carcinoma of the Vulva Treated With Ipsilateral Superficial Inguinal Lymphadenectomy and Modified Radical Hemivulvectomy: A Prospective Study of the Gynecologic Oncology Group.

5. Stehman FB, Bundy BN, Thomas G, et al. GROIN DISSECTION VERSUS GROIN RADIATION IN CARCINOMA OF THE VULVA: A GYNECOLOGIC ONCOLOGY GROUP STUDY. Inr J Radiuriun Onmlog~~ Biol Phvs. 1992;24:389-396.

6. Te Grootenhuis NC, Van Der Zee AGJ, Van Doorn HC, et al. Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) i. Gynecol Oncol. 2016;140(1):8-14. doi:10.1016/j.ygyno.2015.09.077

7. Van Der Zee AGJ, Oonk MH, De Hullu JA, et al. Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol. 2008;26(6):884-889. doi:10.1200/JCO.2007.14.0566

8. Oonk MH, Van Hemel BM, Hollema H, et al. Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study. Lancet Oncol. 2010;11:646-652. doi:10.1016/S1470

9. Oonk MHM, Slomovitz B, Peter ;, et al. Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II. J Clin Oncol. 2021;39:3623-3632. doi:10.1200/JCO.21

10. Levenback CF, Ali S, Coleman RL, et al. Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study. J Clin Oncol. 2012;30:3786-3791. doi:10.1200/JCO.2011.41.2528

11. Hassanzade M, Attaran M, Treglia G, Yousefi Z, Sadeghi R. Lymphatic mapping and sentinel node biopsy in squamous cell carcinoma of the vulva: Systematic review and meta-analysis of the literature. Gynecol Oncol. 2013;130(1):237-245. doi:10.1016/j.ygyno.2013.04.023

12. Mahner S, Jueckstock J, Hilpert F, et al. Adjuvant Therapy in Lymph Node-Positive Vulvar Cancer: The AGO-CaRE-1 Study. JNCI J Natl Cancer Inst. 2015;107(3):426. doi:10.1093/jnci/dju426

13. H D Homesley, B N Bundy, A Sedlis, L Adcock. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes - PubMed. Clinical Trial Obstet Gynecol. Published online 1986:733-740. Accessed June 23, 2024. https://pubmed.ncbi.nlm.nih.gov/3785783/

14. Han SC, Kim DH, Higgins SA, Carcangiu ML, Kacinski BM. CHEMORADIATION AS PRIMARY OR ADJUVANT TREATMENT FOR LOCALLY ADVANCED CARCINOMA OF THE VULVA.; 2000.

15. Gill BS, Bernard ME, Lin JF, et al. Impact of adjuvant chemotherapy with radiation for node-positive vulvar cancer: A National Cancer Data Base (NCDB) analysis. In: Gynecologic Oncology. Vol 137. Academic Press Inc.; 2015:365-372. doi:10.1016/j.ygyno.2015.03.056

16. te Grootenhuis NC, Pouwer AW, de Bock GH, et al. Margin status revisited in vulvar squamous cell carcinoma. Gynecol Oncol. 2019;154(2):266-275. doi:10.1016/j.ygyno.2019.05.010

17. Viswanathan AN, Pinto AP, Schultz D, Berkowitz R, Crum CP. Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma. Gynecol Oncol. 2013;130(3):545-549. doi:10.1016/J.YGYNO.2013.05.036

Sydney Oesch
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