Vulvar

Question 1

Appx how many pts are affected by vulvar cancer per yr in the United States? What is the incidence of vulvar cancer in the United States?

Answer 1

∼6,020 pts are estimated to be affected in 2017 by vulvar cancer in the United States. The incidence is 2.5/100,000 people.

Question 2

Vulvar cancer accounts for what % of gyn malignancies? What % of all malignancies in women are vulvar malignancies?

Answer 2

Vulvar cancer represents 3%–5% of all gyn malignancies. This comprises 1%–2% of all cancers in women.

Question 3

What are the risk factors for vulvar cancer?

Answer 3

Risk factors for vulvar cancer:

1. Increasing age
2. HPV
3. Vulvar intraepithelial neoplasia (VIN)
4. Bowen Dz (squamous cell CIS)
5. Paget Dz (lesions arising from Bartholin gland, urethra, or rectum)
6. Smoking
7. Immune deficiency
8. Lichen sclerosis

Question 4

What HPV subtypes are associated with vulvar cancer?

Answer 4

HPV subtypes associated with vulvar cancer include 6, 16, 18, and 33.

Question 5

What is the function of HPV-associated oncoproteins?

Answer 5

It is thought that HPV-associated oncoproteins bind and inactivate tumor suppressor proteins such as Rb, p53, and p21.

Question 6

What are the subsites of the vulva?

Answer 6

1. Ant and post fourchette
2. Clitoris (clitoral hood and gland)
3. Labia minora and majora
4. Mons pubis
5. Perineal body
6. Urethral meatus
7. Vaginal orifice

Question 7

If a malignancy with the epicenter in the vagina involves the vulva, what is the primary?

Answer 7

Vulvar primary. Considering primary vaginal cancers are rare, any tumor within the vagina touching the vulva should be considered a vulvar primary.

Question 8

What histology constitutes the vast majority of vulvar cancers? Name other histologies of tumors found on the vulva.

Answer 8

The most common vulvar histology is squamous cell carcinoma (80%– 90%). Verrucous is a less aggressive subtype of vulvar SCC with rare LN spread.
2. Other histologies include melanoma, basal cell, Merkel cell, sarcoma, and adenocarcinomas of the Bartholin glands.

Question 9

What are the most common presenting Sx of pts with vulvar cancer?

Answer 9

Common presenting Sx of vulvar cancer: pruritus, vulvar discomfort or pain, dysuria, oozing, or bleeding.

Question 10

In which subsites does vulvar cancer most commonly arise?

Answer 10

70% of vulvar cancers arise from the labia majora/minora.

Question 11

How is “locally advanced” vulvar cancer defined?

Answer 11

Locally advanced vulvar cancer is defined as T2 tumors >4 cm or extension into anus and/or vagina, or T3. Also defined as any burden that cannot be resected without exenterative Sg.

Question 12

What are the 1st-, 2nd-, and 3rd-echelon LN regions in vulvar cancer, and which subsite is associated with skip nodal mets?

Answer 12

LN regions in vulvar cancer:
1st echelon: superficial inguinofemoral
2nd echelon: deep inguinofemoral and femoral
3rd echelon: external iliac nodes

Question 13

The clitoris can drain directly to the deep inguinofemoral or pelvic nodes. What is the strongest predictor of LN involvement in vulvar cancer?

Answer 13

The strongest predictor of LN involvement in vulvar cancer is DOI.

Question 14

Estimate the risk of inguinal LN involvement based on the DOI of a vulvar tumor: <1 mm, 1–3 mm, 3–5 mm, and >5 mm

Answer 14

LN involvement by cervical tumor DOI:
≤1 mm: <5%
1–3 mm: 8%
3–5 mm: 27%
5 mm: 34%

Question 15

What is the rate of pathologic inguinal positivity for cN0 pts?

Answer 15

25%-30%

Van Der Zee et al., GROINSS-V 2008

Question 16

If someone is found to have a positive inguinal LN, what is the rate of positive pelvic LNs and contralat inguinal LNs?

Answer 16

Pelvic LN+: 30%
Contralat inguinal LN+: 25%–30%
(Homesley HD et al., Obstet Gynecol 1986)

Question 17

What is the Bx approach for small (<1 cm) vulvar lesions?

Answer 17

For small (<1 cm) vulvar lesions, excisional Bx with a 1-cm margin, including the skin, dermis, and connective tissue.

Question 18

What is the Bx approach for large (>1 cm) vulvar lesions?

Answer 18

For large (>1 cm) vulvar lesions, wedge Bx including surrounding skin. These should be taken from the edge of the lesion to include the interface b/t
normal skin and the tumor to determine whether there is invasion of adjacent epithelium. (Baldwin P et al., Curr Obst Gyn 2005)

Question 19

What is the basic workup of vulvar cancer?

Answer 19

Vulvar cancer workup:

1. H&P (includes inguinal LN assessment, DRE)
2. EUA if adequate assessment cannot be done due to pain while awake, routine PAP smear of cervix, and colposcopy of the vagina and rest of vulva. Other investigations such as cysto or proctoscopy only if clinically indicated (e.g., involvement of urethra or anus)
3. Labs: CBC (to check for anemia); UA (to r/o infection), HIV testing (to r/o immunodeficiency when clinically indicated), BMP, LFTs
4. Imaging: PET/CT C/A/P with IV contrast. Pelvic MRI to assist in delineating primary and Tx planning.

Question 20

Summarize the FIGO staging for vulvar cancer.

Answer 20

FIGO IA: lesion ≤2 cm, confined to vulva and/or perineum with stromal invasion ≤1 mm, N0
FIGO IB: lesion >2 cm, confined to vulva and/or perineum with stromal invasion >1 mm, N0
FIGO II: lesion of any size with extension to adjacent structures (lowerthird of urethra, lower-third of vagina, or anus), N0
FIGO III: positive inguinofemoral LN
FIGO IIIA: 1–2 LNs each <5 mm
FIGO IIIB: ≥3 LNs each <5 mm or ≥2 LNs = 5 mm
FIGO IIIC: node(s) with extracapsular spread
FIGO IVA: extension into bladder or rectal mucosa (not muscle/wall), pelvic bone fixation, extension into upper 2/3 of urethra or vagina, or fixed or ulcerated regional LN mets
FIGO IVB: DMs, including pelvic LN

Question 21

Summarize the AJCC 2017 staging for vulvar cancer.

Answer 21

T1a = FIGO IA
T1b = FIGO IB
T2 = FIGO II
T3 = FIGO IVA
N0 = No inguinofemoral LN(s)
N0(i+) = ITC† in the inguinofemoral regions, ≤0.2 mm
N1a* = 1–2 LNs <5 mm
N1b = 1 LN ≥5 mm
N2a* = ≥3 LNs each <5 mm
N2b = ≥2 LNs ≥5 mm
N2c = regional LN(s) with extracapsular spread
N3 = fixed or ulcerated regional LN
†Isolated tumor cells
*Includes micromets
*When recording LN results, include size, location, and laterality

Question 22

Which pts with vulvar cancer require inguinal LND?

Answer 22

In vulvar cancer, all pts with clinically suspicious nodes require bilat inguinal LND unless there are bulky unresectable nodes. For pts with no clinically suspicious nodes, the need for nodal evaluation depends primarily on DOI. If the DOI is <1 mm, a nodal evaluation may not be needed unless there is LVSI or high grade.

Question 23

Which pts can have sentinal lymph node biopsy (SLNB) for nodal evaluation?

Answer 23

Pt with low-risk Dz: cN0, unifocal T1–2 (<4 cm) with DOI >1 mm. The GROINSS-V (Groningen International Study on Sentinel Nodes in Vulvar Cancer) study evaluated safety of SLNB in early stage vulvar cancer. 403 pts
with T1/T2 (<4 cm) SCC with DOI >1 mm and cN0 underwent SLNB. If SLNB was negative→ observation. If SLNB positive→ inguinofemoral LND. RT was recommended if ECE or ≥2 LN+ (10% of the SLN+ received). Initial results showed SLN– pts (69%) had an isolated groin recurrence of 2.5%. Morbidity was low in the SLNB-only arm. (Van der Zee et al., JCO 2008)

Updated Results showed the following:
SLNB–: 5-yr LR = 25%; 10-yr LR = 36%; isolated groin recurrence = 2.5%
SLNB+: 5-yr LR = 33%; 10-yr LR = 46%; isolated groin recurrence = 8% 10-yr DSS: SLNB– 91% vs. SLNB+ 65%; if LR: 70% (all comers), SLNB– 81%, SLNB+ 45%
10-yr OS: SLNB– 69% vs. SLNB+ 44%

Size of SLNB from the GROINNS-V was important
DFS decreased with SLNB mets >2 mm (95% → 70%)
Rate of Non-SLNB LN positivity: ITC* = 4%, ≤2 mm = 11%, 2–5 mm = 13%, >5 mm = 48%

*ITC = individual tumor cells

The Gynecologic Oncology Group’s GOG 173 study assessed sensitivity of SLNB. 452 women with SCC limited to vulvar 2–6 cm and DOI ≥1 mm underwent lymphatic mapping, SLNB, and then LND. Only 11 pts with a +LN on dissection were negative on SLNB. Sensitivity of SLNB was 92%. In tumors <4 cm, the FN rate was 2%. (Levenback CF et al., JCO 2012)

Question 24

In which pts with vulvar cancer is a unilat (instead of bilat) LND sufficient for workup?

Answer 24

Pts with a well-lateralized primary (>2 cm from midline) may undergo a unilat LND only.

Question 25

Is the staging system for vulvar cancer surgical or clinical?

Answer 25

FIGO surgical staging is used for vulvar cancer.

Question 26

Do imaging results affect the FIGO stage in vulvar cancer?

Answer 26

No. Imaging results are not included in FIGO staging.

Question 27

What is the Tx for vulvar CIS or VIN?

Answer 27

Pts with vulvar CIS or VIN can be treated with superficial local excision. If the labia minora or clitoris is involved, consider laser ablation.

Question 28

How should the primary of a pt with FIGO stage I or II vulvar cancer be treated?

Answer 28

In a pt with stage I or II vulvar cancer, the primary can be resected via a WLE, which includes resection of the tumor + a gross 1.0-cm margin of normal tissue around it. WLE has the same LR as radical vulvectomy for
stage I and II vulvar carcinomas. (Hacker NF et al., Cancer 1993)

Question 29

Which large retrospective study failed to confirm significance of wide (>8 mm) margins for resected T1–2 lesions?

Answer 29

AGO-CaRE-1 (Arbeitsgemeinschaft Gyn↑kologische Onkologie Chemo and
Radiotherapy in Epithelial Vulvar Cancer): At median f/u of 35 mos, vulvar
recurrence rates were 12.6% in pts with a margin <8 mm and 10.2% in pts
with a margin >8 mm (NSS). (Woelber L et al., Eur J Cancer 2016)

Question 30

What is the next step if margins are positive following surgical resection of vulvar cancer?

Answer 30

Re-excise if possible; otherwise, give adj RT. Adj RT is associated with an increase in LC and survival. (Chapman BV et al., Int J Radiat Oncol Biol Phys 2017; Faul CM et al., IJROBP 1997)

Question 31

What are the guidelines for LN assessment for stage I–II vulvar carcinoma?

Answer 31

• Nodal assessment may be excluded if <1 mm depth invasion and cN0
• All other cN0: SLNB or inguinal LND SLND established for unifocal stage I–II carcinoma, <4 cm, cN0
• If ITC or micromets (>0.2 mm–2.0 mm) → RT or LND
• If macromets (>2.0 mm) → full LND → RT
• Strongly consider adding concurrent chemo for LN positive (Gillet al., Gynecol Oncol 2015)
• Contralat assessment if <2 cm from midline (<3% risk)
• If clinically LN positive → Inguinofemoral LND
• Adequate Inguinal LND
• > 10 nodes each side
• Superficial and deep assessment needed
• LN+ to total LN removed ratio on each size needs to be ≤20% (GOG 37)
• LND increases risk of lymphedema to ∼25% (GROINSS-V)
• Attempts to lower morbidity by superficial dissection alone lead to higher rates of recurrence (GOG 74)

Question 32

In which vulvar cancer pts is adj RT to the bilat groin and pelvis indicated? What RCTs explored this question?

Answer 32

1. Adj RT to the bilat groin and pelvis is recommended in pts with ≥2 +LN, >20% nodal positivity, a single node >5 mm, presence of ECE, or pts with SLN positive yet no nodal dissection was performed.
2. In GOG 37, 114 pts s/p radical vulvectomy + bilat inguinal LND. If LN+ were randomized to pelvic node dissection or pelvic and groin RT. The dose was 45–50 Gy.

Updated Analysis showed pelvic and groin RT group had a higher 6-yr RFS (48→59%) and CSS (49→71%). Subset analysis showed RT benefitted pts with clinical suspected or fixed ulcerated groin nodes or ≥2
groin LN. A ratio of >20% ipsi positive groin node/groin node dissected was associated with a decrease in cancer-related mortality, relapse, and contralat LN mets, but had a better OS in the RT group. The initial 2-yr OS benefit to RT (54→68%) was not significant at 6 yr (41 vs. 51%, p = NS).

The benefit of RT was likely d/t the decrease in groin recurrence (24→5%), as recurrence in the pelvis (2% vs. 5%), vulvar (7% vs. 8%), or DM (15% vs. 16%) were the same. (Kunos C et al., Obstet Gynecol 2009)

Also AGO-CaRE-1 (Arbeitsgemeinschaft yn↑kologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer) was a retrospective study evaluating 1,249 vulvar pts of which 447 (36%) were found to have
positive pathologic groin nodes. 55% (244/447) of node positive pts rcvd adj Tx of which 84% was adj RT and 14% was adj CRT. Part of the analysis evaluated pts treated with or without adj RT or CRT. Adj Tx was
associated with an increase in 3-yr PFS (26→40%). However, on subset analysis, the benefit was only for those with ≥2 positive LNs. (Mahner S et al., J Natl Cancer Inst 2015)

Question 33

Is there data specifically supporting concurrent chemo being added to adj RT for LN positive pts?

Answer 33

Yes. A National Cancer Data Base (NCDB) analysis on pathologic inguinal LN pts treated with adj RT was conducted to determine the impact of the addition of adj chemo. The addition of adj chemo was associated with an increase in unadjusted MS (30→44 mos) and on adjusted propensity score matching, a 38% reduction in risk of death. (Gill BS et al., Gynecol Oncol 2015)

Question 34

In pts with N0 vulvar cancer, does groin RT eliminate the need for inguinal LND? What RCT explored this question?

Answer 34

The need for inguinal node dissection in N0 vulvar cancer prior to groin RT
is controversial. In GOG 88, 58 pts with cN0 vulvar cancer s/p radical vulvectomy were randomized to bilat inguinofemoral and pelvic LND (+nodes rcvd RT) vs. bilat groin-only EBRT (50 Gy). LR, PFS, and OS favored the LND arm. (Stehman FB et al., Cancer 1992)

But there are major criticisms of GOG 88

a. CT was not used for staging.
b. 50 Gy is not adequate for pts with gross nodes evident by CT.
c. Pts were treated with electron fields prescribed to a depth of 3 cm, which may not adequately cover the inguinal/femoral nodal regions. Koh et al. reported the avg femoral vessel depth ranges from 2 to 18 cm. He also reported on 5 pts who recurred after prophylactic RT in GOG 88 and showed all rcvd potential doses of <47 Gy and 3 pts rcvd more than 30% under dosing. (Koh WJ et al., Int J Radiat Oncol Biol Phys 1993)

Question 35

What are the indications for adj RT to the primary site after surgical management?

Answer 35

The relative indications for adj RT to the primary site are based upon Heaps factors.
1. +Margins
2. Close margins (<8 mm fixed specimen or <1 cm by frozen)
3. LVSI
4. 2+ Heaps factors (thickness >2.5 mm, >1 cm deep, LVSI, infiltrative/mixed growth pattern) (Heaps JM et al., Gynecol Oncol 1990)
The most important risk for local recurrence is +margin. Salvage surgery leads to a lot of morbidity.

Question 36

What is the Tx approach for pts with stages III–IV vulvar cancer?

Answer 36

Tx options for stages III–IV vulvar cancer:

1. Surgery (if –margins can be achieved) + RT(+/– chemo)
2. Neoadj CRT (phase II) → surgery; for those initially unresectable
3. Definitive CRT

Question 37

What studies support neoadj CRT in initially unresectable vulvar cancer?

Answer 37

GOG 205 was a phase II trial of 58 pts with T3–4 vulvar SCC unable to obtain radical vulvectomy s/p CRT with 40 mg/m2 of weekly cisplatin. RT was 57.6 Gy @ 1.8 Gy/daily with a CD after 45 Gy to gross Dz + margin
with no Tx break. cCR was 64% and pCR rate was 50% (22% with cCR still had residual Dz). When compared to prior GOG 101, the cCR (48→64%) and pCR (31→50%) was higher. (Moore DH et al., Gynecol
Oncol 2012)

GOG 101 was a phase II study of 73 pts with unresectable vulvar cancer
given concurrent cisplatin/5-FU + RT. RT was bid to 47.6 Gy with planned
Tx break. 97% of pts were converted to resectable Dz. (Moore DH et al., IJROBP 1998)

Question 38

Estimate the 5-yr OS by FIGO stage.

Answer 38

5-yr estimated OS by FIGO stage:
Stage I: 90%
Stage II: 81%
Stage III: 68%
Stage IV: 20%

Question 39

What are the commonly used neoadj, adj and definitive RT doses for
vulvar cancer?

Answer 39

1. Neoadj RT doses
   - Nodal regions and vulva: 45.0–50.4 Gy
   - High-risk sites (gross Dz): 55.8–59.4 Gy
2. Adj RT doses
   - –Margin, +LVSI: 50.4–54.0 Gy
   - Close or margin positive: 56.0–59.4 Gy
   - Inguinal LN positive regions: 50.4–54.0 Gy
   - ECE regions: 56.0–59.4 Gy
3. Definitive RT doses
   - Unresectable Dz: 66–70 Gy to primary site with concurrent weekly cisplatin +/– 5-FU
   - Gross nodal Dz: 56–59.4 Gy

Question 40

What are the anatomic boundaries of the inguinal LNs?

Answer 40

The key point to remember is that the groin nodes are usually very medial to the inguinal–femoral vessels. Therefore, the classic 7 mm–1 cm margin around the vessels, commonly done for pelvic LN contouring is inaccurate.

1. Radial boundaries: Sartorius muscle, Rectus Femoris, Iliopsoas, lat edge of pectinus or medial edge of abductor longus
2. Cranially: Follow the external iliac transitioning to the inguinal vessels
3. Caudal: Either the inf trochanter or 2 cm below the junction of the great saphenous and the common femoral vein

Question 41

What are the ongoing trials for vulvar carcinoma pts?

Answer 41

GOG 279 is a phase II trial evaluating the addition of concurrent gemcitabine and cisplatin to IMRT. Pts with primary locally advanced
(T2/3, N0–3, M0) unresectable by standard radical vulvectomy rcv concurrent weekly gemcitabine and cisplatin with IMRT. Pts rcv a core Bx
to vulvar or if gross Dz present, surgical removal of gross Dz at primary and/or groin LNs, within 6–8 wks after completion of therapy. Primary outcome is pCR. Secondary outcomes are cCR, vulvar-PFS, groin-PFS, and toxicity.

GOG 270/GROINSS-V II

a. T<4 cm w/ DOI>1 mm; cN0
b. Originally: SLNB– → observation, SLNB+ → RT
c. Pts with macromets: 20% risk of additional +LNs vs. 2% with micromets
i. Crossed prespecified safety border in macromets cohort
ii. Amended: SLNB+ (<2 mm) → RT; if >2 mm, LND → RT +/– chemo

Question 42

What are the acute RT toxicities of the vulva, pelvis, and inguinal nodes?

Answer 42

Acute RT toxicities of the vulva, pelvis, and inguinal nodes include severe RT dermatitis of the vulva and groins (which results in need for Tx interruption), n/v, diarrhea, urethritis, cystitis, and myelosuppression.
Strongly consider performing skin checks in the groin and vulvar sites weekly while the pt is on the Tx table before Tx begins.

Question 43

What are the late RT toxicities associated with the vulva and inguinal
nodes?

Answer 43

Late RT toxicities of the vulva, pelvis, and inguinal nodes include vaginal
atrophy, itching and discharge, SBO, lymphedema, and femoral neck fracture.

Question 44

Estimate the risk of femoral neck fracture after 50 Gy.

Answer 44

50 Gy to the femoral neck is associated with an 11% risk of fracture at 5 yrs. (Grisby JS et al., Med Dos 2004)

Question 45

What is the NCCN (2018)-recommended f/u frequency post Tx?

Answer 45

q3–6 mos for 2 yrs, q6–12 mos for 3 yrs, then annually.