Radiation Oncology: A Question-Based Review

Vulvar Cancer

Charles H. Matthews and Daniel G. Petereit

image Background

Approximately how many pts are affected by vulvar cancer per yr in the U.S.? What is the incidence of vulvar cancer in the U.S.?

~3,500 pts are affected by vulvar cancer per yr in the U.S. The incidence is 1/100,000 people.

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

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

What are the risk factors for vulvar cancer?

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, urethra, or rectum)

6.     Erythroplasia

7.     Chronic vaginitis

8.     Leukoplakia

9.     Smoking

10. Employment in laundry facilities

11. Immune deficiency

What HPV subtypes are associated with vulvar cancer?

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

What is the function of HPV-associated oncoproteins?

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

What are the 7 subsites of the vulva?

Subsites of the vulva:

1.     Labia majora

2.     Labia minora

3.     Mons pubis

4.     Clitoris

5.     Vaginal vestibule

6.     Perineal body

7.     Posterior forchette

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

Common presenting Sx of vulvar cancer: pruritis, vulvar discomfort or pain, dysuria, oozing or bleeding, and difficulty with defecation

In which subsites does vulvar cancer most commonly arise?

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

How is “locally advanced” vulvar cancer defined?

Locally advanced vulvar cancer is defined as a vulvar tumor burden that cannot be resected without exenterative surgery.

What % of vulvar cancers are locally advanced at Dx?

30% of vulvar cancers are locally advanced at Dx.

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

LN regions in vulvar cancer:

1.     1st echelon: superficial inguinofemoral

2.     2nd echelon: deep inguinofemoral and femoral

3.     3rd echelon: external iliac nodes

The clitoris can drain directly to the deep inguinofemoral or pelvic nodes.

What are the 2 strongest predictors of LN involvement in vulvar cancer?

The 2 strongest predictors of LN involvement in vulvar cancer are tumor grade and DOI.

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

LN involvement by cervical tumor DOI:

1.     <1 mm: <5%

2.     1–3 mm: 8%

3.     3–5 mm: 27%

4.     >5 mm: 34%

(Hacker NF et al., Cancer 1993)

Estimate the risk of inguinal LN involvement based on the vulvar cancer FIGO stage.

LN involvement by the vulvar cancer FIGO stage:

1.     Stage I: 17%

2.     Stage II: 40%

3.     Stage III: 30%–80%

4.     Stage IV: 80%–100%

What histology constitutes the vast majority of vulvar cancers? Name 3 other histologies of tumors found on the vulva.

The most common vulvar histology is squamous cell carcinoma (80%–90%). Other histologies include melanoma, basal cell, Merkel cell, sarcoma, and adenocarcinomas of the Bartholin glands.

What % of vulvar cancers are multifocal?

~5% of vulvar cancers are multifocal.

image Workup/Staging

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

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

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

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 between normal skin and the tumor to determine whether there is invasion of adjacent epithelium. (Baldwin P et al., Curr Obst and Gyn 2005)

What is the basic workup of vulvar cancer?

Vulvar cancer workup:

1.     H&P

2.     Labs: CBC (to check for anemia); UA (to r/o infection), HIV testing (to r/o immunodeficiency)

3.     EUA with PAP smear, colposcopy, and directed Bx of the cervix, vagina, and vulva; cystoscopy and sigmoidoscopy if clinically indicated

4.     DRE to r/o multifocal Dz

5.     Imaging: CT abdomen/pelvis and CXR, but consider PET and MRI

6.     Stage-specific inguinal nodal evaluation

Which pts with vulvar cancer do not require inguinal lymphadenectomy?

In vulvar cancer, all pts with clinically suspicious nodes require bilat inguinal lymphadenectomy unless there are bulky unresectable nodes. For pts with no clinically suspicious nodes, the need for inguinal lymphadenectomy depends primarily on DOI. If the DOI is <1 mm, a lymphadenectomy may not be needed unless there is LVI or a high grade. The use of sentinel node Bx instead of a full dissection is being studied.

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

Pts with a well-lateralized primary may undergo a unilat lymphadenectomy only.

Is the staging system for vulvar cancer surgical or clinical?

FIGO surgical staging is used for vulvar cancer.

Do imaging results affect the FIGO stage in vulvar cancer?

No. Imaging results are not included in FIGO staging.

Summarize the FIGO (2008) staging for vulvar cancer.

1.     Stage IA: lesion ≤2 cm, confined to vulva or perineum with stromal invasion <1 mm, no nodal mets

2.     Stage IB: lesion >2 cm or with stromal invasion >1 mm, confined to vulva or perineum, no nodal mets

3.     Stage II: lesion of any size with extension to adjacent structures (lower 3rd of urethra, lower 3rd of vagina or anus), no nodal mets

4.     Stage III: lesion of any size with or without extension to adjacent structures (lower 3rd of urethra, lower 3rd of vagina or anus) and positive inguinofemoral LN

5.     Stage IIIA: 1 LN ≥5 mm or 1–2 LNs <5 mm

6.     Stage IIIB: ≥2 LN ≥5 mm or ≥3 LNs each <5 mm

7.     Stage IIIC: node(s) with extracapsular spread

8.     Stage IVA1: lesion invades upper urethra and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone

9.     Stage IVA2: fixed or ulcerated inguinofemoral LN

10. Stage IVB: DMs, including pelvic LNs

image Treatment/Prognosis

What is the Tx for vulvar CIS or VIN?

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

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

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 2-cm margin of normal tissue around it.

In a pt with a stage I or II vulvar cancer, does radical vulvectomy improve the LR rate over WLE?

No. In a pt with stage I or II vulvar cancer, radical vulvectomy and WLE have similar recurrence rates (~7%). (Hacker NF et al., Cancer 1993)

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

Re-excise if possible; otherwise, give adj RT. Retrospective data suggests that adj RT improves LC and possibly survival (Faul CM et al., IJROBP 1997).

How are the inguinal nodes treated in vulvar cancer stage IA? Stage IB? Stage II?

1.     Stage IA: Lymphadenectomy is not necessary (consider for high-grade lesions).

2.     Stage IB: If the lesion is well lateralized, consider unilat dissection. If there is a midline lesion, then bilat groin nodal dissection is required.

3.     Stage II: Bilat lymphadenectomy is recommended.

GOG 173 is an ongoing phase III trial examining the utility of sentinel LN mapping for stage I–II pts.

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

Adj RT to the bilat groin and pelvis is commonly recommended in pts with ≥2 micromets in inguinal nodes, a single node >5 mm, or a single node with ECE.

In GOG 37, 114 pts s/p radical vulvectomy + bilat inguinal lymphadenectomy were randomized to RT to the pelvis and bilat groin vs. pelvic node dissection if node+. The dose was 45–50 Gy. The 2-yr groin recurrence rate decreased with RT (5% vs. 24%), and there was an OS advantage for RT (68% vs. 54%). All the benefits of RT were for >1 +node. The survival benefit appeared to be due to improved control in the groin. In pts with only 1 +node on the dissection, surgery and RT outcomes were similar. (Homesley HD et al., Obstet Gynecol 1986)

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

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 inguinal femoral and pelvic lymphadenectomy (+nodes rcv RT) vs. bilat groin-only EBRT (50 Gy). LR, PFS, and OS favored the lymphadenectomy arm. (Stehman FB et al., Cancer 1992)

What are the major criticisms of GOG 88?

Major criticisms of GOG 88:

1.     CT was not used for staging. 50 Gy may not be adequate for pts with gross nodes evident by CT.

2.     CT was not required for RT planning. Pts were treated with electron fields prescribed to a depth of 3 cm, which may not adequately cover the inguinal/femoral nodal regions. Retrospective data suggests that adequate RT to groins can result in good LC (~90%) (Katz A et al., IJROBP 2003).

What are relative indications for adj RT to the primary site after WLE?

The following factors are relative indications for adj RT to the primary site:

1.     +Margins or close margins (<8 mm fixed specimen or <1 cm by frozen section)

2.     LVSI

3.     DOI >5 mm

(Heaps JM et al., Gynecol Oncol 1990)

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

Tx options for stage III–IV vulvar cancer:

1.     Surgery (if –margins can be achieved) + PORT

2.     Neoadj CRT (phase II) → surgery for those initially unresectable

3.     Definitive CRT

What studies support neoadj CRT in initially unresectable vulvar cancer?

GOG 101 was a phase II study of 73 pts with unresectable vulvar cancer given concurrent cisplatin/5-FU + RT. RT was bid to 4,760 cGy. 97% of pts were converted to resectable Dz. (Moore DH et al., IJROBP 1998)

Estimate the CR rate for unresectable vulvar cancer pts treated with definitive cisplatin/5-FU + RT.

In small prospective trials, CR rates after definitive cisplatin/5-FU + RT vary from 47%–80%GOG 205 is an ongoing trial examining outcomes of T3 or T4 unresectable tumors that rcv cisplatin and RT → surgery to gross residual Dz. This may help us answer this question.

Estimate the 5-yr OS by FIGO stage.

5-yr estimated OS by FIGO stage:

1.     Stage I: 90%

2.     Stage II: 81%

3.     Stage III: 68%

4.     Stage IV: 20%

(Gonzalez-Bosquet J et al., Gyn Oncol 2005)

Describe the “pair of pants” technique to treat vulvar cancer.

The “pair of pants” technique for vulvar cancer:

There are 3 AP fields: a pelvic field and left and right inguinal node fields. There is only one PA field—the pelvic field. The beams are weighted so that both the isocenter within the pelvis and the isocenter within the groins rcv 100% of the dose.

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

Commonly used adj and definitive RT doses in vulvar cancer:

1.     −Margin, +LVSI: 45–50.4 Gy

2.     Early ECE, close or focally positive margins: 59.4 Gy

3.     +Margin, gross residual, extensive ECE, +LN: 63–66 Gy

4.     Unresectable Dz: 66–70 Gy with concurrent weekly cisplatin or cisplatin/5-FU

image Toxicity

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

Acute RT toxicities of the vulva, pelvis, and inguinal nodes include severe RT dermatitis of the vulva and groins, n/v, diarrhea, urethritis, cystitis, and decreased blood counts.

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

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

Estimate the risk of femoral neck fracture after 50 Gy.

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