Vulvar/Vaginal Cancers
Squamous Cell Carcinoma

Epidemiology

The etiology of vulvar cancer is largely unknown. Previous retrospective studies found associations with syphilis or chronic granulomatous disease but these are largely historical and anecdotal in nature only. HPV is associated with vulvar cancer but not as strongly as with CIN. As mentioned previously, HPV is found in 80-90% of VIN but only 50% of vulvar cancers. 1, 4 A history of previous abnormal Papanicoulau smears, genital warts and smoking have been associated with an increased risk of vulvar cancer, 5 and the combination of smoking and genital warts increases that likelihood 35 times. There are likely two epidemiological populations- older women (>70 y.o.) with small localized lesions and a possible association with chronic inflammatory conditions such as lichen sclerosus or granulomatous diseases; and younger women more likely to be associated with HPV infection, VIN, smoking, or history of genital warts.

Presentation

Long term itching or symptoms of a mass, lump, or swelling are present in over 50% of patients. It also may appear as a nodule or ulcer within a larger area of VIN. However, diagnostic delay of 2-16 months is common, either due to patient denial/delay, or physician delay. This emphasizes the importance of obtaining a pathologic diagnosis prior to treating lesions of the vulva medically.

Diagnosis

Diagnosis of vulvar cancer is similar to VIN and requires biopsy for any suspicious lesions. If an ulcerative lesion is present, it is preferable to take the biopsy at the periphery of the lesion as the base will often show only chronic ulceration and inflammation on pathologic examination.

Routes of Spread

Vulvar cancer spreads predominately via the lymphatic system or by direct extension although, hematogenous metastases have been reported. Classically spread is from the lateral vulva to the superficial inguinal lymph nodes on the ipsilateral side, and from there to the deep inguinal lymph nodes and on to the pelvic lymph nodes. [Figure 1] Clinically lesions in the anterior clitoral areas and posterior midline are capable of metastasizing to contralateral or bilateral inguinal nodes (hatched areas). The anterior clitoral areas can also drain directly to the deep femoral nodes or to the pelvic nodes via lymph channels coursing beneath the pubic symphisis. The clinical significance of this is unknown, however- of 58 patients with clitoral involvement, none had pelvic node involvement without inguinal node involvement. 6 Data from intraoperative sentinel lymph node mapping generally supports this view of sequential metastatic spread, however, mapping also demonstrates occasional aberrant channels coursing directly to deep, contralateral, or pelvic lymph nodes. This may explain the occasional unexpected nodal recurrence in low risk patients. Risk factors for metastases to lymph nodes include poorly differentiated tumor grade, lymph-vascular space invasion, increasing tumor thickness and size. 7 Size greater than 2cm is associated with 45% nodal involvement, while <2cm diameter has approximately 20% risk. Importantly, tumor thickness less than 1mm has minimal risk of nodal metastasis. 8, 9 However, 44% of tumors with greater than 5mm invasion had nodal involvement with 15% involvement of the contralateral nodal groups. 7

Staging of Vulvar Cancer

Stage Clinical Findings
I Tumor confined to vulva or perineum; 2cm or less in diameter; no nodal metastases

IA

</= 1mm stromal invasion

IB

>1mm stromal invasion

II >2cm diameter, confined to vulva or perineum; no nodal metastases
III Any size tumor with adjacent spread to lower urethra, lower vagina, or anus; or unilateral regional lymph node mets
IVA Upper urethra, bladder mucosa, rectal mucosa, pelvic bone, or bilateral regional node mets
IVB Distant mets (includes pelvic lymph nodes)

Description of Therapeutic Techniques

Multiple descriptions of different surgical procedures are found in the literature and textbooks and can be somewhat confusing as to their use and extent. The most conservative is the Simple Partial Vulvectomy or local excision (also called partial skinning vulvectomy, partial superficial vulvectomy). This technique removes the skin over the involved part of the vulva while preserving the clitoris and labial fat pad. This technique is usually reserved for VIN lesions and occasionally microinvasive lesions. A Radical Wide Local Excision (WLE), also known as a radical partial vulvectomy or partial deep vulvectomy, is generally a unilateral local resection with adequate surgical margins (at least 1cm). The dissection is carried to the deep perineal fascia and includes the entire perineal fat pad. A Radical Vulvectomy (either partial or total) includes the entire vulva (bilaterally if total, unilateral if partial). In addition, the clitoris is removed along with the posterior perineum and the dissection is carried deeply to the deep perineal fascia removing the vulvar fat pad with the inner margin being the hymenal ring. Historically this incorporated the inguinal node dissection into the same specimen (en bloc “butterfly” technique) however this has been abandoned in the last decade in favor of three separated incisions. Previously the en bloc technique had significant morbidity including a 50% wound breakdown rate 10. The “Triple Incision” Technique separates the nodal incision from the vulvar excision and preserves the radicality of a radical vulvectomy while reducing morbidity (wound breakdown rates as low as 15-20%) 11-15. Initial concern regarding residual metastatic disease in the skin bridge separating groin incision from vulvar incision has since been disproven.

Treatment by Stage

Stage IA (T1 N0 M0)

This involves a lesion <2cm in size with <1mm depth of invasion. Because of the negligible risk of nodal involvement, groin nodal dissection is not performed. A radical vulvectomy or a radical wide local excision (individualized depending on patient and lesion location) with a 1cm margin is adequate therapy. Margin size of greater than 1cm is important as this has been associated with no risk of recurrence compared to a margin of <8mm having 20-50% recurrence. 16

Stage IB (T1 N0 M0)

This is a lesion <2cm size with >1mm depth of invasion. A radical vulvectomy or a radical wide local excision is performed (as for a IA lesion). The risk of nodal involvement approaches 20% therefore inguinal node dissection is warranted. Lesion location determines whether the dissection should be ipsilateral only or bilateral. However, consideration should be given to depth of invasion as patients with >5mm invasion have a 15% rate of metastatic disease to bilateral nodes. Midline lesions (<1cm from midline) should have bilateral node dissection performed, and consideration should be given to bilateral nodes for superior labia minora lesions as well. There is some controversy regarding dissection of the superficial inguinal nodal group only versus also including the deeper femoral node group. Three studies involving 199 patients undergoing superficial node dissection for early stage vulvar cancer 13, 17, 18 found only 1 groin recurrence. However, a Gynecologic Oncology Group prospective study of 121 patients with Stage I tumors undergoing only superficial lymphadenectomy had nine groin recurrences 19. The conclusion of the authors was that the groin recurrences were due to the lack of deep femoral nodal dissection, however this has been criticized due to the large number of patients with midline and labia minora lesions that may explain potential groin failures.

Stage II (lesions >2cm size)

Management of these larger lesions should be with a radical vulvectomy and bilateral superficial and deep inguinal lymphadenectomy. However, recent attention has been given to a more conservative radical WLE with adequate margin (>1cm) if this is possible based on lesion location.

Advanced Disease
(Stage III/IV)

The overlying principle in these patients is individualization of therapy. These tumors can involve the lower urethra, lower vagina, or anus and present difficulty obtaining adequate surgical margins. It is possible to resect the lower 1/3 of the urethra and still maintain continence. Similarly, it is possible to resect significant portions of the vagina to obtain adequate margins as the vaginal mucosa is quite pliable. Anal lesions are more difficult due to the proximity of the anal sphincter however an attempt should be made to resect these surgically as well. For larger lesions that are surgically unresectable consideration should be given to pre-operative radiation in combination with chemotherapy. 20 The radiation should be in the range of 45-50 Gy to the vulva and groin nodes. Chemotherapy regimens have included cisplatin, 5-FU, and Mitomycin C. Complete response rates to chemo/radiation can be as high as 50% with an additional 30% achieving partial response. This has the advantage of shrinking the tumor and often making for a less involved resection, although radiation damage can make the surgery technically demanding. Combining radiation with groin node resection also increases post-operative complication rates significantly, including wound breakdown and lymphedema (chronic leg swelling).

Treatment of Positive Lymph Nodes

Grossly positive groin nodes should be resected if possible. However, occasionally these will be matted to underlying structures or ulcerated and surgical resection in these cases results in excessive complications. A recent prospective study 21 found that pre-operative chemotherapy (using cisplatin/5-FU) combined with a split course of 47 Gy radiation to the vulva, groin, and pelvic lymph nodes allowed subsequent surgical resection in 38 of 40 patients with only 11 subsequent groin or vulvar recurrences. Patients with 2 or fewer groin micrometastases (<5mm) may be offered the option of observation only. However if 3 or more micrometastases or 1 macrometastsis (10mm) are found then they should receive adjuvant radiation to the groin and pelvic nodes. No attempt should be made at pelvic node dissection in these cases as survival is better with radiation. 22

Complications

Complications are related to the extent of the primary surgery and any adjuvant therapy (such as radiation). Early wound breakdown (<30 days) rates are ~20-50% (more likely with infection, smoking, or in combination with radiation) and late wound breakdown occurs in 3% of patients. Perioperative antibiotics and the use of a triple incision technique in place of the en-bloc “butterfly” incision have reduced wound breakdown significantly. Early infection is found in ~35% of patients with late lymphangitis or cellulitus (skin infection) occurring in ~20%. Chronic lower extremity lymphedema (leg swelling) is related to the extent of lymph node dissection as well as any adjuvant radiation and occurs in ~15-30%. This is normally managed conservatively with support hose and physical therapy. Occasionally lymphocysts (collections of lymph fluid in the groin) will occur. These usually resolve spontaneously but may require sterile aspiration of the fluid or occasionally resection. Depending on pre-operative pelvic floor deficits and the extent of surgical resection, urinary or anal incontinence (leakage of urine or stool) and pelvic relaxation can occur. Decreased sexual satisfaction, libido and self image problems are common. Rarely, femoral hernias and fistulas may develop.

Recurrence

Local recurrence is relatively common, especially young patients in the VIN/HPV associated subgroup. This is usually minimally invasive, often involves adjacent VIN3 and is easily managed by subsequent surgical resection with subsequent recurrence-free survival rates of 75% with a negative margin. 23, 24 Prior radiation therapy may make resection of recurrences difficult. Fortunately groin or distant recurrence is rare (5-15%) however these recurrences have a grim prognosis. Various combinations of surgery, chemotherapy, and radiation have been used; all with equally poor outcomes. Isolated groin recurrences may be considered for surgical resection perhaps in combination with chemotherapy. Radiation is an option if it has not been used previously. Doxorubicin and bleomycin are the only tested chemotherapy regimens with efficacy as single agents. Cisplatin, despite good efficacy in ovarian and cervical tumors, has little activity in vulvar and vaginal squamous tumors, except in the neoadjuvant setting. A combination regimen of bleomycin, methotrexate, and CCNU (lomustine) was tested in 28 patients (13 of whom were recurrent) with 3 complete responses and 15 partial responses, although none of the complete responses were in the recurrent disease group. 25 The use of adjuvant chemotherapy in the setting of groin or distant recurrence should be considered palliative.

Prognosis

The majority of tumors are early stage with negative nodes and have an excellent long term survival26 of ~90%. However, only 44% of those with groin or pelvic nodal involvement survive long-term.

Vulvar recurrence occurs in 10-25% of patients but is usually curable (see above). Groin or distant recurrence occurs in 5-15% with dismal survival.