Vulvar cancer accounts for 4% of cancers of the female reproductive organs. Risk factors include advanced age, cigarette smoking, HPV infection, and preinvasive lesions. The majority are squamous cell carcinomas. Treatment involves radical vulvectomy and inguinofemoral lymphadenectomy for early-stage disease. Adjuvant radiation is recommended for lymph node-positive or high-risk disease. Locally advanced tumors are treated with preoperative chemoradiation to allow for organ-preserving surgery if possible. Unresectable disease receives definitive chemoradiation.

1. MAJ SOHAIB
CA VULVA

2. EPIDEMIOLOGY AND ETIOLOGY
 4% of cancers of the female reproductive organs
 0.6% of all cancers in women in the USA
RISK FACTORS
 Patient related
o Age: generally advanced age (median age at diagnosis is 70)
Diagnosis at younger age is associated with HPV and VIN
o Lifestyle: cigarette smoking
o Past medical history: previous or vaginal cancer; previous HPV infection
16, 18, 31; HIV infection; previous cervical or vaginal cancer; hypertension;
chronic granulomatous and dystrophic vulvar lesion; women exposed to
immunosuppression therapy
o Preinvasive lesions: VIN, 2–5% progress; Bowen’s disease; Paget’s
disease, erythroplasia

3. ANATOMY
 The parts of the vulva are the mons pubis, clitoris, labia majora and
minora, and vaginal vestibule
 Anteriorly, the vulva blends with the urinary meatus and posteriorly with
the perineum (body) and anus
 Bartholin’s glands – two small, mucous-secreting glands – are situated
within the subcutaneous tissue of the posterior labia majora
 The ducts of Bartholin’s glands open onto the posterolateral portion of
the vestibule
 The perineal body is a 3- to 4-cm band of skin that separates the
vaginal vestibule from the anus and forms the posterior margin of the
vulva

5. PATHOLOGY
 80–90% of primary vulvar tumors - SCC
 Tumors of the vestibular glands (Bartholin’s glands) often are
adenocarcinomas or adenocystic carcinomas, but 30–50% of SCC have
squamous histology
 The remaining, less common histologies include melanoma, basaloid,
neuroendocrine carcinoma (Merkel cell carcinoma), and sarcoma
 Diagnosis of vulva cancer requires biopsy of the primary tumor, usually
under local anesthesia

6. ROUTES OF SPREAD
Local extension
 Occurs in a stepwise progressive fashion from a distal-to proximal
direction
 Direct involvement of a third of the lower urethra, a third of lower vagina
and/or extension to the anus is first (FIGO stage II)
 More extensive cases: further progression proximally involves upper
urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or
fixation to bony pelvic structures (FIGO stage IVA)
Distant metastasis
 Hematogenous metastasis is rare
 Risk is 66% if ≥3 lymph nodes are involved

7. ROUTES OF SPREAD
Regional lymph node metastasis
 The overall risk of groin node -10 and 50%, and depends on the
presence of one or more of the following factors:
o Size of the primary tumor
o Depth of invasion
o Presence of lymphovascular space Invasion
 Stromal invasion of <1 mm leads to nearly 0% of nodal involvement
(hence, separately staged as 1A);
 Stromal invasion of 2–5 mm of stromal invasion leads to 8–10% chance
of nodal involvement
 Clitoris can theoretically drain directly to pelvic nodes, but this is rare
without inguinofemoral involvement
 Overall incidence of pelvic lymph node metastasis is 5%

8. ROUTES OF SPREAD
Regional lymph node metastasis
 Deep femoral node involvement without superficial inguinal node metastasis
has been reported – from clitoris and Bartholin’s gland tumors
 ~25% clinical negative or nonsuspicious inguinal nodes are pathologically
positive
 65–75% clinically palpable/suspicious nodes are pathologically positive (FNA
of enlarged groin lymph nodes should be performed to determine nodal
involvement)
 Contralateral spread without ipsilateral nodal involvement occurs in <15% of
cases
 A GOG study also found an unexpectedly high incidence of ipsilateral groin
recurrences presumed due to involvement of lymph nodes deep to the
cribriform fascia despite negative superficial nodes. Hence, both superficial
and deep inguinal nodes need to be dissected

9. CLINICAL PRESENTATION
 Vulvar cancer-specific symptoms such as
o Pain
o Spotting or bleeding
o Discharge
o Pruritus
 With advanced disease, symptoms are due to invasion of adjacent
organs, viz.,
o Difficulty urinating or defecating or with intercourse
o Presentation with edema of the lower extremities secondary to disease in
the groins is rare.

10. TNM, FIGO

11. CLINICAL PRESENTATION
 Two prognostic principles applied based on new knowledge:
 (1) size is not a significant factor for survival if the lymph nodes are
negative
 (2) number and size of nodal metastasis seem to be prognostic, and
these have been separated in the new version of staging.

13. PROGNOSIS
For overall survival
 Most important factor is presenting stage, particularly lymph node status
 Patients with 1 groin node involvement have lower risk of recurrence than have those
with 2 or nodes involved
 Patients with unilateral groin nodal involvement have better survival than do those with
bilateral disease
 Positive nodal status reduces survival by 40% (Table 23.6)
 Most deaths are because of uncontrolled locoregional disease, not distant metastasis
For local control
 Positive or close surgical margins (most powerful predictor) of local vulvar recurrence:
margin <8 mm 50% recurrence
 Lymphovascular space invasion
 Deep stromal invasion of >5 mm
 Large primary tumor size

14. OS ACCORDING TO EXTENT OF DISEASE

15. TREATMENT - SURGERY
Vulvectomy/wide local excision plus inguinofemoral lymphadenectomy
 Indications
 The only curative treatment modality
 Radical in concept but function preserving
 It is used for T1 and possibly T2 disease
 Consider induction therapy (chemoradiation) for unresectable tumors or potentially mutilating surgery
 Facts
 Minimum pathological margin of 8 mm around primary tumor is essential to minimize risk of local
recurrence
 The incision should be carried down to the inferior fascia of the urogenital diaphragm
 Inguinal lymph node dissection (LND), including superficial and deep nodes, is usually recommended
for all cases with invasive disease of more than 1-mm depth with clinically negative groins (GOG 88
study)
 Contralateral LND is performed if ipsilateral positive lymph nodes are present
 Bilateral groins dissection (BGND) needed if central vulvar disease present or for stage 2 and above

16. TREATMENT - RADIATION THERAPY
 Indications
 An adjuvant treatment after complete resection to primary tumor and
nodal beds
 Preoperative or defi nitive treatment (with chemotherapy)
 Palliative treatment to primary or metastatic foci
 Techniques
 EBRT using 3D-CRT or IMRT
 Interstitial brachytherapy may have a role in extensive lesions
 where function preserving surgery not possible

17. TREATMENT- CHEMOTHERAPY
 Indications
 Adjuvant treatment after surgery (with EBRT) being studied
 Induction or defi nitive treatment with concurrent EBRT for unresectable
disease
 Mainstay treatment for palliative therapy
 Medications
 Anal cancer protocols often used with 5-FU plus MMC or cisplatin plus
5-FU

18. CLINICAL TRIALS FOR MANAGING NODES
 GOG 88
 Randomized trial of 121 patients with IB–III disease and nonsuspicious nodes
(N0–1) treated with radical vulvectomy
 Patients randomized to bilateral inguinal femoral lymph node dissection or
external radiation (50 Gy to 3 cm below skin surface) to the groin
 If pelvic lymph nodes were involved, patients received radiation to bilateral
inguinal and pelvic nodes
 Study was closed after interim analysis of only 58 patients. Five of 27 patients
(18.5%) in radiation group suffered groin failure
 2-year overall survival rate favored the surgery group (90 versus 70%). Thus,
radiation to groins not recommended for sub-clinical nodes
 Criticisms: poor radiation techniques of radiation dose prescription to a depth
of 3 cm, resulting in all inguinal nodes that recurred receiving less than
prescribed dose

19. CLINICAL TRIALS FOR MANAGING NODES
 Koh et al, Katz et al
 Spiral CT–based 3-D studies demonstrated that the average depth of
the femoral vessels was 6 cm but can range from 2 to 18 cmb
 Using proper radiation planning of techniques, a dose of 50 Gy should
sterilize subclinical microscopic disease, as shown by several series
and spare morbidity of BGND

20. CLINICAL TRIALS FOR MANAGING NODES
 There is little margin for error in detecting occult-positive nodes, because groin
recurrence in vulvar cancer is usually fatal; hence, this is not yet accepted as standard
of care. Except for a few case series, not enough data are available – a Gynecologic
Oncology Group (GOG) 173 validation study is awaiting publication, although initial
results are promising.
 GROningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS-
V)
 403 women with squamous cell vulvar cancer (tumor size <4 cm) had sentinel node
detection with a combination of radioactive tracer and blue dye
 If SLN was detected and negative (n = 276), no further treatment was given; If SLN
was detected and positive or if no SLN was detected, inguinofemoral LND was
performed
 Median follow-up was 35 months, median time to recurrence was12 months; 3-year
survival rate was 97%
 259 patients with unifocal vulvar disease and a negative sentinel node resulted in 6
groin recurrences (i.e., 2.3% recurrence with negative SLNB)
 SLNB only patients had less short- and long-term morbidity, as compared to groin
node dissection (GND) patients.

21. RADIATION THERAPY IN RESECTABLE VULVA CANCER
 The uses of radiation therapy (RT) in resectable vulva cancer are indicated as
follows:
 Preoperative RT (with concurrent chemotherapy) plays a major role in
locoregionally advanced disease or in lesions with extension to the midline
structures. This is combined with inguinal dissection and function-preserving
completion surgery.
 Postoperative RT to primary tumor and nodal beds is determined separately
based on pathological prognostic features of each.
 Adjuvant RT for primary tumor is used when limited surgery has been
performed for organ preservation or when high-risk pathologic features, such
as large tumor (>4 cm), positive or close (<8 mm) surgical
margin, lymphovascular space invasion, and depth of stromal invasion >5
mm, are present.
 Adjuvant RT for nodal regions is indicated in patients with two or more involved
inguinal nodes, gross extracapsular extension (ECE), or gross residual nodal
disease as per the GOG trial 37 (Table 23.10).

22. RADIATION THERAPY IN RESECTABLE VULVA CANCER
 Long-term results of GOG 37 results confirm benefit and demonstrate
importance of a lymph node–positive ratio (Table 23.10). Number of
nodes dissected will influence indication for radiation of groin and pelvis
even if only one node is positive. Generally, > 5 nodes considered
adequate, but there is no consensus. If contralateral groin negative on
dissection in a well-lateralized lesion with a positive ipsilateral groin, the
standard approach is to radiate the opposite pelvis, but some feel this
can be omitted.

23.  Radical vulvectomy has been considered sufficient for treatment for
vulvar carcinoma, and postoperative radiation can be directed only to
the lymph nodes. However, results from a retrospective study suggested
that the application of a midline block to protect the radiosensitive vulva
resulted in a 48% central recurrence rate (versus the less than 10%
reported historically). Long-term results from GOG-37 do not show this,
however. The primary tumor bed should be radiated only if high-risk
features present. The additional benefit of concurrent chemotherapy
with postoperative radiation in patients with high-risk features for
relapse is unclear and is being studied in cooperative group studies.
 Decision making regarding which treatment modalities to be used
depends on location of primary in relation to midline
RADIATION THERAPY IN RESECTABLE VULVA CANCER

24. TRIALS FOR ADJUVANT LYMPH NODE IRRADIATION
 GOG 37
 This was a randomized trial with 114 patients with positive inguinal nodes after
radical vulvectomy and bilateral
 inguinal node dissection
 Patients were randomized to pelvic node dissection versus postoperative
radiotherapy
 Radiation (45–50 Gy prescribed to mid-plane, using AP/PA fields) was
delivered bilaterally to the pelvic and inguinal nodes while shielding the central
vulva area
 Interim analysis revealed a significant survival advantage for patients receiving
radiotherapy (2-year survival of 68 versus 54%) because of a lower rate of
groin relapse in the radiotherapy arm (5 versus 24%)
 Subset analysis suggested that this survival advantage was particularly noted if
clinically suspicious or if fixed, ulcerated groin nodes or 2 or more positive
groin nodes were present

25. TRIALS FOR ADJUVANT LYMPH NODE IRRADIATION
 GOG 37 (long term results)
 GOG 37 trial with a median follow-up of 74 months
 6-year overall survival for radiation arm, 51% compared with 41%;
hazard ratio of 0.61
 Cancer-related death rate significantly higher for pelvic node resection,
as compared with radiation (51% compared with 29%) at 6 years
 A ratio of more than 20% positive ipsilateral groin nodes (number
positive/number resected) significantly associated with contralateral
lymph node metastasis, relapse, and cancer-related death
 Benefits of radiation preserved in long-term follow-up

26. LOCALLY ADVANCED DISEASES (MOST T2–3, N2C-3)
 Primary surgery is either not possible or will result in tremendous
morbidity; hence, the use chemoradiation should be explored. Extended
radical vulvectomy and BGND or pelvic exenteration may be required for
tumors involving the rectum, vagina, or urethra.
 Preoperative radiation or combined chemoradiation therapy, or definitive
chemoradiation, should be considered for organ preservation, to be
succeeded by function-preserving limited surgery.

27. LOCALLY ADVANCED DISEASES (MOST T2–3, N2C-3)
 GOG 101
 Phase II GOG study of patients with stages III–IV (unresectable) squamous cell
vulvar carcinoma
 All patients enrolled judged capable of tolerating chemoradiation succeeded by
surgical resection and bilateral inguinofemoral LND (high performance status)
 Preoperative chemoradiation of 47.6 Gy (twice daily for the 1st week of 2-week
cycle with a split course with an elective 2-week break, and then next 2-week
cycle of chemoradiation); concurrent chemotherapy used cisplatin plus 5-FU
 48.5% of patients with clinical complete response (CR), no visible vulvar
cancer at the time of planned surgery, only 2.8% had residual unresectable
disease
 95% of N2c–N3 groin nodes rendered resectable; in only 3 patients was it not
possible to preserve urinary and/or gastrointestinal continence
 Next GOG trial to increase radiation dose and eliminate “elective break”

28. UNRESECTABLE OR INOPERABLE DISEASES
 Definitive chemoradiation therapy is indicated for unresectable or medically
inoperable vulvar cancers.
 Chemotherapy regimens similar to those used in anal canal cancer, infusional
5-FU plus cisplatin or mitomycin, have been described. High response rates
have been reported, and the majority of patients achieving complete response
have durable local control (Table 23.12; Figure 23.3 for an algorithm for
management of advanced vulva cancer).
 Most of the definitive chemoradiation studies in vulvar cancer are single
institutional and limited by small sample size. There is considerable toxicity
associated with chemoradiation, including severe skin desquamation and
hematologic toxicity, infection, lymphedema, etc. The preferred approach for
patients with inoperable primary tumors or lymph nodes is preoperative
chemoradiation, if a salvage operation can be performed. Chemoradiation is
offered as an alternative to radical surgery in an effort to avoid colostomy and
urostomy in stage IVA disease. If residual disease remains after
chemoradiation, then local resection is indicated. The most recent GOG 205
trial is exploring weekly cisplatin with doses of 57.6 Gy for locally advanced
vulvar cancer and results from this are awaited.

29. COMPARISON OF SURGERY AND PRIMARY CHEMORADIATION
(PCRT) IN ADVANCED SCC OF VULVA
 University of Oklahoma
 A retrospective study of 63 patients with stages III (n = 47) and IV (n = 16) SCC
of vulva
 30 patients received extended primary surgery (PS), and 33 unresectable
tumors by vulvectomy and underwent PCRT
 Patients treated with PCRT were younger (61 versus 72 years; p= 0.09), had
less nodal metastasis (54 versus 83%, p = 0.01), and larger tumors (6 versus
3.5 cm, p = 0.0001), as compared with patients who received PS
 Clinical CR rate was high at >85%, but the majority had undergone node
dissection prior to PCRT
 Despite these differences, OS rates at 31 months were 69 and
76%, respectively, for PS and PCRT groups (p = NS); no differences were seen
in PFS or recurrence rates either between the 2 groups
 Multivariate analysis showed age was the only significant predictor of OS or
PFS

31. RADIATION THERAPY TECHNIQUES
 Simulation
 Patients must be treated with equipment with photon energy of 6 MV for pelvic
irradiation. Computed tomography (CT)-based planning is essential to obtain
the depth of inguinal nodes. Delineation of the femoral lymph nodes is critical
for adequate coverage of the inguinal nodes
 Patients are simulated in supine, frog-leg positions (to minimize the bolus
effect from skin folds) with full bladders (to minimize the volume of small bowel
in the radiation field), with custom immobilizations
 Palpable lymph nodes, vulva tumor, scars, and anal verge should be outlined
with sticky wire for identification on planning CT. Markers to be used to indicate
extent of vaginal involvement if present
 Four-field three-dimensional (3D) conformal technique may spare rectum and
posterior skin as well as femurs, and avoids problems of matching fields

34. RADIATION THERAPY TECHNIQUES-FIELD ARRANGEMENTS
 A wide anterior-posterior (AP) field includes the pelvic and inguinal
regions, and a narrow posterior–anterior (PA) field covers only the pelvis
and spares the femoral heads. The dose to inguinal regions is
supplemented by separate anterior electron fields matched to the PA
field to bring the dose to the inguinal nodal region to 45 Gy (Figure
23.6).
 A wide AP field and narrow PA field with a partial transmission block are
placed in the central portion of the AP field. The desired dose at a
specific depth is delivered to the inguinal nodes through the AP field.

35. RADIATION THERAPY TECHNIQUES-FIELD ARRANGEMENTS
 Wide AP (Figure 23.6)
 Superior: mid–sacroiliac joint to include external and internal iliac node
involvement; L4–L5 to include the common iliac nodes if
internal/external iliac nodes suspicious or positive
 Inferior: flash entire vulva or inferior margin of the tumor (whichever is
lower)
 Lateral: 2 cm beyond the widest point of the pelvic inlet on the PA
field, and greater trochanter to include inguinal lymph nodes in the AP
field
 Narrow PA
 Superior: same as AP field
 Inferior: same as AP field
 Lateral: off femur and match supplemental electron fields

37. RADIATION THERAPY TECHNIQUES-FIELD ARRANGEMENTS
 Narrow PA
 Superior: same as AP field
 Inferior: same as AP field
 Lateral: off femur and match supplemental electron fields

38. RADIATION THERAPY TECHNIQUES-FIELD ARRANGEMENTS
 Supple electron
 Anterior electron fields to the lateral inguinal region
 Matched with the exit PA field
 Energy based on CT depth of femoral vessels
 Cone down Primary tumor and involved inguinal lymph nodes plus 2- to 3-cm
margin after 45 Gy to the pelvis Figure 23.6 Treatment borders demonstrating
the wide anterior field (outer border) and the narrow posterior field (shaded
region). The pelvis, vulva, perineum, and inguinal lymph nodes will be treated
with the AP–PA technique to include lateral inguinal nodes within AP fields but
not PA fields. The patient lies supine with a full bladder
 All fields should be irradiated on daily basis
 Bolus material should be used to ensure adequate dose to the superficial
portions of the groin or tumor

39. INTENSITY-MODULATED RADIATION THERAPY
 Intensity-modulated radiation therapy (IMRT) has been demonstrated to
offer an advantage over 3D-conformal radiation for vulvar cancer by
improving conformality and eliminating matching problems (Figure 23.7).
In addition,
 IMRT reduces the dose to normal structures, such as the
bladder, rectum, small bowel, and femoral heads, and eliminates
problems with matching between electrons and photons.
 Definitions of clinical target volume (CTV) and planning target volume
(PTV) in 3D-CRT and IMRT are as follows:
 CTV: 1-cm margin around the entire vulvar region and around the
bilateral external iliac, internal iliac, and inguinofemoral nodes
 PTV: CTV plus 1 cm

40. INTENSITY-MODULATED RADIATION THERAPY
 The Radiation Therapy Oncology Group (RTOG) has formulated a
(consensus) contouring atlas for IMRT for anal canal tumors, which
includes guidelines for groin nodes. Simultaneous integrated boost (SIB)
can also be delivered with IMRT. An example is shown in Figure
23.7, where clinically negative groin nodes received 45 Gy with
chemotherapy (with sparing of femurs) and vulvar CTV received 53 Gy.
However, long-term results for IMRT for vulva cancer are lacking.

42. RADIATION DOSE IN VULVA CANCER TREATMENT

43. NORMAL TISSUE TOLERANCE
 Organs at risk (OARs) in RT of vulva cancer, in both adjuvant and
definitive settings, include small bowel, bladder, femoral heads, and
vagina. Dose limitation is detailed in Chap. 22, Table 22.17.

44. FOLLOW-UP
 Life-long follow-up (Table 23.15) is required for all patients with vulvar
cancer treated with curative intent for early detection of tumor
recurrence and second primary gynecological malignancies. In addition
to recurrent vulvar cancer, there is a higher risk of cervical and anal
cancer.

45. FOLLOW-UP
 Life-long follow-up (Table 23.15) is required for all patients with vulvar
cancer treated with curative intent for early detection of tumor
recurrence and second primary gynecological malignancies. In addition
to recurrent vulvar cancer, there is a higher risk of cervical and anal
cancer.
 First follow-up 4–6 weeks after RT
 Years 0–2 Every 3–4 months
 Years 3–5 Every 6 months
 Years 5+ Annually

46. FOLLOW-UP
Examinations History and physical
 Complete history and physical examination
Imaging studies
 Chest X-ray (if clinically indicated)
 CT of the abdomen and pelvis (if clinically indicated)

47. ADVERSE EFFECTS AFTER TREATMENT
 Acute
 The most significant is the skin reaction in the vulva–perineal region and inguinal folds
 Moist desquamation by the 3rd–5th weeks of treatment is common; a treatment break is
usually necessary
 Diarrhea and cystitis are other common acute side effects
 Acute hematologic toxicity is common and depends on the type and intensity of the
chemotherapy used
 Late
 Common late toxicities include telangiectasia, atrophy of skin, fibrosis, dryness, and
shortening/narrowing of the vagina
 Avascular necrosis of the femoral head has been reported
 Femoral neck fracture is associated with osteoporosis and smoking
 Groin radiation can cause lymphocyst formation, lymphedema, and infection
 Other
 Significant psychosexual consequences relating to sexual function and body image may
occur

48. THANK YOU ALL