VULVAR CARCINOMA - staging and stagewise management Layers and Pouches of the Anterior Triangle of the Perineum

0.6 - 1% of all cancer of women .

•3 to 5% of all gynecologic malignancies.

•1-2/1,00,000 women

•Mostly in postmenopausal women, 6th , 7th decade of life and does increase with increasing age.

1. VULVAR CARCINOMA STAGING AND MANAGEMENT By Dr Neelam Baranwal

2. INTRODUCTION 0.6 - 1% of all cancer of women . 3 to 5% of all gynecologic malignancies . 1-2/1,00,000 women Mostly in postmenopausal women,  6th , 7th decade of life and does increase with increasing age . Incidence Death-

3. ANATOMY OF VULVA

4. Layers and Pouches of the Anterior Triangle of the Perineum Skin Subcutaneous perineal pouch (compartment, space) Fatty layer (Camper fascia) Membranous layer (Colles fascia) Superficial pouch (compartment, space) Superficial layer of investing fascia of perineal muscles (inferior boundary) Clitoris and its crura Bulb of the vestibule Greater vestibular (Bartholin) gland ischiocavernosus muscle Bulbospongiosus muscle Superficial transverse perineal muscle Deep perineal pouch (compartment, space) Perineal membrane (inferior boundary) External urethral sphincter (sphincter urethrae) Compressor urethrae Sphincter urethrovaginalis

5. Lymphatic drainage . Biopsy at the edge of lesion has been traditionally advocated; however, biopsy should target the most suspicious area

6. Lymph Vessels and Nodes of Perineum: Female

7. RISK FACTORS VIN Multiple sexual partners . Vulvar dystrophy (L. Sclrosus ). Immunodeficiency History of genital warts . Smoking. H/O Cervical or Vaginal cancer .

8. RISK FACTORS CONTI--- Granulomatous infections HPV HPV DNA has been reported in up to 1-69%. Hpv 16 is most common , account for 78 % of HPV associated SCC , Other- hpv 33, 18 and 52. Incidence of HPV -in 61.5 % of case of vulvar cancer if age is <45 yrs but - in only 10 % of cases if age is > 45 yrs Incidence is increasing in young women –age 20-35 yrs b/o hpv infection. Chronic immunosuppression - eg HIV positive , renal transplant patient Tobacco smoking

9. Vulvar dermatoses - Chronic vulvar inflammatory lesions vulvar dermatoses , including LS,LP,LCS , VIN (HSIL/VIN 2,3usual and differentiated type) 32% of nonhpv VC is associated with LP. LICHEN SCLEROSUS LS----->invasive cancer risk at 2 years-> 1-2 % at 10 years -> 5 % at 25 years -> 36.8 % topical steroid , periodic survelliance and selective biopsies decrease risk of VC

10. LICHEN PLANUS- Finnish study - n=9,030 10% develop VC in 43 years follow up. VIN 2-3- VIN (HSIL/VIN 2,3usual and differentiated type) Jones study n=405 3.8 % develop VC in 1-7 years ( mean 3.9 years) VIN 2-3 - 21 % have hidden invasive cancer. dVIN - 70.4 % have assiciated SCC. Basaloid and warty VC are associated with hpv and classic risk factor of cervical cancer. Field effect-13 % of VC had second genital squmous neoplasm . so these patients should be evaluated for coexistent lesion.

11. CLINICAL PRESENTATION Most patients present with a vulvar lump or mass Pruritus is a common complaint. Unifocal vulvar plaque. Ulcerative Lesion Mass (fleshy, nodular, leukoplakic or warty) . occasionally a palpable metastatic mass in the groin. Site- labia majora- most common labia minora Site Perineum. Clitoris. Multifocal in 5 percent of cases.

12. Metastasis Metastasize in 3 way -local extention to adjacent organ (eg, vagina, urethra, clitoris, anus). -lymphatic spread regional LN -haematogenous -rare in absence of 3-4 lymph node metastasis Lymphatic metastases may occur early in the disease Inguinal LN metastsis predicted by -tumor diameter - histological grade - depth of stromal invasion - lymphovascular space invasion metastasis to contralateral LN is rare in te absense of ipsilateral groin LN metastasis.

13. The superficial inguinal lymph nodes lie along the saphenous vein, deep to Camper's fascia and superficial to the fascia lata ( cribriform fascia) which overlies the femoral vessels. In a triangle -bounded by the inguinal ligament superiorly, sartorius muscle laterally, adductor longus muscle medially. There are appoximately 8-10 superficial lymph nodes. The deep inguinal lymph nodes - located medial to the femoral vein and under the cribriform fascia. There are approximately 3 to 5 deep nodes. The superior-most node is located under the inguinal ligament and is called Cloquet's node Rob et al. reported that 16% of sentinel nodes were in the femoral group

14. Lymphatic drainage of vulva labia majora and minora -> superficial inguinal LN 10-12 superficial inguinal LN lies along the saphenous vein and it’s tributries in T shape manner , 1 cm below ing ligament it is divided in 4 quadrant with opening of saphenous in centre clitoris can directly drain into ext iliac or pelvic node still it’s unusual to find pelvic node metastasis in absense of IF LN metastasis , even in cancer involving clitoris

15. Route of lymphatic spread Lymphatic metastases may occur early in the disease. Initially, spread is usually to the inguinal lymph nodes drainage from the vulva and anus ->The superficial Inguinal lymph nodes -> -> the deep inguinal (femoral) lymph nodes-> -> external iliac lymph nodes, then to the common iliac lymph nodes and to the paraaortic lymph nodes. Direct lymphatic pathways from the clitoris and Bartholin gland to the pelvic nodes can occur

16. PELVIC NODE METASTASES Metastases to pelvic nodes are uncommon, the overall reported frequency being approximately 9%. 20% of patients with positive groin nodes had positive pelvic nodes . ( Elective pelvic lymph node dissection is rarely performed today but early papers from the 1970s and 1980s indicated this) Pelvic nodal metastases more common with - three or more positive groin nodes tumor with invasion >4 mm

17. Stagewise LN metastases stage IA -> < 1% stage IB 8% stage II -> more than 8% Depth of invasion affect LM metastsis DOI upto 1 - <1% LN metastasis DOI 1.1-3 - 6 - 12 % LN metastasis DOI 3.1 -5 - 15-20 % LN metastasis

18. Lymph node metastasis is most important prognostic factor . It depends on mainly- depth of invasion size of tumor LVSI

19. HPV associated is frequently multifocal but HPV independent is usualy unifocal

20. DIAGNOSIS Biopsy is confirmatory. depth of invasion is central issue in management . . Biopsy at the edge of lesion has been traditionally advocated; however, biopsy should target the most suspicious area biopsy should include cutaneous lesion with underlying stroma. it should be punch or key biopsy under local anaesthesia Should not to excise an entire lesion in order to facilitate a subsequent sentinel node procedure Selecting the most appropriate site for biopsy in women with condyloma, chronic vulvar LS, multifocal high-grade squamous intraepithelial lesions (VIN 3), or Paget’s disease can be difficult, and multiple biopsies may be required. If multiple abnormal areas are present; then multiple biopsies should be taken.

21. Biopsy Indications A visible lesion that cannot definitively be diagnosed clinically A persistent lesion or ulcer that doesn’t heal Vulvar symptoms with suspected vulvar dermatosis A symptomatic growth Any lesion that is increasing in size, changing color, or becoming irregular in shape concern for melanoma. Apply ABCDE evaluation of the lesion ABCDE Warning Sign Asymmetry Irregular Border Variated Color Diameter greater than 6 mm Evolving (growing or changing)

22. DOI conti-- Measurement from the surface, rather than from the adjacent dermal papillae as may result in - Serious underestimation, and understaging - in ulcerated lesion overestimation and overstaging- in epithelial acanthosis, thickening, or hyperkeratosis, With large tumors, and some tumors with invasion deeper than 1 mm, thickness may be the only reliable measurement because of the lack of identifiable adjacent dermal papillae

23. DIAGNOSTIC EVALUATION Evaluation regarding Clinical extent of disease and Coexisting medical illnesses. Initial evaluation should include a detailed physical examination Measurements of the primary tumor, extension to adjacent mucosal or bony structures, record the distance from vital structures such as the clitoris, urethral meatus, and anus, since these structures limit the ability to obtain adequate surgical margin Clinical evaluation of the inguinal LNs. s. Field effect-13 % of VC had second genital squmous neoplasm . so these patients should be evaluated for coexistent lesion. Evaluation of the vagina and cervix (including cytologic smears) should be emphasized due to the multifocal nature of squamous cell intraepithelial neoplasia.

24. Diagnostic evaluation conti-- Suspicious lymph nodes should be biopsied complete blood count (CBC), and LFT ,RFT. (chest x-ray). If an abnormality is seen, then chest CT without contrast pelvic and perineum MRI to aid in surgical and/or radiation treatment planning CT, PET/CT, and MRI may be used to delineate the extent of tumor and/or for treatment planning. Examination-under-anesthesia (EUA) cystoscopy or proctoscopy should be considered as indicated. cervical HPV testing, and cytology testing. Consider HIV testing, especially in younger patient FDG-PET/CT may be considered in patients with positive sentinel nodes to evaluate for undissected nodal disease in the groin or pelvis that needs additional treatment

25. FIGO 2021 , Staging VC Staging involves complete surgical resection of the primary vulvar tumor(s) with at least 1-cm clinical gross margins and either a unilateral or bilateral inguinofemoral lymphadenectomy or an SLNB in select patients.

26. New (2021) FIGO staging for carcinoma of the vulva

27. HISTOLOGIC TYPES Squamous cell carcinomas (90%). Melanoma (2ed most common). Bartholin gland / Adenocarcinoma. Sarcoma. Basal cell carcinoma (rodent ulcer). Verrucous carcinoma. Paget's disease.

28. Pathology Commonly arise on- labia minora, clitoris, posterior fourchette, perineal body and medial aspects of the labia majora. Mostly arise in abnormal epithelial cell adjacent HSIL (VIN 3) - in 60-85 % A djacent lichen sclerosus, with dVIN, or HSIL (VIN 3) 15% to 40%

29. Tumor growth pattern influences the rate of LN metastasis and survival It is of 3 type confluent; compact (pushing pattern); and fingerlike (or spray or diffuse), a pattern also described as poorly differentiated .

30. Compact- well differentiated minimal stromal desmoplasia maintains continuity with the overlying epithelium well-defined and well-circumscribed tumor mass, thickness ≤5 mm rarely invade vascular space

31. Confluent growth - composed of interconnected tumor >1 mm in dimension Characteristic of deeply invasive SCC Associated with stromal desmoplasia

32. Fingerlike growth - (or spray or diffuse), islands of poorly differentiated tumor cells found within the dermis or submucosa deeper than the bulk of the tumor mass Typically associated with- desmoplastic stromal response lymphocytic inflammatory cell infiltrate higher frequency of inguinal lymph node metastasis

33. Grading of SCC GOG proposed the following grading system for vulvar SCC , based onproportion of poorly differentiated component Grade 1 tumors are composed of well differentiated tumor and contain no poorly differentiated element. Grade 2 - upto 1/3 poorly differentiated portions making . Grade 3 - >1/3rd but less than 1/2 of the tumor the poorly differentiated portion composing Grade 4 - 1/2 or more of the tumor composed of the poorly differentiated elements.

34. PROGNOSTIC FACTORS (a) historical and demographic risk factors; (b) characteristics of the primary tumor, including location, laterality, size (cm), DOI, lymph vascular space invasion and margin width; (c) Inguinal LNs status (d) probability of distant metastatic disease. Predictor of recurrance and mortality -nodal status is most important perticularly- number of positive nodes, size of the largest metastasis, and the presence or absence of extracapsular extension, are the most important Nodal involvement is the single most important determinant of recurrence , OS and disease-specific mortality.

35. LN Metastasis Lymph node metastases depends upon- DOI, tumor size, and lymph-vascular space invasion stromal invasion There is no imaging modality with a sufficiently high negative predictive value to allow for exclusion of surgical groin LN evaluation

36. Treatment Two major objectives of management are :- Tailored primary tumor resection with clear margin Removal of any potential sites of nodal metastasis. Depending on the size and extent of the primary tumor, simple partial/total vulvectomy or radical partial/total vulvectomy outcomes between these resection techniques -retrospective data suggest no difference in recurrence and/or survival

37. Treatment Historically, en bloc vulvectomy with wide margins was combined with complete inguinofemoral (IF) lymphadenectomy to treat vulvar cancer - Hallstedian concept Basset in France, was the first to suggest an en bloc dissection of the vulva, groin, and iliac lymph nodes, although he performed the operation only on cadavers. Taussig, in the United States, and Way in Great Britain, pioneered the radical en bloc dissection for vulvar cancer, and reported 5-year survival rates of 60–70%. For patients with disease involving the anus, rectum, or proximal urethra, pelvic exenteration was often combined with radical vulvectomy. this was associated with high morbidity like - wound complications, -20-40% lymphedema, 30-70% decreased sexual function, adverse impacts on body image

38. Conservative approach without compromising outcome Since approximately 1980, there has been a gradual paradigm shift in the approach to vulvar cancer (17,18). The most significant advances have included the following: 1. Individualization of treatment for all patients with invasive disease 2. Vulvar conservation for patients with unifocal tumors and an otherwise normal vulva. 3. Omission of the groin dissection for patients with T1 tumors and no more than 1 mm of stromal invasion (i.e., FIGO stage T1a) 4. Elimination of routine pelvic lymphadenectomy. 5. The use of separate groin incisions for the groin dissection to improve wound healing (29). 6. Omission of the contralateral groin dissection in patients with lateral T1 lesions and negative ipsilateral nodes .

39. 7. The use of preoperative radiation therapy or definitive radiation therapy to obviate the need for exenteration in selected patients with advanced disease. 8. The use of postoperative radiation to decrease the incidence of groin recurrence and improve survival of patients with multiple positive groin nodes. 9. Resection of bulky positive groin and pelvic nodes without complete node dissection to decrease the risk of lymphedema prior to pelvic and groin radiation . 10. The use of sentinel node biopsy to obviate the need for complete groin dissection in carefully selected patients with early vulvar cancer 11. The use of definitive regional radiation therapy in selected patients with extensive regional disease (36,37) University of Miami (38) and the Mayo Clinic (39). Both centers reported a trend toward a more conservative approach, and both reported decreased postoperative morbidity, without compromised survival

40. Separate groin incisions Separate groin incisions Understanding that the mode of metastatic spread is embolic rather than continious . Less morbidity. No compromise of survival.

41. Local treatment-primary tumor tesection

42. Historical Background 1912,- Basset emphasized that a wide excision of the entire and complete IFLND was the minimum treatment procedure for vulvar carcinoma. 1940-Way and Taussig first to raise the idea of an individualized pelvic lymphadenectomy according to the metastatic status of IFLN. In the 1980s, DiSaia et al11 and Hacker et the concept of minimal resection margins,which was validated by a prospective studyconducted by the Gynecologic OncologyGroup. . Stehman FB, Bundy BN, Dvoretsky PM, et al. Early stage I car_x0002_cinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol. 1992;79:490–497.

43. Type of vulvectomy -based on depth

44. Radical vulvectomy

45. RADICAL VULVECTOMY/MODIFIED RADICAL VULVECTOMY Mark 2-cm margins from visible lesion circumferentially ( Dennis Chi and TE LINDE’S) Adjust marking to account for sensitive structures such as urethra and clitoris if resection is not planned. Mark reconstruction sites if applicable Perform skin incision with scalpel A circumferential inner incision encircling the urethra and vaginal introitus is performed. Continue incision sharply or with cautery to the level of the urogenital diaphragm. If pudendal vessels are encountered these can be ligated and divided. The incision deepens down to the subcutaneous fatty tissue and afterwards down to the inferior fascia of urogenital diaphragm which is termed as perineal membrane,

46. The outer incision on the labia majora and skin is combined with the inner incision, which is around the vaginal introitus, and the vulvar specimen is excised totally contents of the superficial perineal space ( ischiocavernosus, bulbospongiosus and superficial transverse perineal muscle ) are excised with the vulvar specimen. The arterial supply from the internal pudendal artery come from the 5 and 7 o’clock directions and they should be ligated or sutured. Divide base of vulva with cautery and release specimen. Orient specimen for pathologic analysis (place suture at 12 o'clock) Achieve hemostasis and then close deep layers with 2-0 Vicryl. Close skin with interrupted 4-0 undyed vicryl suture, or if small defect can consider subcuticular closur

47. Local treatment-primary tumor tesection conti-- Extending primary excision in a superficial fashion to include adjacent differentiated vulvar intraepithelial neoplasia is highly recommended Every attempt should be made to preserve structures such as the clitoris and urethral meatus Deep margins are rarely a problem except on the perineum, where thereis little or no subcutaneous fat. In this case, removal of the capsule of the anus or some of the sphincter muscle itself can be performed without loss of anal function. Surgical resection of 1 to 1.5 cm of the distal urethra to achieve a negative surgical margin does not appear to compromise bladdercontinence It is acceptable and often desirable to limit radicality in order to preserve structure and function When invasive disease extends to the excision margins of the primary tumor, re-excision Minimum 1 cm tumor free margin

48. Tumor free margin Both surgical approaches involve resection of approximately - 1- to 2-cm radial margin of grossly normal tissue and to the deep fascia or a minimum of a 1-cm deep margin. 8 mm pathologic free margin an incision 2 cm laterally, from the tumor will be optimal for clear margins. The resection margin will decrease to 1 cm around the urethra and anus to protect the functions of these structures. 4-year recurrence-free rates of 82%, with negative 63%, with close 37% with positive margins, Highest risk of recurrence was associated with margins less than or equal to 5 mm

49. Close or positive margin 2 options ar e - re-resection to obtain negative margins or adjuvant external beam RT (EBRT) to the primary site EBRT is preffered i/c/o close or positive margins involving the urethra, anus, or vagina, patients with close or positive margins who have inguinal node involvement requiring adjuvant treatment with EBRT ±concurrent chemotherapy.

50. Groin treatment Groin treatment should be performed for tumors >T1a -SLNB-For unifocal tumors <4 cm without suspicious inguinofemoral lymph nodes on clinical examination and imaging For tumors ≥4 cm and/or in case of multifocal invasive disease, inguinofemoral lymphadenectomy by separate incisions is mandatory. Contralateral inguinofemoral lymphadenectomy may be performed when ipsilateral lymphadenectomy has demonstrated metastatic disease When lymphadenectomy is indicated, superficial and deep femoral nodes should be removed Preservation of the saphenous vein is recommended

51. Lymph Node Evaluation stage IA -LN evaluation can be omitted . stage IB/II - SLNB Ipsilateral IFLN evaluation (IF lymphadenectomy or SLN biopsy) less than 4 cm in diameter, located at least 2 cm from the vulvar midline, In others , bilateral LN evaluation If negative unilateral IFLN have <3% risk of contralateral metastases IF lymph node (IFLN) evaluation must be adequate at initial presentation ,because- groin relapses are dificult to treat .

52. SLNB Morbidity with IFLND are high. Wound complication - 20-40 % Lymphodema- 3- -70 % Sentinal lymph node- The SLN is defined as the first draining LN of a tumor, The modern SLN concept was first described by Morton and colleagues in cutaneous melanoma; shortly thereafter, it was described in vulvar cancer SLN of the vulva is always in the inguinal LN basin and can be identified in most patients . Levenback C, Burke TW, Morris M, et al. Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol. 1995;59(2):216–220. 93. Decesare SL, Fiorica JV, Roberts WS, et al. A pilot study utilizing intraoperative lymphoscintigraphy for identification of the sentinel lymph nodes in vulvar cancer. Gynecol Oncol. 1997;66(3):425–428.

53. Recommendations for SLNB In stage IB /selected stage II clinically/radiologically negative groin nodes, unifocal primary tumor < 4 cm, no history of previous vulvar surgery Mapping by using dual tracers (ie, radiocolloid and dye)

54. The safety and accuracy of SLNB-Assessed in 2 study-

55. GOG 173-- no=, 452 females with vulva-confined primary tumors 2–6 cm, at least 1-mm invasion, and clinically node negative Underwent SLN mapping and biopsy followed by IF lymphadenectomy. SLNs were identified in 418 females, 132 females were node positive (including 11 false-negative nodes). SLN biopsy had a sensitivity of 91.7%, NPV of 96.3%, FNPV was 3.7% The FNPV false-negative predictive value is a prediction of the chance of a positive non-SLN when the SLN is free of tumor and a lymphadenectomy has not been performed. In GOG 173, the FNPV by groin was 2.7%; for patients with tumors <4 cm, it was 2%. This means that a patient with a tumor <4 cm, no palpable LNs, and a negative SLNB has a 2% chance of a groin relapse

56. GROINSS-V I-- multicenter observational study no = 403 females with tumor size < 4 cm. If SLN were negative on ultrastaging - omit IF lymphadenectomy median follow-up period of 35 months (24-month minimum), groin recurrences were (2.3%) with a unifocal primary tumor and negative SLN. Long-term results in 377 patients with unifocal disease 5 and 10-year local vulvar recurrence rate - 24.6% and 36.4% -for sentinel node-negative and 33.2% and 46.4% sentinel node-positive patients, (p = 0.03) The isolated groin recurrence rate was at 5 year 2.5% for SLN-negative patients and 8.0% for SLN_x0002_positive patients The resultsof these studies indicate that, for appropriately selected women the risk of groin relapse following a negative SLNB is 2% to 3%

57. • Selective frozen section of sentinel node may guide the intraoperative decision regarding need for completion unilateral or bilateral inguinofemoral lymphadenectomy For lateralized and near midline tumors with unilateral SLN metastasis, unilateral groin treatment by either inguinofemoral lymphadenectomy or RT is acceptable. If IFLN macrometastases( >2 mm in diameter) - Complete IF lymphadenectomy is SOC If IFLN micrometastases( =/<2 mm in diameter) - can be treated with RT For midline tumors with unilateral SLN metastasis, unilateral groin treatment can be performed if the contralateral groin has negative sentinel node or negative inguinofemoral lymphadenectomy. Inadequate nodal dissection - defined as node positivity ≥20% of dissected nodes

58. procedure of SLNB Tc-99m sulfur colloid is commonly used . injected 2–4 hours prior to procedure. The blue dye most commonly used is Isosulfan Blue 1%. Approximately 4 cc of dye is injected intradermally peritumorally using a four-point injection technique at 2, 5, 7, and 10 o’clock. SLN procedure is performed prior to the excision of the vulvar tumor , Additionally, the injected blue dye will only transiently localize (ie, for 30–60 minutes) in the first group of nodes that correspond to the primary vulvar tumors. • Use of a gamma probe before groin incision . Indocyanine green (ICG) with technetium has also been used for SLN mapping in vulvar cancer with encouraging results. A preoperative lymphoscintigraphy may be performed to aid in anatomically locating the sentinel node.

59. If the ipsilateral SLN is positive, completion lymphadenectomy or treatment of the affected groin is warranted. The contralateral groin should be evaluated surgically and/or treated with EBRT. In select cases of a single, small-volume, unilateral, positive inguinal node with a well-lateralized small primary tumor and depth of invasion less than or equal to 5 mm and with a clinically negative contralateral groin examination, a contralateral groin lymphadenectomy or radiation may be omitted.

60. Management of Sentinel Lymph Node(s) Mapping

61. INGUINOFEMORAL LYMPHADENECTOMY Make incision 2 cm below inguinal ligament Perform skin incision and incise Camper fascia. Create superior and inferior skin flaps Identify the borders of the femoral triangle (adductor longus tendon, insertion of sartorius muscle, inguinal ligament) Dissect the superficial lymph node bundle Identify the fossa ovalis and incise the fascia lata vertically Dissect the deep lymph node bundle and Cloquet node from medial aspect of femoral vein. Achieve hemostasis Place suction drains brought out through separate incision. Achieve layered subcutaneous closure and skin closure

62. Early-Stage Disease- individualized tumor excision with IFLN evaluation. Stage 1 with DOI =/< 1 mm -> simple partial vulvectomy; IFLN evaluation is not required due to the low risk of LN metastasis ( <1%) stage IB (>1-mm invasion) or select stage II- radical partial vulvectomy + IFLN evaluation primary treatment is dictated by tumor location. lateralized lesions located =/> 2 cm from the midline radical partial vulvectomy + ipsilateral IFLN evaluation Central vulvar lesions radical partialvulvectomy + bilateral IF node evaluation IF lymphadenectomy is required on side(s) for which sentinel nodes are not detected Adjuvant therapy is informed by primary tumor risk factors and nodal surgical pathology

63. Adjuvant RT and Chemoradiation - Local recurrance -40-50 % , Groin and pelvic recurrances are usually fatal Indication Adj groin ChemoRadiation more than one metastatic IF lymph node and extracapsular spread single IFLN with greater than 2-mm metastasis. Parthasarathy A, Cheung MK, Osann K, et al. The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma. Gynecol Oncol. 2006;103(3):1095–1099. Mahner S, Jueckstock J, Hilpert F, et al. Adjuvant therapy in lymph node-positive vulvar cancer: the AGO-CaRE-1 study. J Natl Cancer Inst. 2015;107(3). Xanthopoulos E, Mitra N, Grover S, et al. Adjuvant radiation therapy in node_x0002_positive vulvar cancer. Int J Radiat Oncol Biol Phys. 2013;87(2):S128–S129

64. SINGLE IFLN METASTASIS NCCN and Dennice Chi- need adjuvant RT after comprehensive IFLND In ESGO - No need of adj RT

65. Dose of RT Elective radiation- 45–50.4 Gy in 1.8GY nodal macrometastases is present, or extracapsular extention, without residual disease - to 54–56 Gy EQD2 If macrometastases are found which have not been removed-64–66 Gy In case of positive resection margin of the primary vulvar cancer, a boost to 60–66 Gy Concurrent radiosensitizing chemotherapy should be considered Radiotherapy should be performed with intensity-modulated radiotherapy techniques [

66. GROINSS-V II The GROINSS-V II/GOG 270 observational study (NCT01500512) complete IF LYMPHADENECTOMY VS ADJUVANT RT IN SLNB + Among 322 patients with metastatic SLN, 160 had micrometastases (≤2 mm) and 162 patients had macrometastases (>2 mm) Radiotherapy was given to a total dose of 50 Gy in 25–28 fractions of 1.8–2 Gy, 5 fractions/week. RT started within 6 weeks patients with SLN micrometastases, received IF radiotherapy, ipsilateral isolated groin recurrence rate at 2 years of 1.6%. patients with SLN macrometastases, case with one or more additional lymph node metastasis and/or extracapsular tumor spread IF lymphadenectomy followed by RT; vs RT High groin recurrence rate at 2 years was in RT group(22% vs 6.9% in IFL (P =.011). Based on these findings, the trial protocol was modified to mandate completion IF dissection and then possible adjuvant RT for patients with macrometastases defined as >2 mm

67. EBRT Vs pelvic LND GOG 37, n=114 patients with IF node-positive vulvar cancer after radical vulvectomy and bilateral IFLN Long-term follow-up (median = 74 months) revealed higher rates of disease-related death for the group receiving pelvic node resection compared with pelvic/groin RT (51% vs. 29%) AGO-CaRE-1 retrospective study--RT were most clear for patients with greater than or equal to 2 positive LNs.

68. GROINSS-V III The ongoing GROINSS-V III/NRG-GY024 phase 2 study is investigating the feasibility and safety of replacing IF lymphadenectomy with chemoradiation in patients with early-stage vulvar cancer with a macrometastasis and/or extracapsular extension in the sentinel node.

69. Role of adjuvant RT to the primary tumor site Indication of Adj RT close tumor margins LVSI, large tumor size, >4 CM >5 mmdepth of invasion, and pattern of invasion (spray or diffuse). Those with positive margins should undergo re-excision, or if unresectable without removing proximal urethra/bladder/anus, adjuvant EBRT RT dose - 50 gy in 25-28 # lower risk of recurrence with =/> 56 Gy. Viswanathan AN, Pinto AP, Schultz D, et al. Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma. Gynecol Oncol 2013;130:545-549

70. Recommendation OTT-optimal treatment time from surgery to end of adjuvant rt- adj RT should be started <8 weeks adj RT should not exceed 8 weeks surgery to completion of adj RT <105 days

71. Locally advanced VC Tumor may be fixed to vital organs or vessels, rendering the disease unresectable without significant morbidity Multimodality treatment was explored to improve organ preservation and reduce surgical treatment morbidity. The panel recommends that all patients with locally advanced disease receive EBRT with concurrent chemotherapy EBRT coverage should include the primary tumor, groin, and pelvic nodes.

72. Preoperative radiotherapy -NART GOG 101 and GOG 205 were two landmark clinical trials evaluating pre-operative chemoradiotherapy .

73. Conclusion: Preoperative chemoradiotherapy in advanced squamous cell carcinoma of the vulva is feasible, and may reduce the need for more radical surgery including primary pelvic exenteration. In the GOG 101 study, preoperative chemoradiation was examined in 73 patients with stage III/IV disease to avoid pelvic exenteration Only 3% of patients (2/71) had residual unresectable disease , preservation of urinary and/or gastrointestinal (GI) continence was possible in 96% of patients (68/71).

74. surgery after chemoradiation GOG 101 n= 46 vulvar SCC and N2/N3 Subsequent surgery was performed on 38 patients Local control of nodal disease was achieved in 36 of 37 patients Local control of primary tumor in 29 of 38 patients.

75. The GOG 205 study - T3/T4 tumors that were initially unresectable by radical vulvectomy examined the feasibility of surgery after chemoradiation Definitive radical vulvectomy was performed about 6–8 weeks following completion of pre-operative chemoradiotherapy. Complete clinical response was noted in 64% .of it 78 % had pathologic complete response 50% had a pathologic complete response.

76. surgery after NART An analysis of NCDB data (2004–2012) compared outcomes of 2046 females with locally advanced vulvar cancer who received primary radiation (RT or chemoradiation), or preoperative radiation (RT or chemoradiation) followed by surgery. there was longer OS in RT followed by surgery (57.1% vs. 41.7% at 3 years, respectively; P < .001). However, multivariate analysis revealed survival was not significantly worse if the dose exceeded 55 Gy Natesan D, Hong JC, Foote J, et al. Primary Versus Preoperative Radiation for Locally Advanced Vulvar Cancer. Int J Gynecol Cancer 2017;27:794-804. Available at: Chemo drug for radiosenstization Cisplatin is commonly used for radisenstization other drug- cisplatin/fluorouracil carboplatin capecitabine/mitomycin, gemcitabine, and paclitaxel

77. Management of bulky nodes Either: 1) primary cytoreductive surgery of the bulky LNs followed by platinum-based chemotherapy and radiation to the bilateral groins and primary vulvar tumor; OR 2) platinum-based chemotherapy and radiation to the bilateral groins and primary vulvar tumor alone. Two factors impact management of regional disease: radiation can have a significant impact on sterilizing or eradicating small-volume nodaldisease; surgical resection of bulky nodal disease improves regional control, and probably enhances the curative potential of RT. In multivariate analysis, Hyde et al. found that, for patients with clinically positive groin nodes who underwent surgery followed by RT, the method of surgical groin node dissection (nodal “debulking” vs. full groin dissection) had no prognostic significance

78. POST NART After NA EBRT with concurrent chemotherapy- No clinical evidence of residual tumor - should undergo surveillance. Biopsy of the tumor bed can also be considered to confirm pCR. Residual tumor -should be considered for resection In the case of positive margins on resection, consider additional surgery, additional EBRT, and/or systemic therapy, or best supportive care. For unresectable residual disease, providers should consider additional EBRT and/or systemic therapy, or best supportive care.

79. Primary chemoradiotherapy Primary chemoradiotherapy is the treatment of choice in patients with unresectable disease. The recommended dose to the primary tumor is 64–70 Gy EQD2 in 1.8–2 Gy per fraction The optimal dose to involved inguinofemoral lymph nodes is controversial, but should be 60–66 Gy EQD2 to macroscopic disease while the elective nodal dose is 46–50.4 Gy in fractions of 1.8–2 Gy. Assessment of response should be performed at 12 weeks following completion of treatment. In case of residual disease surgery should be considered . The 5-year overall survival was significantly higher in the chemoradiotherapy group compared with radiotherapy, Rao YJ, Chin R-I, Hui C, et al.. Improved survival with definitive chemoradiation compared to definitive radiation alone in squamous cell carcinoma of the vulva: a review of the National Cancer Database. Gynecol Oncol 2017;146:572–9. 10.1016/j.ygyno.2017.06.022

80. RECONSTRUCTIVE PROCEDURE Most vulvar defects can be closed primarily by adequate tissue mobilisation. Primary closure may not be feasible. When large portions of the vulva have been resected, when tissue mobility is poor, or when RT has been administered previously, In these cases reconstruction is by fasciocutaneous flaps and myocutaneous flaps. Local advancement flaps can be used for smaller defects, For larger defects -pedicled flaps harvested from the inner thigh, gluteal fold, and the abdomen are used.

81. Fasciocutaneous Advancement Flaps These flaps include skin, underlying subcutaneous tissue, underlying fascia. Type of F-C flap V-Yadvancement flap, with or without incorporation of the gracilis muscle rhomboidp pedicle flap lotus pedicle flap

82. Myocutaneous Flaps . Include a segment of muscle also. These are usually large, thick tissue sources that are best suited for the reconstruction of substantial defects. Several types of myocutaneous flaps- gracilis, gluteus maximus, tensor fascia lata, vastus lateralis, and vertical rectus abdominus flaps, Disadvantage of myocutaneous flap- increased intraoperative complexity, requirement for meticulous wound care postoperatively, and requirement for larger incisions. sacrifice of functional muscles.

83. Complications of radical vulvectomy & groin dissection Wound breakage. Lymphocyst. Lymphangitis. Chronic swelling of the leg (lymphedema). Sexual dysfunction & Psychological concerns. Infection. Thrombo-embolic disease. Bleeding. Anesthesia conplications. skin flaps necrosis.

84. Metastatic disease beyond pelvis

85. Metastatic disease- Systemic treatment Systemic treatment for metastatic or recurrent unresectable disease-Platinum-based combination chemotherapy cisplatin (80 mg/m2, q21d) + vinorelbine (25 mg/m2 Single-agent therapy with paclitaxel (175 mg/m2 q21d) Receptor Targeted Therapies The cohort of vulvar cancer patients of the KEYNOTE-158- addition of pembrolizumab in cases with PD-L1 expression with CPS≥1 and/or bevacizumab to platinum-based chemotherapy may be considered for selected patients in first line, although these drugs do not have specific approval for vulvar cancer The CHECKMATE-358 trial assessed the efficacy of nivolumab in patients with virus-associated tumors VGFRi-Bevacizumab - Targeting angiogenesis is an attractive therapeutic strategy in HPV-related tumors EGFRi -Olawaiye et al. (190,191) reported two dramatic PRs to single-agent erlotinib ( EGFRi) in women with advanced, treatment-refractory disease; GOG trial using erlotinib in 41 patients with advanced or recurrent vulvar cancer described PRs in 28% and SD in 40% of patients. Unfortunately, responses were not durable,

86. Metastasis Beyond the Pelvis stage IVB vulvar cancer should be considered palliative. EBRT for control of locoregional disease and symptom palliation, and/or systemic therapy Best supportive care is also an alternative

87. Omitted routine pelvic lymphadenectomy, No patients with negative groin nodes had positive pelvic nodes. Positive bilateral groin nodes five year survival <20 % patient’s who have positive inguinal nodes, end up getting radiation therapy to the whole pelvis anywhay that include pelvic node .

88. Surveillance Most recurrences of vulvar cancer occur within the first 1 to 2 years, every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, then annually cervical/vaginal cytology test can be misleading in patients who have received pelvic radiation as radiotherapy Imaging are recommended as indicated by suspicious examination findings or symptoms of recurrence. Patient education regarding symptoms suggestive of recurrence or vulvar dystrophy is recommended, as well as periodic self-examination

89. 5 years survival STAGE I / II -> 85.6 % STAGE III / IVA -> 47.5% STAGE IVB -> 23.3 % Patients with negative lymph nodes had a very good prognosis, regardless of the size of their primary tumors. Authors from the Royal Hospital for Women in Sydney reported a 96.4% 5-year survival for 121 patients with stages I or II disease 90% - with negative groin nodes, and that’s for stage I and stage II. 57% with positive groin nodes 20% - positive pelvic lymph nodes .

90. Take home massage Retrospective study oF Gynecologic Oncology Group (GOG) trials by Homesley HD, Bundy BN, Sedlis A, et al in n=586 patient through 1984, shows that independent predictors of survival included - presence and number of involved LNs and primary tumor size. LN metastasis is considered the most important prognostic factor and determinant of treatment in vulvar cancer, extracapsular extension has been linked to poorer prognosis. Factors that may be predictive of recurrence and/or survival include- depth of invasion, pathologic margin distance, tumor thickness, presence of lymphovascular space invasion (LVSI).

91. WHAT IS NEW An ontogenetic approach -Innovative gynaecologic cancer surgery approaches -proliferating groups of cells in each compartment is called anlagen or primordia -the theory of cancer as inverse morphogenesis tell ,that malignant tumours propagate within ontogenetic cancer fields

92. Superficial urogenital sinus-genital folds complex Ontogenetic anatomy emerges as an alternative to classic anatomy, focusing on embryologically defined compartments and subcompartments rather than organs and structures. The ontogenetic theory -> cancer is initially confined to the ontogenetic compartment of origin and only after phenotypic changes is able to spread to adjacent compartments. all vulvar structures originates Superficial urogenital sinus except the labia majora . Superficial urogenital sinus derivative subdivided into three subcompartments, from central to peripheral It has, therefore, had a considerable impact on oncologic surgery. The most dramatic example is colorectal cancer,

93. : Ontogenetic stages of vulvar carcin (A) oT1 (peripheral subcompartment), (B) oT1 (intermediate subcompartment), (C) oT1 (central subcompartment), (D) oT2 (vulvar compartment), (E) oT3a (derivatives of the external genital field), (F) oT3b(derivatives of the urogenital plate field), (G) oT4 (derivatives of the cloacal membrane field). Only superficial perineal structures are shown. From stage oT3a onwards, the cancer fields also comprise deep structures

94. MELANOMA Vulvar melanoma is the second most common vulvar malignancy, but represents less than 1% of all melanomas. The 5-year survival rates reported in the literature range from 35% to 50%. Prognostic factors lymph node status as the most powerful prognostic indicator for vulvar melanoma, ulceration tumor thickness of the primary lesion th

95. Melanoma AJCC staging system for cutaneous melanoma, Breslow thickness, and Clark level Breslow’s thickness was associated with recurrence (p =0.002) but not survival; however, the AJCC-2002 staging system was predictive of overall survival primary tumor thickness (using Breslow’s method) and nodalstatus are the primary determinants of survival in this disease However, are the presence or absence of ulceration and mitotic rate; are also important

96. Melanoma WLE and Radical local excision carries a similar rec. rates. Melanomas <1 mm thick should be treated with 1 cm skin margins; margins should be 2 cm for melanomas 1 to 4 mm thick. The depth should be at least 1 cm . If clinically evident nodal disease <<LND. LND is prognostic only (got no curative role).

97. The Gynecologic Cancer InterGroup recomendation Following recommendations: a simple vulvectomy with 1-cm visual margin for Breslow level of ≤2 mm, simple vulvectomy with a 2-cm visual margin for Breslow level of greater than 2 mm, SLN evaluation for clinically node-negative patients, and lymphadenectomy for clinically nodepositive patients. Performance of lymphadenectomy for cases of positive SLN continues to be a topic of debate

98. Basal cell carcinom locally invasive but rarely spread via lymphatics. a Radical local excision with a wide base. Rarely metastasize. Inguinofemoral lymphadenectomy is not required.

99. Bartholin gland carcinoma Bartholin’s gland abscess in PM women should be biopsied. Radical local excision. Inguinofemoral lymphadenectomy (unilateral) is indicated. 30 Adenocarcinoma. Radical local excision. LND (unilateral vs BL) is indicated.

100. Verrucous carcinoma locally destructive and rarely metastasizes to lymph nodes. HPV 6, 11 Modified radical vulvectomy without inguinofemoral lymphadenectomy is the most appropriate therapy, Suspicious lymph nodes should be biopsied; if positive<< LND RT is contraindicated because it can induce Anaplastic Transformation and increase the likelihood of metastases. Recurrences are treated surgically.

101. Based on verified HRAS and PIK3CA mutations, VAAD is thought to be a precursor lesion of verrucous carcinoma

102. Excision, or at the least, biopsy should be performed for women greater than 40 years of age, anyone with a suspicious mass, or after previous benign biopsy of a Bartholin gland mass that does not respond to therapy as anticipated managed similarly to squamous cell carcinomas Radical local excision is the main procedure; however, these cancers tend to invade deeper structures and may require more extensive resections that can include portions of the vagina, perineal body, anal sphincter complex, anus, distal rectum, or levator muscles. This requires an interdisciplinary team approach for preoperative or postoperative treatment. Approximately 40% of these cancers will have metastatic lymph nodes, so bilateral inguinofemoral lymphadenectomy should be performed.

103. Sarcoma WLE with out LND. Lymphatic metastases are uncommon. Rhabdomyosarcomas:( children ) treated with primary chemotherapy followed by surgery as needed.

104. Paget's disease WLE with out LND. Adenocarcinoma should be rulled out (5-15%). Check for extra-vulvar pagets (20-30%) Breast Rectum Bladder Urethra Cervix Ovary

105. pagets disease The WHO classification explicitly mentions the possibility of immunohistochemical HER2 detection for Morbus Paget . A meta-analysis of 713 patients demonstrated that HER2 expression was present in 30% of cases, and steroid hormone receptor positivity for ER, PR and AR was present in 13%, 8% and 40% respectively 21 . These may serve as a basis for possible therapeutic targets.

106. Histological type of SCC of vulva The usual types include SCC, keratinizing type SCC, nonkeratinizing type basaloid carcinoma warty (condylomatous) carcinoma . Less common types include acantholytic SCC, SCC with tumor giant cells and spindle cell squamous carcinoma, SCC with sarcoma-like stroma, sebaceous carcinoma, verrucous carcinoma, Adenoid squamous carcinoma (pseudoangiosarcomatous carcinoma, acantholytic SCC, pseudoglandular SCC) refers to SCCs with pseudoglandular features. higly aggressive poorly differentiated does not contain sialomucin,( but adenosquamous carcinoma typically does contain mucin within the adenocarcinoma component). SCC with tumor giant cells has multinucleated tumor giant cells , resemble amelanotic melanoma ( IHC differ)