Staging,Pathogenesis,Diagnosis Sentinel Lymph node biopsy of Vulvar Cancer Dr. Bhavin P.Vadodariya, Resident Doctor in Surgical Oncology, Apollo CBCC Cancer Care, Ahmedabad Date-24/02/18

Incidence  Constitutes  5% of all the malignancies of female genital tract  0.6% of female cancer  Estimated new cases and deaths from vulval cancer in the United States in 2015  New cases: 5150  Deaths: 1080  Rare malignancy (28 th ) in the United States and accounts for 0.3% of all new cancers. Cancer Facts and Figures Atlanta American Cancer Society, 2015.

SEER Stat Fact Sheets: Vulvalcancer  Lifetime Risk of Developing Cancer : Approximately 0.3 percent  0.2% of all cancer deaths (Estimated).  5-years survival rate of 71.2% Based on data

TRENDS IN RATES  Using statistical models for analysis, rates for new vulvar cancer cases have been rising on average 0.5% each year over the last 10 years. Death rates have not changed significantly over SEER 9 Incidence & U.S. Mortality , All Races, Females. Rates are Age-Adjusted.

Age  A disease of older women.  Delayed diagnosis is typical, despite vulva being an external organ.  Vulvar cancer is most frequently diagnosed among women aged  Median Age at Diagnosis is 68 years. SEER Stat Fact Sheets: Vulval cancer, 2014

Etiology - HPV  Approximately, 40% vulvar cancers are HPV (Human Papilloma Virus) Positive.  Of these HPV positive invasive vulvar cancers – 85% are attributed to HPV 16.  Prophylactic HPV vaccines have the potential to decrease the incidence of invasive vulvar cancer by about one-third overall, and to be even more effective in younger women. Smith JS et al. Human Papillomavirus Type-Distribution in Vulvar and Vaginal Cancers and Their Associated Precursors Obstet Gynecol. 2009; 113:917-24

Etiology – Vulval Intraepithelial Neoplasia (VIN)  The International Society for the Study ofVulvovaginal Disease (ISSVD) in 2004 officially divided VIN into two types:  VIN Usual Type – HPV infection related (warty/ basaloid /mixed)  VIN Differentiated Type - unrelated to HPV infection  The older classification of VIN 1, 2, and 3 was based on the degree of histologic abnormality, but there is no evidence that  the VIN 1 to 3 morphologic spectrum reflects a biologic continuum,  or that VIN 1 is a cancer precursor

Etiology – Vulval Intraepithelial Neoplasia (VIN)  There has been a significant increase in the incidence of vulvar intraepithelial Neoplasia (VIN) in recent decades, and this has been attributed to  changing sexual behavior,  human papillomavirus (HPV) infection, and  cigarette smoking.

 In a study designed to investigate the malignant potential of the vulvar premalignant conditions, Eva et al. identified 580 women from Birmingham, England, who had vulvar biopsies showing VIN, lichen sclerosus, or Squamous hyperplasia over a 5-year period. These women were studied for the presence of a synchronous or metachronous vulvar cancer.  differentiated VIN had a higher risk of malignancy (85.7%) than  usual VIN (25.8%),  lichen sclerosus (27.7%) or  Squamous hyperplasia (31.7%). Eva et al. Differentiated type VIN has a high-risk association with vulval squamous cell carcinoma Int J Gynecol Cancer 2009;19:

Etiology  The increased risk of a subsequent cancer to be 1.3-fold.  Most of the second cancers were related to  smoking (i.e., cancers of the lung, buccal cavity, pharynx, nasal cavity, or larynx) or  human papillomavirus infections (e.g., cervix, vagina, or anus).

Basloid or warty type  multifocal  In younger  Related to HPV infection  Vulvar Intraepithelial Neoplasia  Cigarette smoking Keratinizing type  Unifocal  In older  Not related to HPV  In area adjacent to lichen sclerosis and Squamous hyperplasia(80%)  VIN uncommon - Differentiated type Types

Pathology  Squamous cell carcinoma = 85–90%  Basal cell, Invasive paget’s disease, bartholin glands Ca, Sarcoma

SURVIVAL  Historically, (in early 20 th century) – presentation with advanced diseases.  5-years survival – 20-25% ONLY  Radical en-bloc dissection by Taussig - US (1940) and Way - Britain (1960) – Improved survival of 60-70%. (High post- operative morbidities –  wound breakdown, infection, and  prolonged hospitalization,  pelvic exenteration- for patients with disease involving the anus, rectum, or proximal urethra)

Survival  Overall 5 years survival rate in USA is 71.2% Based on data from SEER  The earlier vulvar cancer is diagnosed, the better chance a person has of surviving five years after being diagnosed.

 For vulvar cancer, 59.2% are diagnosed at the local stage.  The 5-year survival for localized vulvar cancer is 85.8%.

CARCINOMAS OF THE VULVA 19 HISTOPATHOLOGIC GRADING: - Differentiated carcinoma: begins at the surface and presents a pattern of broad buds with rounded borders composed of well-differentiated tumour cells that contain abundant cytoplasm, keratin, keratohyaline granules, and intercellular bridges. Poorly differentiated carcinoma: is generally found at the epithelial stromal junction. It is characterized by small tumor cells with scant cytoplasm showing little or no differentiation that infiltrates the stroma either in elongated streaks or small clusters (spray pattern).

CARCINOMAS OF THE VULVA 20 Poorly differentiated component occupies less than or equal to 25% of the total area of the tumor. Grade 3: Poorly differentiated component occupies greater than 25%, but less than or equal to 50% of the total area of the tumour. Grade 4: Poorly differentiated component occupies greater than 50% of the tumour area. HISTOPATHOLOGIC GRADING: - Grade 1: No poorly differentiated component. Grade 2:

CARCINOMAS OF THE VULVA 21 Ninety per cent of these epithelial malignant tumours are squamous cell carcinomas, the remainder being basal cell carcinomas, melanomas, or adenocarcinomas The malignant melanoma should be reported seperately

Cases should be classified as carcinoma of the vulva when the primary site of the growth is in the vulva. Tumours present in the vulva as secondary growth from either a genital or extra-genital site should be excluded. A carcinoma of the vulva that has extended to the vagina should be considered as a carcinoma of the vulva.

Squamous Cell Carcinoma of Vulva 23 Risk of metastatic spread is linked to the size of tumour, depth of invasion, and involvement of lymphatic vessels. The inguinal, femoral, pelvic, iliac, and periaortic lymph nodes are most commonly involved. Ultimately, lymphohematogenous dissemination involves the lungs, liver, and other internal organs.

Patients with lesions less than 2 cm in diameter have a 60% to 80% 5-year survival rate after treatment with one-stage vulvectomy and lymphadenectomy; larger lesions with lymph node involvement yield a less than 10% 5-year survival rate.

Verrucous carcinoma of vulva 25 An uncommon variant of squamous cell carcinoma with low malignant potential. It may, however, grow very large. These lesions were originally described as occurring in the oral cavity but have also been described involving the vagina, cervix, and vulva. Clinically, these tumours are very slow growing and carry an excellent prognosis. The lesion grossly appears cauliflower-like in nature.

Verrucous carcinoma of vulva 26 This rare variant of squamous cell carcinoma may also resemble condyloma acuminatum and present as a large fungating tumor.

Verrucous carcinoma of vulva 27 Local invasion confirms the malignant nature of the lesion, but it rarely metastasises and can be cured by wide excision. If there are suspicious groin nodes, FNA or excisional biopsy should be carried out.

Paget’s Disease of Vulva 28 Rare lesion of the vulva, and sometimes the perianal region, is similar in its skin manifestations to Paget disease of the breast. As a vulvar neoplasm, it manifests as a pruritic red, crusted, sharply demarcated, map like area, occurring usually on the labia majora. It may be accompanied by a palpable submucosal thickening or tumor.

Paget’s Disease of Vulva 31 In contrast to Paget’s disease of the nipple, in which 100% of patients show an underlying ductal breast carcinoma, vulvar lesions are most frequently confined to the epidermis of the skin and adjacent hair follicles and sweat glands.

Paget’s Disease of Vulva The prognosis of Paget’s disease is poor in the uncommon cases with associated carcinoma, but intraepidermal Paget’s disease may persist for many years, even decades, without the development of invasion. However, because Paget’s cells often extend into skin appendages and may extend beyond the confines of the grossly visible lesion, they are prone to recurrence. It is considered as nothing more than a variant of VIN

Paget’s Disease of Vulva 33 The diagnostic microscopic feature of this lesion is the presence of Paget cells, large tumor cells lying singly or in small clusters within the epidermis and its appendages. These cells are distinguished by a clear separation ("halo") from the surrounding epithelial cells and a finely granular cytoplasm containing periodic acid-Schiff stain-, Alcian blue-, or mucicarmine-positive mucopolysaccharide. Ultrastructurally, Paget cells display apocrine, eccrine, and keratinocyte differentiation and presumably arise from primitive epithelial progenitor cells.

Malignant Melanoma 34 Melanomas of the vulva are rare, representing less than 5% of all vulvar cancers and 2% of all melanomas in women. Their peak incidence is in the sixth or seventh decade;

Malignant Melanoma They tend to have the same biologic and histologic characteristics as melanomas occurring elsewhere and are capable of widespread metastatic dissemination. Because it is initially confined to the epithelium, melanoma may resemble Paget’s disease, both grossly and histologically.

Malignant Melanoma 36 It can usually be differentiated by its uniform reactivity, with immunoperoxidase techniques, with antibodies to S100 protein, absence of reactivity with antibodies to carcinoembryonic antigen, and lack of mucopolysaccharides.

Malignant Melanoma Prognosis is linked principally to depth of invasion, with greater than 60% mortality for lesions invading deeper than 1 mm. The overall survival rate is less than 32%, presumably owing to delays in detection and a generally poor prognosis for mucosal melanomas.

Basal cell carcinoma 38 Vulva is a very unusual site for this lesion. When it occurs, its features are similar to rodent ulcer of the face. This is an invasive squamous cell carcinoma, which penetrates into the dermis and deeper tissues. Its spread is slow and it does not metastasizes, Local excision is curative.

Diagnostic Evaluation

Physcial examination Measurements of primary tumour Assesment of extension to adjacent mucosal and bony structures Distance from vital structures,,e.g urethra,anus,clitoris

Punch biopsy For diagnosis and to know DOI Inguinal node FNAC or Biopsy if it can change the plan

Diagnsotic imaging Required in obese women to identify lymphnodes

EUA,Cystourethroscopy or Proctosigmoidoscopy Large fixed tumors

PAP smear Etiology is same. All women with vulval cancer should undergo pap smear De bie et al.,British journal of cancer 2009

SENTINEL LYMPHNODE MAPPING

Prognostic Factors Demogrpahical Risk Factors Tumor Factors Size,location,DOI, Laterality, LVSI Inguinal nodes Distant metastasis

First draining lymph-node in the lymphatic basin that recieves primary lymph flow from the tumor. Use of comprehensive serial sectioning, Immunohistochemistry (IHC), and reverse transcription-polymerase chain reaction have been investigated as potential methods to detect the earliest signs of metastatic disease.

Sentinel lymph node biopsy (SLNB) represents the largest innovation in the care of patients with vulvar cancer in the past decade.

PROCEDURE 1-2mlofisosulfan blue dyeor 400mCi of technetium labeled sulfur colloid injected circumferentially intradermally around the tumor, and lymphoscintigraphy was performed. The sites of the SLNsmarked on the skin with a pencil. SLNs identified using a handheld probe and the dissection of blue- stained lymph vessels and lymph nodes.

Intra operative gamma counter to identify for identification of the nodes and lymphatics. The removed SLNs sent to the pathologist separately. Ultrastaging consisted of performing serial sectioning and IHC analysis with cytokeratins.

GROINNS – V- I

Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva. STUDIESDetails GROINSS-V403patients 26% metastatic sentinel nodes 3% groin recurrences GOG women underwent the planned procedures, 418 had at least one sentinel lymph 132 node-positive women 11 (8.3%) with false- negative 23% true positive detected by IHC sensitivity was 91.7% False-negative predictive value 3.7%

VariablesSN -VeSN +ve Local recurrence at 5 yr 24.6%33.2% Local recurrence at 10 yr 36.4%46.4% Isolated groin recurrences at 5 years 2.5%8% Disease specific survival rate at 10 years 91%65%

Reliance on the SLN is dependent on accurate injection of the blue dye and/or radioisotope, interpretation of the preoperative lymphoscintigraphy, and proper handling of the node by the pathologist, including serial sectioning and IHC analysis. Implementation in the routine treatment of early-stage vulvar cancer requires quality control at each step of this multidisciplinary procedure.

Learning curve associated with the SLN procedure Success of the procedure is surgeon dependent (requires a surgeon with successful experience SLN procedure followed by full lymphadenectomy in at least 10 patients.) Finally, to keep the experience at a high level, an exposure of at least 5–10 SLN procedures per year per surgeon is likely necessary. In a rare tumor such as vulvar cancer, this requires centralization of early stage vulvar cancer treatment in oncology centers

Take Home message 1. Invasive vulvar cancer is a relatively rare tumor, accounting for 4% of all female genital malignant neoplasms. 2. Squamous cell carcinoma of the vulva develops by human papillomavirus- (HPV-) dependent and HPV- independent pathways. 3. Sentinel lymph node biopsy represents the largest innovation in the care of vulvar cancer patients in the past decade.

SLNB Take home Clearly, the current approach to the management of patients with vulvar cancer is far from settled. The criteria for preoperative evaluation are not standardized The surgeon's learning curve is critical in determining the success of the procedure Yet to set definitive standards with regard to the management of isolated tumor cells or micrometastases found in the sentinel node in vulvar cancer