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Diagnostic Applications of Nuclear Medicine: Vulvar Cancer

  • Sonia Mahajan
  • Weining Ma
  • Neeta Pandit-TaskarEmail author
Living reference work entry

Abstract

Vulvar cancer is an uncommon malignancy in females and is less frequently seen as compared to cervical or endometrial cancer. Human papillomavirus (HPV) infection, chronic lichen simplex infection, and genital warts are considered some of the predisposing factors. While metastases occur in late-stage disease (usually via lymphatic spread), many lesions are seen in the early stages. Anatomic imaging is the mainstay of evaluation for local extent. [18F]FDG PET imaging has incremental value for evaluation of equivocal lesions, assessing nodal status and detecting distant metastasis. Lymphoscintigraphy for sentinel node mapping is useful for surgical planning and limiting postoperative morbidity from extensive nodal dissection. This review summarizes the current status and emerging trends in imaging vulvar cancer using radiopharmaceuticals.

Keywords

Vulvar cancer Vulvar cancer imaging [18F]FDG PET/CT in vulvar cancer Lymphoscintigraphy Sentinel node mapping 

Glossary

[18F]FDG

2-deoxy-2-[18F]fluoro-D-glucose

AJCC

American Joint Committee on Cancer

CT

X-ray computed tomography

FIGO

International Federation of Gynecology and Obstetrics

GOG

Gynecologic Oncology Group

GROINSS V

GROningen INternational Study on Sentinel Lymph Nodes in Vulvar Cancer

HPE

Histopathology exam

HPV

Human papillomavirus

ICG

Indocyanine green

ILN

Inguinal lymph nodes

LN

Lymph node

LSG

Lymphoscintigraphy

M

Metastasis status according to the AJCC/UICC TNM staging system

MIP

Maximum intensity projection

MRI

Magnetic resonance imaging

N

Lymph node status according to the AJCC/UICC TNM staging system

NA

Not available

NCCN

National Comprehensive Cancer Network

NIRF

Near-infrared fluorescent imaging

NPV

Negative predictive value

OS

Overall survival

p16

Gene encoding the cyclin-dependent kinase inhibitor 2A, also known as multiple tumor suppressor 1

p53

Gene encoding for tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

PPV

Positive predictive value

SCC

Squamous cell carcinoma

SLN

Sentinel lymph node

SN

Sensitivity

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/Computed tomography

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

TNM

AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status), and “M” (distant metastasis status)

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasound

VIN

Vulvar intraepithelial neoplasia

Introduction

Introduction and Epidemiology

Vulvar carcinoma comprises of about 0.4% of all new cancer cases and approximately 5.4% of all gynecologic cancers with 5,950 estimated new cases in the USA in 2016 [1]. It accounts for approximately 0.2% of all cancer-related deaths. Based on 2009–2013 statistics, the number of new cases of vulvar cancer was 2.4 per 100,000 women per year, and the number of age-adjusted deaths was 0.5 per 100,000 women per year [1]; a steady increase in vulvar cancer incidence has been noted over the past 40 years [2].

The median age for vulvar cancer at diagnosis is 65–70 years and that for vulvar intraepithelial neoplasia (VIN) is 45–50 years. It has slightly higher preponderance in whites and Native Americans compared to Asians and blacks. The higher incidence of VIN in women younger than 55 years is probably related to human papillomavirus HPV16 infection. An increasing incidence of vulvar cancers involving clitoral and periurethral region [2] has been noted that is generally associated with worse prognosis as compared to those not involving these regions [3]. A majority of vulvar cancers are usually detected in early clinical stages (59.2%) that are associated with a high 5-year survival rate of about 85.8% as against 55.4% for those with regional metastasis and 15.5% for those with distant metastatic disease. The age of the patient and characteristics of the tumor including size of the lesion, depth of invasion, cellular differentiation and grade, nodal status, and extranodal extension are independent prognostic variables associated with vulvar cancer with lymph nodal status the most important factor [4, 5].

Environmental factors and genetic predisposition: Cigarette smoking is considered a cofactor of HPV in the development of vulvar squamous cell carcinoma [6]. Certain studies have linked smoking to immunosuppression, and although the exact mechanism underlying the association is unknown, it is also postulated that the presence of nicotine, cotinine, and other constituents may be seen in cervical mucus which affect the presence of cervical Langerhans cells and T lymphocytes [6]. Active smokers have about greater than threefold increased risk of developing vulvar SCC compared to nonsmokers, while former smokers may have little or no increased risk [7].

Persistent infection with HPV, an encapsulated DNA virus, is a known risk factor for hyperplasias associated with low-risk HPV types as well as for premalignant lesions caused by high-risk HPV types such as 16, 18, 31, 33, and 45 [8]. While the mechanism of such association is not fully known, it appears to be related to disruption of cellular gene functions caused by insertion of HPV genomes into host genomes [9]. It has been noted that following infection there is replication of viral DNA in basal cells with stable retention of multiple copies in preneoplastic lesions (episomal state). The viral DNA then integrates with the genome of the cell, and transcription of specific viral gene products occurs in invasive state [9, 10], some of which directly interfere with function of p53 and pRB.

The p16 and p53 expression has also been associated with variable presentation and prognosis [11, 12]. Diffuse p16 expression has been associated with younger age at presentation and basaloid and warty subtypes, while p53 immunopositivity is negatively associated with VIN [11]. Nonneoplastic epithelial cell disorders of vulva such as lichen sclerosis, squamous hyperplasia, and other dermatoses may develop cellular atypia or VIN in about 10% cases. Higher p53 mutations are more likely associated with HPV-negative tumors and point mutations more likely in metastatic lesions, suggesting a role in disease progression [12].

Prevention of HPV infections by vaccines can help decrease the incidence of vulvar intraepithelial neoplasias, genital warts, and cervical cytological abnormalities [13, 14, 15]. General recommendation is to offer vaccination to adolescents/young adults in three-dose series at 0, 2, and 6 months interval [16, 17, 18].

Histopathologic categories of vulvar cancer (Table 1): The most common histology of vulvar cancer is squamous cell carcinoma that forms more than 90% of the total, followed by vulvar melanoma that accounts for 2–4% of primary vulvar malignancies [19, 20]. The squamous cell carcinomas are further divided as keratinizing, warty, or basaloid. Keratinizing subtype is more commonly (60–80%) seen in postmenopausal women, is generally well to moderately differentiated, and is not associated with VIN or HPV, while warty or basaloid subtypes occur more commonly in pre- or perimenopausal women and are associated with VIN [21]. Verrucous carcinoma is a variant of SCC that is slow growing and less aggressive and rarely metastasizes though can be locally invasive. Basal cell carcinomas present in about 2% of patients who generally have other lesions in the body. The lesion may appear as discoloration or plaque and may be indolent. Sarcomatous lesions are less frequent and occur in less than 2% of patients. These are associated with poor prognosis and higher recurrence is seen in those with high-grade histology and large tumor size (>5 cm). Paget’s disease of the vulva is rare (<1%) and presents as an eczematoid well-demarcated lesion. It can be multifocal and may be associated with invasive adenocarcinoma in deeper tissues.
Table 1

Histological variants of vulvar carcinoma [21, 22, 23]

1. Squamous cell carcinoma

(a) Invasive

(b) Squamous variant of Bartholin gland carcinoma

2. Malignant melanoma

3. Anaplastic carcinoma

4. Vulvar intraepithelial neoplasia – high grades II and III (4% develop invasive cancer)

5. Paget’s disease (5–10% are associated with underlying adenocarcinoma)

6. Adenocarcinoma

(a) Invasive

(b) Adenocarcinoma variant of Bartholin gland carcinoma

7. Other tumors

(a) Transitional cell variant of Bartholin gland carcinoma

(b) Adenoid cystic carcinoma – variant of Bartholin gland carcinoma

(c) Primary mammary adenocarcinoma

(d) Verrucous carcinoma

(e) Basal cell carcinoma

(f) Histiocytosis X

(g) Sebaceous carcinoma

(h) Sarcomas

Staging and Prognosis

The clinical staging of vulvar cancer is generally performed based on the International Federation of Gynecology and Obstetrics (FIGO) classification [24, 25] (Table 2). The classification is based on lesion size, tumor grade, and depth of invasion [24]. Vulvar melanomas are staged similar to cutaneous melanomas (Table 3). Staging of vulvar melanomas is based on Breslow’s and modified Clark’s classification [27].
Table 2

FIGO (2009) and AJCC classification [26]

FIGO stage

Description

I

Tumor confined to the vulva

Ia

Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1 mm, no nodal metastases

Ib

Lesions >2 cm in size or with stromal invasion >1 mm, confined to the vulva or perineum, with negative nodes

II

Tumor of any size with extension to adjacent perineal structures (lower third of the urethra, lower third of the vagina, anus) with negative nodes

III

Tumor of any size with or without extension to adjacent perineal structures (lower third of the urethra, lower third of the vagina, anus) with positive inguinofemoral nodes

IIIa

With 1 lymph node metastasis (≥5 mm) or with 1–2 lymph node metastases (<5 mm)

IIIb

With 2 or more lymph node metastasis (≥5 mm) or with 3 or more lymph node metastases (<5 mm)

IIIc

Positive lymph nodes with extracapsular spread

IV

Tumor invades other regional (upper two thirds of the urethra, upper two thirds of the vagina) or distant structures

IVa

Tumor invades either upper urethral/vaginal mucosa, bladder mucosa, rectal mucosa, fixed to pelvic bone, or fixed/ulcerated inguinofemoral lymph nodes

IVb

Any distant metastases including pelvic lymph nodes

TNM staging

Primary tumor (T)

Tx – Primary tumor cannot be assessed

T0 – No evidence of primary tumor

Tis – Carcinoma in situ (preinvasive)

T1a – Lesions ≤2 cm, confined to the vulva or perineum and with stromal invasion ≤1 mm (FIGO IA)

T1b – Lesions >2 cm or any size with stromal invasion >1 mm, confined to the vulva or perineum (FIGO IB)

T2 – Tumor of any size with extension to adjacent perineal structures (distal third of the urethra, distal third of the vagina, anal involvement) (FIGO II)

T3 – Tumor of any size with extension to any of the following proximal two thirds of the urethra, proximal two thirds of the vagina, bladder mucosa, or rectal mucosa or fixed to pelvic bone (FIGO IVA)

Regional lymph nodes (N)

Nx – Regional lymph nodes cannot be assessed

N0 – No regional lymph node metastasis

N1a – 1 or 2 lymph node metastases, each <5 mm (FIGO IIIA)

N1b – 1 regional lymph node metastasis ≥5 mm (FIGO IIIA)

N2a – 3 or more lymph node metastases, each <5 mm (FIGO IIIB)

N2b – 2 or more regional lymph node metastases ≥5 mm (FIGO IIIB)

N2c – Regional lymph node metastasis with extracapsular spread (FIGO IIIC)

N3 – Fixed or ulcerated regional lymph node metastasis (FIGO IVA)

Distant metastasis (M)

M0 – No distant metastases

M1 – Distant metastases (including to pelvic lymph nodes) (FIGO IVB)

Table 3

Breslow’s classification and Clark’s classification

Stage

Depth

Breslow’s classification

Stage I

Less than or equal to 0.75 mm

Stage II

0.76–1.50 mm

Stage III

1.51–2.25 mm

Stage IV

2.26–3.0 mm

Stage V

Greater than 3.0 mm

Clark’s classification

Level 1

Melanoma confined to the epidermis (melanoma in situ)

Level 2

Invasion into the papillary dermis

Level 3

Invasion to the junction of the papillary and reticular dermis

Level 4

Invasion into the reticular dermis

Level 5

Invasion into the subcutaneous fat

Early-stage disease (stage I) has a very good overall 5-year survival (84.0%) as against FIGO stage II, III, and IV patients with overall survival (OS) of approximately 74.6%, 47.8%, and 9.4%, respectively. Nodal metastasis is correlated with worse prognosis; pooled data showed a 5-year OS of 84.5% for patients without LN metastasis and 30.1% for patients with three or more LN metastasis [28]. Inguinal and/or femoral node involvement is the most significant prognostic factor for survival in patients with vulvar cancer [29]. Other factors like tumor size and thickness, depth of invasion, and lympho-vascular space invasion also adversely affect prognosis. The presence of high mitotic rate, aneuploidy, infiltrative growth pattern, and basaloid histologic pattern is correlated with poor prognosis [30, 31]. Extranodal extension, defined as the extension of tumor from the node to adjacent soft tissue, is also associated with adverse outcomes. In a meta-analysis, Luchini et al. showed significant increase in all-cause mortality, cancer-specific mortality, and recurrence in patients with extranodal extension of tumor as compared to those without [32].

Clinical presentation and management: Vulvar cancer can present in various forms either as subtle nonspecific presenting symptoms or as a frank ulcerating lesions or mass. Patients most commonly present with chronic itching or pain in introitus. The lesion may appear like lichen sclerosis, contact dermatitis, or warts and can be overlooked as inflammatory or benign condition. Patients may have skin changes including discoloration or thickening. Lesions may appear like plaques or exophytic or fungating growths. A chronic condition of the vulva that recurs or does not respond to treatment should be therefore further investigated and preferably biopsied [33]. Diagnosis is usually made with wedge biopsy; however, excision biopsy is preferred for lesions that are <1 cm. Clinical examination helps to rule out multifocal or multicentric involvement, while colposcopic examination is required to know the extent [34].

Surgical excision is the mainstay of management of vulvar cancer. Radical vulvectomy with wide excision of the vulva up to the deep fascia of the thigh and urogenital diaphragm is performed in order to achieve a tumor-free margin ≥1 cm to minimize local recurrence. Unilateral or bilateral inguinal nodes may be sampled and dissected based on extent of the primary lesion. Lesions in the midline or crossing the midline may spread to bilateral inguinal nodes seen in up to 3–5% of cases; however, the rates vary with inclusion of other factors such as tumor size and depth of invasion [30, 35]. Pelvic node involvement is not common and occurs in about 5% of patients [36]. T1 lesions without extension to adjacent perineal structures (i.e., urethra, vagina, and/or anus) may be effectively treated by wide local excision [37]. NCCN guidelines for SCC of vulva [38] recommend wide local resection followed by observation for early-stage T1 and smaller T2 lesions less than or equal to 4 cm that have ≤1 mm invasion. For lesions greater than 1 mm invasion, radical local resection or modified radical vulvectomy is recommended. For midline lesions, bilateral inguinofemoral groin lymph node dissection should be considered with or without sentinel lymph node detection. For a lesion that is lateral (≥2 cm from midline), ipsilateral lymph node dissection with or without sentinel lymph node detection is performed. T2 lesions with extension to adjacent perineal structures are best treated with radical vulvectomy or hemivulvectomy. In locally advanced disease, neoadjuvant radiation and chemotherapy is administered; residual tumor, if present, is surgically excised [38, 39].

Role of Imaging

Diagnosis of vulvar cancer initiated based on clinical history and examination; a suspicious lesion is biopsied. Imaging plays a limited role in the evaluation of primary disease. For evaluation of disease extent and treatment planning, contrast-enhanced CT or MRI or PET with 2-deoxy-2-[18F]fluoro-D-glucose be used based on clinical need and suspicion. In patients with locally advanced disease, chest radiograph, CT, and/or MRI is recommended to establish staging (Fig. 1). Assessment of inguinofemoral region is critical for management and to segregate patients for nodal sampling and surgical dissection prior to treatment with chemotherapy and/or radiation.
Fig. 1

MR pelvis (a) axial T2-weighted (b) gadolinium-enhanced T1 image shows a left vulvar soft tissue mass (M); T2 mildly hyperintense with homogenous enhancement invading through the pelvic floor with involvement of posterolateral urethral, lower vaginal, and anal walls (white arrow). (c) Coronal fused PET/CT image showed [18F]FDG avid (SUVmax 10.8) left vulvar mass (white arrow), B: urinary bladder. HPE revealed moderately differentiated invasive SCC

MRI is useful in evaluating the local extent of disease in patients with advanced tumor, especially for assessment of extent in the perineum and extension to the vagina or anus, and therefore useful for surgical planning. The tumor is best visualized in T2-weighted sequences and may be seen as a mass or skin thickening with intermediate to high signal intensity. The extent of the lesion is better visualized on contrast-enhanced fat-suppressed T1-weighted images. MRI may also be useful to assess the depth of tumor invasion and local extent, especially involvement of the clitoris or urethral meatus [40]. MRI provides accurate assessment of lymph node metastasis [41, 42] and is highly specific in identifying abnormal lymph nodes by using size criteria and morphology. However, the sensitivity is low ranging between 40% and 50% [37]. Using short/long axis (S/L) ratio as a quantitative marker for diagnosing lymph node metastasis, a higher sensitivity of 87% and specificity of 81% have been reported [37].

Ultrasound (US) is used mainly to detect abnormal inguinal lymph nodes or for ultrasound-guided biopsy of suspicious lymph nodes. Focused ultrasound imaging is performed using a high-frequency transducer (linear 8–18 MHz). Abdominopelvic CT scans may be useful in detecting local and distant lymph nodes or other distant metastases and are generally used in conjunction with US and MRI for staging or restaging based on patient’s clinical presentation and suspicion.

Radiopharmaceutical imaging: Of the various techniques and tracers available, [18F]FDG-PET/CT imaging and lymphoscintigraphy are primarily used for imaging and evaluation of patients with vulvar cancer. Currently, the role of [18F]FDG PET/CT has not been fully established though early data suggests a complimentary role and advantages in assessing distant disease [43, 44].

[18F]FDG PET Imaging

Generally vulvar cancer shows avid uptake of [18F]FDG (Figs. 2 and 3). For initial staging, FDG PET is more often used to detect distant metastatic disease while assessment of nodal disease is less critical. Anatomic imaging provides superior details in determining local extent, and [18F]FDG PET may play a complimentary role in evaluating equivocal findings on conventional imaging, especially in assessing nodal disease in non-enlarged or borderline-sized nodes (Fig. 4). In a small prospective study in vulvar SCC (n = 15, stages IB–IV), [18F]FDG PET was performed prior to surgery and compared with results of groin dissection (Table 4). All patients showed avid uptake in primary tumors [45]. [18F]FDG PET showed suspicious nodes in six out of nine groins (in four out of five patients) that were pathologically positive. In a single patient, [18F]FDG PET was also positive for pelvic nodes that were further treated with radiation. Other distant sites that showed uptake included adrenal gland adenoma and physiologic prominent uptake in the cecum.
Fig. 2

Primary vulvar carcinoma (VIN III). A 28-year-old with biopsy-proven high-grade squamous intraepithelial lesion (a) MIP (black arrow) and (b) axial fused PET/CT image of pelvis show minimal asymmetric [18F]FDG uptake in the perineum (SUVmax 1.9) (white arrow); no gross disease is seen on the noncontrast CT (c). No other metastatic lesion was seen in the rest of the body. (e) Patient underwent presurgical lymphoscintigraphy. LSG planar and SPECT images, following 99mTc-sulfur colloid injection intradermally, show lymph nodes in bilateral groin region and pelvis (arrow, injection site)

Fig. 3

Primary vulvar carcinoma. A 76-year-old with left vulvar lesion that shows intense [18F]FDG uptake on MIP (a) and fused PET/CT images (b, SUVmax 10.7). The lesion measured 2.8 × 1.6 cm as seen on axial CT (c). No other metastatic lesion was seen in the rest of the body (a)

Table 4

FDG PET in vulvar cancer – literature

Author, year

Type

Indication

Number of patients/stage

Comparative imaging (CT or MRI)

Histopathology confirmation (yes/no)

Sensitivity/specificity/accuracy

Lin et al., 2015

Prospective

Primary staging (n = 17), response assessment (n = 7), restaging (n = 14) (38 PET studies)

23: SCC (n = 15) stages I–IV, adenocarcinoma (n = 2), melanoma (n = l), Paget’s disease (n = 4), small cell ca (n = l)

CT/MRI

Yes

ILN: [18F]FDG– 92%/91%/91%; CT/MRI – 92%/100%/97%

Kamran et al., 2014

Retrospective

Staging: detection of inguinal and femoral LN

20 SCC stage I/II (n = 8), III (n = 12)

No

Yes

50%/100%/70%

Cohn et al., 2002

Prospective

Staging: detection of groin lymph node metastases

15 SCC stage IB (n = 3), M (n = 7), Nl (n = l), IVA (n = 4)

No

Yes

Per patient basis – 80%/90%/NA. Per groin basis – 67%/95%/NA

Dolanbay et al., 2015

Prospective

Staging: assessment of inguinofemoral lymph nodes

8 SCC stage IB (n = 4), IIIB(n = 4)

No

Yes

100%/100%/NA

SCC squamous cell carcinoma, ILN inguinal lymph nodes

Fig. 4

Patient with vulvar carcinoma referred for staging of the disease. Whole-body MIP (a, black arrow) image shows increased [18F]FDG uptake in the primary lesion seen on CT (b, white arrow) and fused PET/CT image (c, SUVmax 4.7). Additional uptake is seen in inguinal lymph nodes (d, e, white arrow) (SUVmax 1.1). On whole-body PET/CT, multiple suspicious lesions showing mildly increased [18F]FDG uptake were noted in both lungs (f, g, h, white arrows)

In a prospective study that analyzed CT, MRI, and [18F]FDG PET imaging in 23 patients, [18F]FDG PET showed high uptake in the primary tumor with an average SUV of 11; however, the values ranged between 2.4 and 28.5. In 2/17 patients, [18F]FDG had a positive impact on management by either detecting a distant metastasis or excluding pelvic metastasis [46]. For those evaluated for recurrence, 2/14 had unknown metastatic sites detected on [18F]FDG PET as compared to other conventional imaging. However in this study, the overall accuracy and specificity of [18F]FDG PET imaging were lower as compared to CT and/or MRI [46]. In evaluating the role of [18F]FDG PET in staging prior to planned radical vulvectomy and inguinofemoral lymphadenectomy, imaging analysis in 20 patients showed high uptake in vulvar lesions ranging from 2.5 to 14.7 and uptake of 2.4–3.0 in groin nodes [47]. In a very small study (n = 8), [18F]FDG localized to all primary well-differentiated SCC of the vulva; the nodal uptake was higher (SUV range of 3.5–15) in metastatic nodes versus reactive nodes (SUV range of 1.7–3.1) [48].

[18F]FDG PET has been evaluated for assessing nodal status especially the involvement of inguinofemoral lymph nodes and as a noninvasive tool for preoperative assessment [45, 46, 47, 48] (Figs. 5 and 6). Kamran and colleagues evaluated the usefulness of FDG in categorizing stage III disease accurately and in comparison to histopathology; while the specificity was high (100%), the sensitivity and overall accuracy were low for nodal assessment. In this small study, it was noted that there were larger, multiple, and bilateral nodal metastases in those with a more avid primary tumor versus those with a less avid primary tumor. Due to low negative predictive value (NPV) of [18F]FDG the low-risk patients could not be reliably identified; however, the high PPV suggested that it could be a useful guide in proceeding with a full lymphadenectomy [47]. This however needs to be evaluated in a more systematic and larger group.
Fig. 5

A 36-year-old woman with history of recurrent vulvar carcinoma referred for restaging. (a) Whole-body MIP image shows [18F]FDG uptake in the perineum (SUVmax 8.8) (long arrow) localizing to thickening in vulvar region noted on CT (b, white arrow) and fused PET/CT image (c, white arrow). Additional foci of uptake are seen in bilateral inguinal regions (MIP image a, short arrow) (d, e, SUVmax 2.5 on the left side) which were considered equivocal. The patient underwent radical vulvectomy with bilateral inguinal lymph node dissection; histopathology showed invasive squamous cell carcinoma vulva and negative nodes. (Teaching point-faint uptake in nodes is nonspecific and may be related to reactive uptake; however, assessment is best correlated with clinical suspicion)

Fig. 6

A 41-year-old with vulvar SCC was initially referred for pretreatment evaluation of the primary disease and extent Panel a: Whole-body MIP image a1 (arrow) shows abnormal uptake in vulvar region also noted on fused images a2 (SUVmax 7.8). Increased uptake was also seen in left inguinal node (a3, SUVmax 4.3) as well as in left obturator node (a4, SUV 8.0). Foci of increased uptake superiorly in bilateral pelvis corresponded to physiologic uptake in bilateral adnexa (a5). Panel b: The patient was treated with chemoradiation and a follow-up [18F]FDG scan showed resolution of focal uptake in the vulva (b1, b2 arrows) as well as decreased uptake in the inguinal and obturator nodes (b3). Heterogeneous uptake in the mons pubis corresponding to ill-defined infiltrative changes and mildly avid right inguinal node (b4, b5) was likely postradiation changes. Patient underwent partial vulvectomy and left inguinal node dissection. Panel c: Patient returned for routine follow-up imaging after 6 months. The scan showed several new lesions suspicious for metastatic disease including T3 vertebra (SUVmax 8) (c2 long arrow), right axillary (c2 short arrow), subcarinal and hilar lymph nodes (c3, arrows), and right lung lower lobe (c4, SUVmax 10.4). Mild focal uptake was also noted in the liver (c5, SUVmax 4.4), suspicious for metastatic lesion. Lung lesion was positive for malignant disease, and while the liver lesion was negative on biopsy, a follow-up CT revealed a large lesion in the same region and additional lesions in the liver, positive for metastatic disease (c6, arrows). Teaching point: [18F]FDG PET can help detect unknown distant metastatic sites and early lesions

Cohn and colleagues evaluated [18F]FDG PET for detecting groin nodal metastasis in correlation with pathologic finding and detected higher sensitivity for nodal detection on a per patient basis as against nodal basin-based analysis (80% vs 67%); however, the specificity was higher in site-specific analysis (95% vs 90%). The positive and negative predictive values for nodal detection were about 80–90%. The overall sensitivity was however less optimal to preclude surgical lymphadenectomy using [18F]FDG data only [45]. Similar result, though with lower sensitivity, was noted by Kamran et al.; [18F]FDG PET had sensitivity of 50% only, though high specificity of 100% was seen with a positive predictive value of 100 [47].

In those with high-risk disease, [18F]FDG PET can help detect metastatic disease especially to the distant sites (Fig. 6) and affect management change. A recent study that analyzed the impact of [18F]FDG PET/CT in the management of 54 patients with vulvar cancer showed a change in prognosis in 54% of which 33% (18/54) had improved prognosis and 20% (11/54) had worse prognosis [49]. Though the data is combined with vaginal cancer patients, it appears that additional disease sites were detected by [18F]FDG PET in lungs and adrenals that contributed to worsening of prognostic outlook with an overall change in management in 36% of the combined population.

Recurrences are common in vulvar cancer patients. In a study of 502 patients, reported rates were 22% for stage I, 35.8% for stage II, and about 44–45% for stage III and IV disease with higher recurrences seen in the inguinal region as against pelvic regions [29]. [18F]FDG PET/CT may play a role in restaging and planning treatment in recurrent disease (Fig. 7). Extent of local, groin, and other sites of disease helps guide salvage or palliative therapy in individual cases. The data is limited for systematic evaluation of the use of [18F]FDG PET in restaging as well as for the assessment of treatment response (Figs. 7 and 8) and would need well-designed studies.
Fig. 7

Patient with poorly differentiated adenosquamous vulvar carcinoma referred for follow-up evaluation of extent of disease. Patient was prior treated with radical vulvectomy and nodal dissection. Whole-body MIP showed foci of increased [18F]FDG uptake in the pelvis and abdomen (a, arrows) localizing to right obturator lymph node (c1, c2 SUVmax 4.5) and left para-aortic lymph node (e1, e2 SUVmax 11.6 thick arrow). Patient was treated with chemoradiation; a follow-up PET/CT to assess response showed complete resolution of disease and pelvic lymph nodes (d1, d2 arrows) with partial response in para-aortic lymph node (f1, f2 SUVmax 3.3, thick arrow)

Fig. 8

A 72-year-old female with vulvar adenocarcinoma was referred for pretreatment evaluation of disease. Whole-body MIP image (a) showed abnormal uptake in the vulvar region (arrows a, b, c, SUVmax 9.0) and inguinal lymph nodes (d, SUVmax 4.9). A 6-month follow-up scan post chemoradiotherapy showed resolution of all the disease sites seen previously in the vulvar region and inguinofemoral nodes. However, a new focal uptake was noted in the right chest (e, black arrow) localizing to a nodule in the right lung upper lobe (f, SUVmax 5.9), which showed progression (g, SUVmax 12.6) on further follow-up imaging obtained after 3 months and was positive on pathology for metastatic disease

Lymphoscintigraphy

The concept of sentinel lymph node (SLN) mapping was initially developed by Cabanas in 1977 for penile cancers [50] which was extended to map nodes in melanoma using isosulfan blue dye intraoperatively [51]. Later, radionuclide scintigraphy was used in conjunction with blue dye that yielded superior results in nodal localization in breast cancer and melanoma [52, 53]. Extensive nodal dissection can lead to significant morbidity which can be considerably alleviated by sentinel node technique.
Table 5

Lymphoscintigraphy in vulvar cancer

Author and year

Type

Number of patients: FIGO staging

Histopathology confirmation (yes/no)

Comparison with blue dye (detection rate)

Sensitivity of LSG

de Hullu et al., 2000

Prospective

59: SCC stage I (n = 25), II (n = 34)

Yes

Yes (60%)

100%

Van der Zee et al., 2008

Prospective

403: SCC stage I

Yes

Yes

94.10%

Lindell et al., 2010

Retrospective

77: SCC stage I/II (n = 76), IVA (n = l)

Yes

Yes (94% blue dye alone n = 17) (98% LSG and blue dye n = 60)

NA

Levenback et al., 2012

Prospective

452: SCC stage I

Yes

Yes (92.4%)

By patient basis 91.7%, by groin basis 92.1%

Klapdor et al., 2015

Prospective

40: SCC stage IA (n = 5), IB (n = 26), II (n = 8), III (n = l)

Yes

Yes

100%

Collarino et al., 2015

Prospective

83: SCC stage IB (n = 51), II (n = 9), III (n = 18), IVA (n = 2), melanoma (n = 2), adenocarcinoma (n=l)

Yes

Yes

96.30%

Bogliolo et al., 2015

Retrospective

45: SCC stage I (n = 14), II (n = 31)

Yes

No

90%

SCC squamous cell carcinoma, LSG lymphoscintigraphy, NA not available

SLN with filtered 99mTc sulfur colloid is performed as a single-day procedure either on the day of surgery or a day prior to surgery. Intradermal, subcutaneous, or intratumoral injections may be performed. The intradermal injection is administered at the periphery of the lesion, approximately at the four corners of the lesion or post biopsy scar site. Dynamic images are obtained soon after the injection in the anterior projection. This is followed by static images in anterior, posterior, and lateral projections. A SPECT/CT may be performed, and is increasingly used, to localize the nodal site especially if there is a suspicion of localization of a deeper node. Blue dye (isosulfan blue) is injected intraoperatively as the transit is fast; many times the initial nodes may not be visualized. Handheld gamma probes have been used for detecting “hot nodes” for removal during surgery. In vivo and ex vivo counts are done over the node. Generally, nodes with counts more than ten times the background levels are considered sentinel.

SLN mapping is increasingly being used in gynecological cancers including vulvar cancer (Table 5) to prevent morbidity from en bloc inguinofemoral dissection. Standard treatment of vulvar SCC in those with T1–2, N0–1, and M0 tumor includes surgical excision of the tumor with unilateral or bilateral nodal dissection of the inguinofemoral nodal basins. The recurrence rate in the groin in those with pathologic negative nodes is less than 2%, and even in those with positive nodes on pathology, recurrence rates range between 5% and 10% [54, 55]. Total lymphadenectomy is associated with postoperative sequelae including cellulitis and lymphedema that results in increased morbidity and lower quality of life. SLN mapping is useful in allowing sampling of nodes and planning lymphadenectomies.

In an observational multicenter study (GROningen INternational Study on Sentinel lymph nodes in Vulvar cancer – GROINSS V), 276/403 patients with early-stage disease (T1/T2, primary lesion <4 cm, and clinically non-suspicious inguinofemoral LN) had negative SLN and did not undergo lymphadenectomy. Groin recurrence rate was 3% at 2 years. Low incidence rates of short- and long-term morbidity were reported in patients who had negative SLN versus patients who underwent lymphadenectomy following positive SLN procedure, such as wound breakdown (11.7% vs 34%) and cellulitis (4.5% vs 21.3%). Incidence rates of long-term morbidities such as lymphedema and recurrent erysipelas were also more common in patients who underwent SLN with lymphadenectomy as compared to the group with only SLN (25.2% and 16.2% vs 1.9% and 0.4%, respectively) [56].

Histopathological sampling guided by SLN mapping using blue dye and 99mTc-sulfur colloid has been reported to be an effective method to detect inguinofemoral LN involvement in patients with early-stage disease with primary lesions less than 4 cm in size [57]. In a GOG 173 study, false-negative predictive value of SLN in those with primary lesion measuring less than 4 cm was only 2% but was higher at 7.4% for lesions measuring 4–6 cm. On a patient-based analysis, SN of the SLN procedure was 91.7% and false NPV was 3.7% [56, 57].

Using lymphoscintigraphy and intraoperative gamma probe, Decesare and colleagues reported sensitivity and NPV of 100% in a small number of patients [58]. In a slightly larger study, using the same technique, SN of SLN detection was 90% [59]. Using a combination of 99mTc-nanocolloid and blue patent dye to identify the sentinel node [60], de Hullu et al. noted superior (100%) localization of sentinel nodes by 99mTc-nanocolloid as against 56% with blue dye. A number of studies subsequently [61, 62, 63] have reported high detection rates using both blue dye and radiocolloid scintigraphy with sensitivity ranging between 90% and 100%. 99mTc-phytate also has been used for mapping with comparable results [64]. With midline vulvar cancer, the drainage is often to bilateral nodes that may miss detection [65] and bilateral lymphadenectomy is recommended. In a GOG 173 study, Coleman and colleagues studied the significance of SLN in those with larger tumors measuring 2–6 cm, lateral, midline, or lateral ambiguous tumors; many of these may have bilateral lymphatic drainage necessitating bilateral inguinal nodal dissection. In 234 patients with early-stage disease, lymphoscintigraphy however detected only unilateral drainage in 32 of 105 patients with midline tumor, which prevented nodal dissection on the contralateral side. Also larger tumors showed more ambiguous drainage suggesting value of SLN mapping in this subgroup of patients [66].

SPECT/CT imaging is more sensitive and combines the tracer localization with anatomic details providing a superior three-dimensional localization, thereby facilitating surgical excision (Fig. 9). It is reported to identify sentinel nodes in higher number of patients [67]. In a prospective study of 40 patients with direct comparison of planar vs SPECT/CT imaging, a higher number of nodes were detected with SPECT/CT; mean nodes/patient for SPECT were 8.7 vs 5.9 for planar imaging. In 17.5%, aberrant lymph drainage was noted with localization to gluteal, paravaginal, vesical, paravesical, and retrovesical regions [67]. Overall sensitivity and NPV was 100% for inguinofemoral nodal SLN detection in correlation with histopathology. About 71% (5/7) of patients with aberrant nodal drainage had midline tumors, highlighting the importance of SLN mapping in midline tumors. Similar experience in small number of patients was reported by another group [68]. Overall, the existing data documents feasibility and usefulness of LSG in vulvar cancer.
Fig. 9

Patient with vulvar cancer. LSG with 99mTc-sulfur colloid shows tracer at the site of injection and no significant transit elsewhere in dynamic imaging (a). Static image b shows tracer at injection site and bilateral groins, localizing to inguinal regions on SPECT/CT (c). Fused image d shows tracer at the site of vulvar lesion

There has also been increasing interest in the use of fluorescent dyes like indocyanine green (ICG) [69] for evaluation of nodes based on near-infrared fluorescent imaging (NIRF). The faster transit and change in color that can be easily detected by the surgeon using infrared light are significant advantages of the use of fluorescent dyes. In a pilot study of ten patients with early-stage SCC of vulva, SLN were mapped using 99mTc-nanocolloid blue dye, and ICG to evaluate the feasibility of ICG SLN mapping. While largest numbers of nodes were mapped using nanocolloid, ICG mapped most of the SLN with added advantage of transcutaneous localization, especially in leaner patients [70].

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Sonia Mahajan
    • 1
  • Weining Ma
    • 1
  • Neeta Pandit-Taskar
    • 1
    Email author
  1. 1.Memorial Sloan Kettering Cancer CenterNew YorkUSA

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