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GYNECOLOGIC CANCER: Edited by Gottfried E. Konecny

New treatment standards for vulvar cancer 2020

Woelber, Linn; Jaeger, Anna; Prieske, Katharina

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Current Opinion in Obstetrics and Gynecology: February 2020 - Volume 32 - Issue 1 - p 9-14
doi: 10.1097/GCO.0000000000000595
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Abstract

INTRODUCTION

Over the last 15 years, the incidence of vulvar squamous cell carcinoma (VSCC) has almost doubled and especially younger women aged 30–49 years are increasingly affected [1,2]. Nevertheless, VSCC is still a rare disease of mostly postmenopausal women. Infections with high-risk human papillomavirus (HPV) account for up to 40% of VSCC; the majority, however, is non-HPV related and arises from chronic inflammatory skin disease like lichen sclerosus. Other risk factors include nicotin abuse and immunosuppression. Just recently, a higher risk for anogenital (pre)cancerous lesions has been shown in a registry-based cohort study of 4261 renal transplant patients compared with 213 673 nonrenal transplant recipients [3▪]. The risk for vulvar intraepithelial neoplasia (VIN) and VSCC was significantly increased in the transplant cohort [hazard ratio = 16.4; 95% confidence interval (CI): 10.4–25.8 for VIN and hazard ratio = 31.7 95% CI: 13.7–73.4 for VSCC]. Because of the rarity of VSCC, the knowledge of potential molecular subtypes is limited and not used to guide treatment decisions [4▪]. Locally restricted disease without clinical lymph-node involvement is mostly curable with local excision of the tumor and (except for tumors FIGO stage IA [5▪]) surgical staging of the groins with bilateral sentinel node biopsy (SNB) as well as full groin dissection in case of nodal metastases. The prognosis of patients with VSCC strongly depends on lymph-node status. Nodal metastases to the groin significantly reduce overall survival (OS) and disease-free survival (DFS): The 3-year DFS and OS rates of node positive (N+) patients are 35.2 and 56.2% compared with 75.2 and 90.2% for node-negative (N–) patients [6]. Adjuvant radiotherapy is applied in high-risk disease.

Box 1
Box 1:
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RECENT ADVANCES IN SURGICAL THERAPY

Local surgical treatment has been deescalated from complete radical vulvectomy to wide excision with a tumor-free pathological margin of at least 8 mm, which was regarded standard of care for years. Still, this can easily result in mutilation, especially when the primary tumor is located close to the clitoris as it is in up to 25–37% [7,8]. In a subgroup analysis of the large Arbeitsgemeinschaft Gynäkologische Onkologie (AGO)–(Chemo and Radiotherapy in Epithelial Vulvar Cancer) CaRE-1 cohort 289 node-negative (N–) patients with R0 resection, known margins and surgical treatment only were analyzed [9]. The AGO-CaRE-1 study is a large retrospective cohort study, evaluating treatment patterns and prognostic factors in VSCC. In total, 1618 patients with stage IB-IV disease, treated from 1998 to 2008 at 29 AGO centers in Germany, were included. Reported vulvar recurrence rates were 12.6% in patients with a margin less than 8 mm and 10.2% in patients with a margin at least 8 mm. No significant difference in DFS was observed in univariate or multivariate analysis between the groups.

Tumor-free resection margins distance has no effect on local recurrence

The data of the AGO CaRE-1 study were recently confirmed in a retrospective analysis of 287 patients treated at two Dutch centers from 2000 to 2010 [10▪]. The strength of this study is the exceptionally long follow-up of 80 months. Ten years after the treatment, the recurrence rate was as high as 42.5%. However, the pathologic tumor-free margin distance did not influence the risk of local recurrence [hazard ratio 1.03 (95% CI: 0.99–1.06)]. In this study, margins were examined for lichen sclerosus and differentiated VIN (dVIN) or usual type VIN. A higher local recurrence rate was observed in patients with accompanying dVIN and lichen sclerosus [hazard ratio 2.76 (95% CI: 1.62–4.71)]. No differences in local recurrences were found between patients who did or did not receive adjuvant radiotherapy to the vulva. These data strengthen the recommendation for a more intense and life-long follow-up for VSCC patients with a history of lichen sclerosus or dVIN.

COURSE OF DISEASE

For a long time, isolated vulvar recurrence was deemed to be of minor importance. This belief has first been challenged by Grootenhuis et al.[11] in 2016 showing a 21.7% decrease in OS after local recurrence. In a recently published subgroup analysis of the AGO-CaRE-1 study, 1249 patients with surgical groin staging and known lymph-node status (35.8% N+) were analyzed with regard to prognosis after recurrence [12▪]. In total, 360 patients (28.8%) developed disease recurrence; thereof 193 (53.6%) at the vulva only as the most frequent site for first recurrence. As described before, the risk for local recurrence persisted over several years after initial diagnosis without a clear decrease [8]. Isolated local recurrence at the vulva increased mortality 5.9-fold [hazard ratio for OS: 5.9 (CI: 4.3–8.2)]. One-year DFS rate after vulvar recurrence was only 58.5%. Thirty percent (58 of 193) of the patients with isolated local recurrence developed a second recurrence at the vulva. Second recurrences to the groins, pelvis and distant locations were more seldom but with high impact for OS. Patients with initial nodal involvement had a significantly higher risk for vulvar recurrences (2-year recurrence rate 19 vs. 13.5% for N– disease) and a significantly higher overall risk for disease recurrence (2-year recurrence rate 42.7 vs. 21.1%) [13].

Obesity has been associated with worse prognosis in several cancers. In another subgroup analysis from the AGO-CaRE-1 cohort of 849 patients with documented height and weight, this could now also be shown for VSCC [13]. In fact, a higher local recurrence rate (33.3 vs. 18.5%, P < 0.01) in patients with a BMI at least 30 kg/m2 was observed, whereas the rate of groin and distant recurrences was not elevated. In multivariate analysis, patients with a BMI at least 30 kg/m2 had a significantly shorter DFS (hazard ratio 1.811, 95% CI 1.005–3.262, P = 0.048). These data support the need for counseling cancer patients regarding a healthier lifestyle. Equally important, but also often regarded of minor importance is the psychotherapeutic guidance in cancer patient care. In a presentation of data from an ongoing study in early-stage gynecological cancer patients (stage I/II) at the 2019's ASCO [14], psychosocial outcomes were compared between ovarian, endometrial, vulvar/vaginal and cervical cancer. Surprisingly, and often disproportional to the prognosis, vulvar cancer patients reported greater cancer-related distress, anxiety and posttraumatic stress disorder-scores than ovarian cancer patients. This fact should especially be highlighted, as too many patients are still subjected to adjuvant radiation of the vulva or re-excision because of close margins with high morbidity and possible deterioration in psychosocial outcome.

MANAGEMENT OF THE GROIN

Groin recurrence occurs early in the course of disease and has repeatedly been reported as almost always fatal with a median OS of only 6–10 months. In the prospective GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS)-V-I study, all patients with groin recurrence eventually died from their disease despite radical rescue treatment [15]. Therefore, independent of the size of the lymph-node, metastasis radical inguino-femoral lymphadenectomy (LNE) is recommended whenever nodal involvement is detected [16].

Recently, the dogma of a mandatory full groin dissection has been questioned by a retrospective single center analysis of 159 patients. In this cohort, seven patients with micrometastasis (≤2 mm) in the groin were treated by SNB and radiation only. No recurrences occurred in the irradiated groins [17▪▪]. These results are promising and suggest the omission of radical groin dissection in selected cases. The GROINSS-VII study is looking at the recurrence rates after adjuvant radiation only for patients with SNB and detection of micrometastases. In an interim analysis presented at the 2013's ESGO Biennal Meeting by van der Zee, no increased groin recurrence rate was shown in these selected patients (recurrence rate: 2.1%, 1 of 46). Final results of the trial are still pending.

TUMORBIOLOGY AND MOLECULAR MARKERS

Several potential molecular pathological markers have been analyzed in VSCC, mainly immunohistochemically (IHC). However, results were ambiguous or even contradictory and not valuable for clinical practice. Especially the molecular landscape underlying VSCC development remains largely unknown. Currently, at least two types of VSCC, an HPV dependent and an HPV independent, should be seen as different entities. In head and neck cancers, which show a similar biological behavior like VSCC, HPV-related disease has been demonstrated to have a much more favorable prognosis. However, until recently, no consistent data with regard to an improved prognosis for patients with HPV-dependent VSCC were available.

Human papillomavirus-independent vulvar carcinoma is correlated with a significantly worse prognosis

HPV-independent VSCC is often linked to lichen sclerosus, harboring TP53 mutations, whereas HPV-dependent tumors mostly overexpress p16 as a surrogate marker for HPV-induced malignant transformation [4▪,18]. In total, 648 tumor samples were analyzed in a translational subproject of the AGO-CaRE-1 study [4▪]. p16 IHC was positive in 30.2%. HPV DNA was detected in 74.8% of the p16+/p53– tumors, with HPV 16 being the most common subtype (85.1%). p53 IHC was positive in 31.3%. Interestingly, in a large third (sub)group, neither p16 nor p53 overexpression could be detected. Patients with p16+ tumors were generally younger at diagnosis (63 vs. 70 years for p16– tumors) and showed lower rates of lymph-node involvement (29.0 vs. 39.7%) as well as fewer recurrences. In the survival analysis, the p16+ subgroup demonstrated a significantly improved prognosis in comparison to p53+ tumors: 2-year DFS was 65.5 vs. 47.0% (P < 0.001), also, 2-year OS was significantly improved with 82.7 vs. 70.4% (P = 0.003). In a considerably smaller, recently published retrospective single center analysis of 114 VSCC, HPV-independent VSCC determined by PCR and p16 IHC was likewise associated with a significantly worse prognosis [19]. The questions of discrepancies between p16 IHC positivity and HPV detection via PCR as well as lack of p53 IHC detection because of potential knockout mutations remain unclear at this point. However, these data [10▪] show a clear positive prognostic impact of HPV in VSCC. In a first step, p16/p53 IHC as a widely recognized marker could be performed in each VSCC specimen. Even though p53/p16 IHC might not yet guide treatment decisions, follow-up, for example, should be more stringent in p53-positive disease.

The evolving molecular landscape of vulvar cancer

Most interestingly, the AGO-CaRE-1 translational data also suggest a potential third subtype in VSCC that has not routinely been described. The third subgroup (p16–/p53– in IHC) displayed an intermediate prognosis with a 2-year DFS of 53% and 2-year OS of 72.6%. So far, very few studies have looked at underlying genetic alterations in VSCC (Table 1). Merely one small targeted next-generation sequencing analysis by Nooij et al.[20] of 17 genes in 36 VSCCs has described a p16–/p53– subgroup before and demonstrated a high number of NOTCH1 and HRAS mutations in this VSCC cohort. TP53 mutations were identified in 68% of HPV-negative VSCC and only 28.6% (two of seven) of HPV-positive cases (HPV dependency determined with PCR).

Table 1
Table 1:
Overview of next-generation sequencing analysis in vulvar cancer

Other, most recently published relevant publications on this topic also show a high frequency of TP53 mutations [21▪▪,22▪,23], mostly in HPV-negative disease. The mutational frequency of other oncosupressor and tumorsupressor genes was variable (Table 1) between the different analyses. Although data are relatively consistent in reporting on two etiological pathways with HPV+/TP53 wt and HPV–/TP53+ VSCC, a mutational pattern other than this is difficult to extract. Except for one study, all groups have been using panel analysis of the most known tumor driver genes and only one has analyzed normal corresponding DNA as a control. Furthermore, the definition of HPV-dependent disease is questionable when based on PCR only, as the pure detection of HPV DNA is not synonymic with HPV drivenness of the tumor. Consequently, the cohorts might not be comparable between the different studies. Large-scale genomic analyses as they have been performed for various types of human cancers by the Cancer Genome Atlas (TCGA) are missing in VSCC and would be most desirable to identify major driver-gene mutations and potential therapeutic strategies.

THERAPY IN ADVANCED DISEASE

Given the current small study populations and variation of inclusion criteria, determination of the best therapy regimen is difficult [24]. Consequently, no improvement in survival could be achieved in the last two decades for locally advanced, recurrent or metastatic disease where systemic therapy is required. However, with the increasing knowledge of tumor biology and genetic alterations, VSCC patients have the opportunity for inclusion in ‘basket-trials’. This has led to at least some data with regard to immunoncology in VSCC.

Immunoncology in vulvar cancer

Most recently, the PD-1 inhibitor pembrolizumab has been approved for treatment of two HPV-induced cancers. In June 2018, the U.S. Food and Drug Administration (FDA) announced approval for patients with recurrent or metastatic cervical cancer with progression during or after firstline chemotherapy and PD-L1 expression [combined positivity score (CPS) ≥1] [25]. In head and neck cancer, FDA approval of pembrolizumab has been granted for first-line therapy of metastatic disease based on the results of the phase III KEYNOTE-048 trial [26]. Approval was obtained as a single agent for tumors that express PD-L1 (CPS≥1), and in combination with chemotherapy irrespective of PD-L1 expression. As VSCC shares distinct molecular pathologic features with cervical and head and neck cancers, the same treatment regimens could prove effective for VSCC.

In VSCC, PD-L1 expression has been described in 20–72% of primary tumors [27,28▪,29▪]. In a series from 55 VSCCs, PD-L1 expression was correlated with low tumor stage, but no association with other clinicopathological parameters was observed [29▪]. However, in a previous series, high PD-L1 expression (defined as ≥5% of PD-L1 stained cells) was associated with HPV-negativity and impaired prognosis in 103 VSCCs. In that analysis, PD-L1 expression triplicated the risk of relapse (recurrence-free survival hazard ratio: 3.029, CI 1.228–8.471, P = 0.0018) [30]. As a substantial subgroup of VSCC expresses PD-L1, immune checkpoint-inhibition constitutes a rational for future trials. In a ‘basket trial’ (KEYNOTE-028), PD-L1 expression, as well as T-cell inflamed gene-expression and tumor mutational burden in patients treated with pembrolizumab, was analyzed [31▪▪]. Eighteen patients with VSCC were among the overall cohort of 471 patients. In this phase Ib trial, patients with PD-L1-positive advanced solid tumors received pembrolizumab 10 mg/kg q2w. The primary end point was objective response rate by RECIST v1.1 (investigator review) that ranged from 0% in pancreatic cancer to 33% in small cell lung cancer. For the group of VSCC patients, the overall response rate was rather disappointing with 6% and a median progression free survival of 3.1 months – corresponding with the shortest median OS of 3.8 months within the total cohort.

CONCLUSION

Research has been focussing on deciphering the molecular mechanisms of carcinogenesis in VSCC. Increasing knowledge has not yet changed clinical decision making. In line with many other entities, clinical research has concentrated on deescalating surgical treatment in VSCC. Regarding the primary tumor, this has led to the abandonning of wide safety margins. Results from the GROINSS-V-II trial on radiation vs. inguino-femoral LNE in N+ disease are still pending but are expected to be a milestone concerning deescalation of groin surgery. Checkpoint inhibition as monotherapy or in combination with other agents might be one strategy to improve outcome in advanced disease. To offer new targeted agents to VSCC patients, academic organizations as well as pharmaceutical companies must take on responsibilty.

Acknowledgements

None.

Financial support and sponsorship

L.W. has received grants from medac oncology for the AGO CaRE-1 study and its translational subproject without restriction in the study protocols or analyses.

Conflicts of interest

L.W., K.P. and A.J. declare no conflicts of interest concerning this article.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

REFERENCES

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2. Springer Medizin, Buttmann-Schweiger N, Barinoff J, Waldmann A, et al. Epidemiology of Vulvar and Vaginal Cancer in Germany. 2019; Der Onkologe. 25. 10.1007/s00761-019-0565-6.
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This cancer registry study describes the increased risk of renal transplant recipients for HPV-dependent (pre)cancerous lesions of the anogenital region.

4▪. Woelber LL, Prieske K, Eulenburg C, et al. p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: a TMA based study by the AGO-CaRE-translational study group. J Clin Oncol 2019; 37: (15_suppl): 5592–5602.

This is the largest retrospective analysis on p53/p16 expression and HPV status in VSCC to report on a statistically significant improved DFS and OS of p16+/p53– tumors.

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This retrospective case series describes the excellent prognosis of FIGO IA VSCC.

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No cut off for an increased risk of local recurrence after VSCC can be shown for a margin of 3, 5 or 8 mm. Local recurrence in general is high (43%) within 10 years after the treatment.

11. Grootenhuis te NC, van der Zee AGJ, van Doorn HC, et al. Sentinel nodes in vulvar cancer: long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I. Gynecol Oncol 2016; 140:8–14.
12▪. Woelber L, Eulenburg C, Kosse J, et al. Predicting the course of disease in recurrent vulvar cancer: a subset analysis of the AGO-CaRE-1 study. Gynecol Oncol 2019; 154:571–576.

In this large subgroup analysis of the CaRE-1 study, N+ patients had a higher risk for isolated vulvar recurrence. Patients with isolated local recurrence have a decreased DFS and OS.

13. Klapdor R, Hillemanns P, Woelber LL, et al. The influence of obesity on tumor recurrence in vulvar cancer patients. J Clin Oncol 2019; 37: (15_suppl): e17130–e17140.
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17▪▪. Nica A, Covens A, Vicus D, et al. Sentinel lymph nodes in vulvar cancer: management dilemmas in patients with positive nodes and larger tumors. Gynecol Oncol 2019; 152:94–100.

This study reports on seven patients with micrometastasis to the groin who were treated by radiotherapy only. No recurrences occurred in the irradiated groins. This observation supports to omit full groin dissection for micrometastatic disease in the sentinel.

18. Chen AS, Karnezis AN, Jordan S, et al. p16 immunostaining allows for accurate subclassification of vulvar squamous cell carcinoma into HPV-associated and HPV-independent cases. Int J Gynecol Pathol 2016; 35:385–393.
19. Allo G, Yap ML, Cuartero J, et al. HPV-independent vulvar squamous cell carcinoma is associated with significantly worse prognosis compared With HPV-associated tumors. Int J Gynecol Pathol 2019; doi: 10.1097/PGP.0000000000000620. [Epub ahead of print].
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21▪▪. Zięba S, Kowalik A, Zalewski K, et al. Somatic mutation profiling of vulvar cancer: exploring therapeutic targets. Gynecol Oncol 2018; 150:552–561.

In an next generation sequencing panel analysis of 81 VSCC tumors, TP53 and CDKN2A mutations were identified as the most common genetic alterations. The study highlights the activation of the PI3K/AKT/mTOR pathway in vulvar cancer.

22▪. Han M-R, Shin S, Park H-C, et al. Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva. Exp Mol Med 2018; 50:e442–e452.

First whole-exome sequencing analysis of 15 VSCC and paired normal tissue.

23. Weberpals JI, Lo B, Duciaume MM, et al. Vulvar squamous cell carcinoma (VSCC) as two diseases: HPV status identifies distinct mutational profiles including oncogenic fibroblast growth factor receptor 3. Clin Cancer Res 2017; 23:4501–4510.
24. Amant F, Nooij L, Annibali D, et al. Brief report on 3-weekly paclitaxel carboplatin efficacy in locally advanced or metastatic squamous vulvar cancer. Gynecol Obstet Invest 2018; 83:620–626.
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26. Rischin D, Harrington KJ, Greil R, et al. Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). J Clin Oncol 2019; 37: (15_suppl): 6000.
27. Chinn Z, Stoler MH, Mills AM. PD-L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy. Histopathology 2019; 74:256–268.
28▪. Thangarajah F, Morgenstern B, Pahmeyer C, et al. Clinical impact of PD-L1 and PD-1 expression in squamous cell cancer of the vulva. J Cancer Res Clin Oncol 2019; 145:1651–1660.

This study reports on a high PD-L1 expression in tumor and tumor-associated immune cells of VSCC patients and therefore indicates a rationale for a clinical trial on immune checkpoint inhibition in vulvar cancer.

29▪. Choschzick M, Gut A, Fink D. PD-L1 receptor expression in vulvar carcinomas is HPV-independent. Virchows Arch 2018; 473:513–516.

In this immunohistochemical analysis, PD-L1 overexpression is detected in VSCC independent of HPV status and suggested as therapeutic target.

30. Hecking T, Thiesler T, Schiller C, et al. Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with nonviral etiology. Oncotarget 2017; 8:92890–92903.
31▪▪. Ott PA, Bang Y-J, Piha-Paul SA, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol 2019; 37:318–327.

In this phase IB clinical trial with pembrolizumab in advanced solid tumors, patients with VSCC showed limited treatment response.

Keywords:

human papillomavirus; immunotherapy; TP53; vulvar squamous cell cancer; vulvar cancer

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