Treatment and Prevention Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
Management of Human Papillomavirus-Related Gynecological Malignancies Viola A. Heinzelmann-Schwarz a · André B. Kind b · Francis Jacob c
a Gynecological
b Dysplasia
Cancer Center, Clinic and Hospital, University of Basel, Basel, Switzerland
c Gynecological
Cancer Group, Women’s University
Abstract Human papillomavirus (HPV) infections affect women in every age group and in various benign, premalignant as well as malignant gynecological conditions. As a benign condition, condylomata acuminata of the whole female genital tract can be observed, transmitted by low risk HPV types 6 and 11, whilst dysplastic changes of the vulva appear as vulvar intraepithelial neoplasia, of the vagina as vaginal intraepithelial neoplasia and of the cervix as cervical intraepithelial neoplasia, and are caused by high risk HPV types most notably 16 and 18. These dysplastic changes give rise to precursor lesions of vulvar and cervical cancer, both driven via immune regression and potentially hormonal changes by promoting the malignant transformation profile of HPV subtypes. Attributes which can support this process are smoking, immunodeficiency, vitamin deficiency, stress, vaginal infections and hormonal influence. The causal relationship between persistent infection with high-risk HPV genotypes and vulvar and cervical cancer has been clearly demonstrated and is stronger than the relationship observed between smoking and lung cancer. New global cancer prevention can be envisaged by implementing vaccination against HPV in young women, with 2 vaccines currently approved by the Food and Drug Administration: the quadrivalent Gardasil (HPV-6, -11, -16, -18) and the bivalent Cervarix (HPV-16, -18).
Vulva cancer is a rare gynecological cancer, representing about 4% of gynecological malignancies. As a precursor lesion, vulvar intraepithelial neoplasia (VIN) has long been divided into VIN grades 1, 2 and 3 with the concept that all three represent lesions which can be identified easily with a low interobserver variability and linear progression. Since the International Society for the Study of Vulvovaginal Disease (ISSVD) classifications of 2004, VIN has now been divided into (a) the classical VIN, representing the former types VIN2, VIN3 and the basaloid, condylomatous or mixed type (fig. 1a) as well as (2) the differentiated VIN, representing the simple type (fig. 1b).
Downloaded by: Univ. of California San Diego 198.143.33.65 - 9/1/2015 6:11:45 AM
© 2014 S. Karger AG, Basel
a
b
c
d
e
f
Classical VIN is more common (90%), affects younger patients (30–50 years), is human papillomavirus (HPV) related, expresses p14/p16 and Ki-67 and is flat or polypoid with large numbers of koilocytes and a complex deterioration of the histological architecture [1]. In contrast, differentiated VIN is more commonly found in the older patient, is probably lichen sclerosus and lichen planus related and p53 driven, showing basal atypia, a large cytoplasm and broadened epithelium [2]. In contrast to classical VIN differentiated VIN is not HPV associated. Whilst HPV typing is not advisable in high-grade lesions and cancers, its positivity, particularly of high-risk types 16 and 18, can help in the risk assessment and differential diagnosis. No screening program for VIN has been established so far, therefore it remains for the gynecologist, during the routine yearly checkup, to ask about symptoms like pruritus and burning, but patients are frequently asymptomatic. The appearance of VIN is heterogenous. White, red, hyperpigmented, erosive, flat or warty like lesions may be seen while carefully inspecting the vulva, introitus perineum and perianal region. There is no benefit of applying acetic acid during a routine visit; however, if changes seem to be present, the patient needs to be referred to a specialized dysplasia clinic. In such an expert clinic, any skin irritation on the vulva should be examined carefully, particularly with vulvoscopic assessment using a colposcope. Any acetowhite area needs to be examined histologically by taking a properly sized punch biopsy under local anesthesia at the outer border of the lesion. Infec-
HPV-Related Gynecological Cancers Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
217
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Fig. 1. a Classical VIN3. b Differentiated VIN3. c Recurrent squamous cell cancer of the vulva at 7 o’clock on the basis of extensive lichen sclerosus with preoperative vulva mapping biopsies. d CIN3 acetowhite area at 6 o’clock. e CIN3 in the same patient using Lugol’s solution. f Squamous cell cancer of the cervix.
218
Heinzelmann-Schwarz · Kind · Jacob Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
Downloaded by: Univ. of California San Diego 198.143.33.65 - 9/1/2015 6:11:45 AM
tions and various other skin conditions and disease need to be considered in the differential diagnosis. The aim of introducing the ISSVD 2004 classification was to represent the clinical relevance of the truly important VIN. This is due to fact that there has been too much interobserver discrepancy, and the direct clinical relevance of VIN1 is not completely understood. From US data an increase of 400% in VIN has been described in women 50 years [3]. Similar observations have been made in large cohort studies from Norway, New Zealand, Italy and Austria with an increase in VIN by 300–400% in the last 10–20 years. Nevertheless, the incidence of vulvar cancer is not rising to this extend, indicating that spontaneous regression in VIN as a premalignant lesion is rare, but progression to invasive vulvar cancer is not mandatory. Unfortunately, no progression marker is known at present [4]. Various therapeutic options can be envisaged in the case of VIN. Firstly, there are destructive techniques like laser evaporization, cryotherapy, photodynamic therapy and electrocauterization [5]; secondly, the classical surgical excision is a wide local excision with the formerly used vulvectomies now considered unnecessary and obsolete techniques. No significant differences in risk for recurrence in VIN3 have been found comparing laser evaporization with classical surgical techniques; however, 3.3% of occult cancers have been observed in the laser treatment group [4]. Independently of margins or treatment, 30% of patients will eventually have a recurrence. It is important that young patients be counseled by psycho-oncologists, particularly as they often show multifocal disease [6–8]. An interesting topical therapy for classical VIN has evolved in the form of the immune response stimulator 5% imiquimod (Aldara®, MEDA Pharma, Sweden). Since its license in 1997, it has been used efficaciously and safely for condylomata acuminata and has therefore been evaluated in the treatment of VIN3. In a systematic review of 162 patients, 51% showed complete remission, 25% partial remission and 16% recurrence after 32 months, following imiquimod treatment. We use imiquimod as first line treatment for classical VIN in our Dysplasia Clinic, successfully. Patient satisfaction is high and local side effects can be handled well with some experience. It has to be pointed out, that topical treatment with immune modulators is currently not registered for use in VIN and is considered an ‘offlabel use’ [9]. The use of the HPV vaccine, tested in 18,174 women, has shown 100% efficacy against VIN2/3 (classical VIN) in women who were HPV naïve at the time of immunization. In contrast, 79% efficacy was found in women with a subclinical HPV infection at the time of immunization [10]. Vulva cancer is predominantly squamous in origin (90%); the two main types can be divided into (a) cancer of the older woman (70–80 years) with a long-standing history of lichen sclerosus and (b) often multifocal cancer of the younger woman (45– 50 years) which is associated with HPV infection and/or immunodeficiency. Five-year survival is good (76%) when diagnosed at FIGO stage I, when the disease is located exclusively at the vulva. In order to diagnose the extent of the disease, mapping biopsies
HPV-Related Gynecological Cancers Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
219
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of the neighboring regions to the cancer need to be taken (fig. 1c). Similarly to other cancers, surgical aggressiveness has been continuously reduced from the days where radical vulvectomies with en bloc bilateral inguinofemoral lymphadenectomies were undertaken (butterfly incision, Stanley-Way) towards a radical local excision with separate small inguinofemoral lymphadenectomy sites or even only sentinel lymph node sampling. For localized lesions, this is as effective as radical techniques in preventing local recurrence [11]. In treating vulvar cancer, there is no standard operation; the emphasis is on performing the most conservative operation consistent with cure of the disease. In early stage disease, a deep margin at the inferior fascia of the urogenital diaphragm and lateral margins of at least 1 cm should be achieved, even if the resection of the distal urethra might be required [12]. Sentinel lymphadenectomy is not yet established due to high false-negative predictive values, particularly as positive inguinofemoral lymph nodes are the most important independent prognostic factor in vulvar cancer [13]. Up to 2 positive lymph nodes result in a 5-year overall survival rate of 80% and have a low local and systemic metastatic potential (2.9 vs. 3.8%, respectively). This changes dramatically from 3 lymph nodes u pwards, with a survival of only 12% and a high local and particularly far distant metastatic risk (33 vs. 66%, respectively) [14]. Risk factors for bilateral lymph node metastases are tumors of midline or anterior vulvar localization, multifocality and depth of invasion [15]. In advanced stage disease, it is advisable to determine the status of the groin nodes prior to planning the further management; if a frozen section of enlarged nodes is negative, a full groin dissection should be undertaken [12]. Whilst radiation therapy is commonly used in vulvar cancer, there is currently no role for chemotherapy treatment in this disease. Cervical cancer is the second most common cancer worldwide. It is the most common cause of death from cancer in women, particularly as 80% of new cases present in developing countries, mostly with advanced disease, eroding into the bladder, rectum, bone and pelvic nerves [16]. A causal relationship between persistent infections with high-risk HPV has been found, with a prevalence of 99.75% [17, 18]. Hereby, HPV-16 and -18 are responsible for 70% of cervical cancers. As most HPV infections are transient, being cleared or suppressed by cell-mediated immunity within several months to 2 years, the persistent high-risk HPV infection of the cervical epithelium appears to trigger neoplastic progression. Therefore, cervical cancer progresses slowly from preinvasive cervical intraepithelial neoplasia (CIN) to invasive cancer, with a time delay of approximately 10 years in immunocompetent women. The mean age at presentation is 51 years [19], with the clinical risk factors being young age at first coitus (
Management of Human Papillomavirus-Related Gynecological Malignancies Viola A. Heinzelmann-Schwarz a · André B. Kind b · Francis Jacob c
a Gynecological
b Dysplasia
Cancer Center, Clinic and Hospital, University of Basel, Basel, Switzerland
c Gynecological
Cancer Group, Women’s University
Abstract Human papillomavirus (HPV) infections affect women in every age group and in various benign, premalignant as well as malignant gynecological conditions. As a benign condition, condylomata acuminata of the whole female genital tract can be observed, transmitted by low risk HPV types 6 and 11, whilst dysplastic changes of the vulva appear as vulvar intraepithelial neoplasia, of the vagina as vaginal intraepithelial neoplasia and of the cervix as cervical intraepithelial neoplasia, and are caused by high risk HPV types most notably 16 and 18. These dysplastic changes give rise to precursor lesions of vulvar and cervical cancer, both driven via immune regression and potentially hormonal changes by promoting the malignant transformation profile of HPV subtypes. Attributes which can support this process are smoking, immunodeficiency, vitamin deficiency, stress, vaginal infections and hormonal influence. The causal relationship between persistent infection with high-risk HPV genotypes and vulvar and cervical cancer has been clearly demonstrated and is stronger than the relationship observed between smoking and lung cancer. New global cancer prevention can be envisaged by implementing vaccination against HPV in young women, with 2 vaccines currently approved by the Food and Drug Administration: the quadrivalent Gardasil (HPV-6, -11, -16, -18) and the bivalent Cervarix (HPV-16, -18).
Vulva cancer is a rare gynecological cancer, representing about 4% of gynecological malignancies. As a precursor lesion, vulvar intraepithelial neoplasia (VIN) has long been divided into VIN grades 1, 2 and 3 with the concept that all three represent lesions which can be identified easily with a low interobserver variability and linear progression. Since the International Society for the Study of Vulvovaginal Disease (ISSVD) classifications of 2004, VIN has now been divided into (a) the classical VIN, representing the former types VIN2, VIN3 and the basaloid, condylomatous or mixed type (fig. 1a) as well as (2) the differentiated VIN, representing the simple type (fig. 1b).
Downloaded by: Univ. of California San Diego 198.143.33.65 - 9/1/2015 6:11:45 AM
© 2014 S. Karger AG, Basel
a
b
c
d
e
f
Classical VIN is more common (90%), affects younger patients (30–50 years), is human papillomavirus (HPV) related, expresses p14/p16 and Ki-67 and is flat or polypoid with large numbers of koilocytes and a complex deterioration of the histological architecture [1]. In contrast, differentiated VIN is more commonly found in the older patient, is probably lichen sclerosus and lichen planus related and p53 driven, showing basal atypia, a large cytoplasm and broadened epithelium [2]. In contrast to classical VIN differentiated VIN is not HPV associated. Whilst HPV typing is not advisable in high-grade lesions and cancers, its positivity, particularly of high-risk types 16 and 18, can help in the risk assessment and differential diagnosis. No screening program for VIN has been established so far, therefore it remains for the gynecologist, during the routine yearly checkup, to ask about symptoms like pruritus and burning, but patients are frequently asymptomatic. The appearance of VIN is heterogenous. White, red, hyperpigmented, erosive, flat or warty like lesions may be seen while carefully inspecting the vulva, introitus perineum and perianal region. There is no benefit of applying acetic acid during a routine visit; however, if changes seem to be present, the patient needs to be referred to a specialized dysplasia clinic. In such an expert clinic, any skin irritation on the vulva should be examined carefully, particularly with vulvoscopic assessment using a colposcope. Any acetowhite area needs to be examined histologically by taking a properly sized punch biopsy under local anesthesia at the outer border of the lesion. Infec-
HPV-Related Gynecological Cancers Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
217
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Fig. 1. a Classical VIN3. b Differentiated VIN3. c Recurrent squamous cell cancer of the vulva at 7 o’clock on the basis of extensive lichen sclerosus with preoperative vulva mapping biopsies. d CIN3 acetowhite area at 6 o’clock. e CIN3 in the same patient using Lugol’s solution. f Squamous cell cancer of the cervix.
218
Heinzelmann-Schwarz · Kind · Jacob Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
Downloaded by: Univ. of California San Diego 198.143.33.65 - 9/1/2015 6:11:45 AM
tions and various other skin conditions and disease need to be considered in the differential diagnosis. The aim of introducing the ISSVD 2004 classification was to represent the clinical relevance of the truly important VIN. This is due to fact that there has been too much interobserver discrepancy, and the direct clinical relevance of VIN1 is not completely understood. From US data an increase of 400% in VIN has been described in women 50 years [3]. Similar observations have been made in large cohort studies from Norway, New Zealand, Italy and Austria with an increase in VIN by 300–400% in the last 10–20 years. Nevertheless, the incidence of vulvar cancer is not rising to this extend, indicating that spontaneous regression in VIN as a premalignant lesion is rare, but progression to invasive vulvar cancer is not mandatory. Unfortunately, no progression marker is known at present [4]. Various therapeutic options can be envisaged in the case of VIN. Firstly, there are destructive techniques like laser evaporization, cryotherapy, photodynamic therapy and electrocauterization [5]; secondly, the classical surgical excision is a wide local excision with the formerly used vulvectomies now considered unnecessary and obsolete techniques. No significant differences in risk for recurrence in VIN3 have been found comparing laser evaporization with classical surgical techniques; however, 3.3% of occult cancers have been observed in the laser treatment group [4]. Independently of margins or treatment, 30% of patients will eventually have a recurrence. It is important that young patients be counseled by psycho-oncologists, particularly as they often show multifocal disease [6–8]. An interesting topical therapy for classical VIN has evolved in the form of the immune response stimulator 5% imiquimod (Aldara®, MEDA Pharma, Sweden). Since its license in 1997, it has been used efficaciously and safely for condylomata acuminata and has therefore been evaluated in the treatment of VIN3. In a systematic review of 162 patients, 51% showed complete remission, 25% partial remission and 16% recurrence after 32 months, following imiquimod treatment. We use imiquimod as first line treatment for classical VIN in our Dysplasia Clinic, successfully. Patient satisfaction is high and local side effects can be handled well with some experience. It has to be pointed out, that topical treatment with immune modulators is currently not registered for use in VIN and is considered an ‘offlabel use’ [9]. The use of the HPV vaccine, tested in 18,174 women, has shown 100% efficacy against VIN2/3 (classical VIN) in women who were HPV naïve at the time of immunization. In contrast, 79% efficacy was found in women with a subclinical HPV infection at the time of immunization [10]. Vulva cancer is predominantly squamous in origin (90%); the two main types can be divided into (a) cancer of the older woman (70–80 years) with a long-standing history of lichen sclerosus and (b) often multifocal cancer of the younger woman (45– 50 years) which is associated with HPV infection and/or immunodeficiency. Five-year survival is good (76%) when diagnosed at FIGO stage I, when the disease is located exclusively at the vulva. In order to diagnose the extent of the disease, mapping biopsies
HPV-Related Gynecological Cancers Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 216–224 (DOI: 10.1159/000358408)
219
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of the neighboring regions to the cancer need to be taken (fig. 1c). Similarly to other cancers, surgical aggressiveness has been continuously reduced from the days where radical vulvectomies with en bloc bilateral inguinofemoral lymphadenectomies were undertaken (butterfly incision, Stanley-Way) towards a radical local excision with separate small inguinofemoral lymphadenectomy sites or even only sentinel lymph node sampling. For localized lesions, this is as effective as radical techniques in preventing local recurrence [11]. In treating vulvar cancer, there is no standard operation; the emphasis is on performing the most conservative operation consistent with cure of the disease. In early stage disease, a deep margin at the inferior fascia of the urogenital diaphragm and lateral margins of at least 1 cm should be achieved, even if the resection of the distal urethra might be required [12]. Sentinel lymphadenectomy is not yet established due to high false-negative predictive values, particularly as positive inguinofemoral lymph nodes are the most important independent prognostic factor in vulvar cancer [13]. Up to 2 positive lymph nodes result in a 5-year overall survival rate of 80% and have a low local and systemic metastatic potential (2.9 vs. 3.8%, respectively). This changes dramatically from 3 lymph nodes u pwards, with a survival of only 12% and a high local and particularly far distant metastatic risk (33 vs. 66%, respectively) [14]. Risk factors for bilateral lymph node metastases are tumors of midline or anterior vulvar localization, multifocality and depth of invasion [15]. In advanced stage disease, it is advisable to determine the status of the groin nodes prior to planning the further management; if a frozen section of enlarged nodes is negative, a full groin dissection should be undertaken [12]. Whilst radiation therapy is commonly used in vulvar cancer, there is currently no role for chemotherapy treatment in this disease. Cervical cancer is the second most common cancer worldwide. It is the most common cause of death from cancer in women, particularly as 80% of new cases present in developing countries, mostly with advanced disease, eroding into the bladder, rectum, bone and pelvic nerves [16]. A causal relationship between persistent infections with high-risk HPV has been found, with a prevalence of 99.75% [17, 18]. Hereby, HPV-16 and -18 are responsible for 70% of cervical cancers. As most HPV infections are transient, being cleared or suppressed by cell-mediated immunity within several months to 2 years, the persistent high-risk HPV infection of the cervical epithelium appears to trigger neoplastic progression. Therefore, cervical cancer progresses slowly from preinvasive cervical intraepithelial neoplasia (CIN) to invasive cancer, with a time delay of approximately 10 years in immunocompetent women. The mean age at presentation is 51 years [19], with the clinical risk factors being young age at first coitus (
