Abnormal vaginal bleeding in women with gynaecological malignancies

Abnormal vaginal bleeding is a common gynaecological symptom, and most causes are benign. International Federation of Gynaecology and Obstetrics proposed a PALM-COEIN classification in 2011 to decrease heterogeneity in studies. The gynaecological malignancies that present with abnormal bleeding vary according to the age of the patient and the origin (upper versus lower genital tract). It is important that a thorough history and examination is performed to make this distinction. The common malignancies presenting symptoms and treatment are discussed in this article according to the age of the patient. There is a considerable overlap between the reproductive age and menopause. This article focuses on children, adolescents and women in the reproductive age group.

Introduction

Almost a third of women will experience abnormal vaginal bleeding in their lifetime, and in many cases, the cause will be benign. However, abnormal vaginal bleeding is an important symptom of a possible underlying gynaecological malignancy and should always be investigated until a clear diagnosis can be made. With perimenarchal and perimenopausal bleeding, it can be particularly difficult to separate physiological disturbances related to the hypothalamic-pituitary-ovarian (HPO) axis from pathological causes. Many terminologies have been used to describe abnormal bleeding leading to confusion, excess heterogeneity of studies and making interventions difficult to compare. As a result, the PALM-COEIN system of classifying abnormal bleeding (see Table 1 ) was proposed by FIGO (International Federation of Gynaecology and Obstetrics) in 2011 .

Table 1
PALM-COEIN Classification Nomenclature.
• P Polyps
• A Adenomyosis
• L Leiomyoma
• M Malignant and premalignant
• C Coagulopathies
• O Ovarian dysfunction
• E Endometrial dysfunction
• I Iatrogenic
• N Not otherwise classified

This article specifically aims to review causes and management of abnormal vaginal bleeding in women presenting with a gynaecological malignancy. An anatomical approach is often used, but it is sometimes useful to consider bleeding according to the age and reproductive period of women as there are considerable differences.

Bleeding in children and adolescents

Bleeding in children should always be considered to be clinically important. Common causes of bleeding in children include infections (vulvovaginitis), foreign bodies, trauma (whether accidental or physical and sexual abuse) as well as bleeding secondary to a urethral prolapse. Malignancies of the genital tract in children are rare. These include bleeding secondary to vaginal or cervical sarcomas, malignant germ cell ovarian tumours as well as malignant sex cord stromal ovarian tumours.

Paediatric cancers represent approximately 1% of all new cancers in the United States of America (US) . Some of the cancers that occur in children are rarely seen in adults, as those cancers originate from developing tissues (embryonal cells) and organs. The American Cancer Society reported that the cancers that are most common in children (ages 0-14) in the US are acute lymphocytic leukaemia (26%), brain and CNS (21%), neuroblastoma (7%) and non-Hodgkin’s lymphoma (8%) .

It is recommended that children be treated in specialized units well versed in treating paediatric cancers. This ensures a multidisciplinary team, as well as specific treatment protocols for specific kinds of cancers based on large numbers of patients.

Adolescents

The most common cancers among adolescents (ages 15-19) in the US are Hodgkins’s lymphoma (15%), thyroid cancer (11%), brain and CNS (10%) and testicular germ cell tumours (8%) .

There are significant inequities in care between developed and developing countries. In 2008, the United Nations reported that the worldwide population of young people aged 10-24 years of age was more than 1.8 billion. This represents 27% of the population . A systematic analysis in this age group specifically used the DALY (disability adjusted life years) to assess the burden of disease, where one DALY represents the loss of the equivalent of 1 year of full health. This analysis found that the total number of DALYs for young people aged 10-24 years of age was about 236 million. This represented 15.5% of the total DALY burden for all age groups, but more importantly to note was the fact that 93% of these DALYs were in low- and middle-income countries and more than 50% of these were in Africa . Similarly, it is also estimated that 175,000 cases of cancer in children less than 15 years of age are diagnosed annually worldwide, and less than 40% of patients are from high-income countries where they could receive adequate diagnosis and treatment . In a less-developed country, not only is a child’s probability of surviving cancer poorer, but they may also not have access to palliative care when required, and thus, they may experience extreme discomfort in this setting.

Bleeding in children and adolescents

Bleeding in children should always be considered to be clinically important. Common causes of bleeding in children include infections (vulvovaginitis), foreign bodies, trauma (whether accidental or physical and sexual abuse) as well as bleeding secondary to a urethral prolapse. Malignancies of the genital tract in children are rare. These include bleeding secondary to vaginal or cervical sarcomas, malignant germ cell ovarian tumours as well as malignant sex cord stromal ovarian tumours.

Paediatric cancers represent approximately 1% of all new cancers in the United States of America (US) . Some of the cancers that occur in children are rarely seen in adults, as those cancers originate from developing tissues (embryonal cells) and organs. The American Cancer Society reported that the cancers that are most common in children (ages 0-14) in the US are acute lymphocytic leukaemia (26%), brain and CNS (21%), neuroblastoma (7%) and non-Hodgkin’s lymphoma (8%) .

It is recommended that children be treated in specialized units well versed in treating paediatric cancers. This ensures a multidisciplinary team, as well as specific treatment protocols for specific kinds of cancers based on large numbers of patients.

Adolescents

The most common cancers among adolescents (ages 15-19) in the US are Hodgkins’s lymphoma (15%), thyroid cancer (11%), brain and CNS (10%) and testicular germ cell tumours (8%) .

There are significant inequities in care between developed and developing countries. In 2008, the United Nations reported that the worldwide population of young people aged 10-24 years of age was more than 1.8 billion. This represents 27% of the population . A systematic analysis in this age group specifically used the DALY (disability adjusted life years) to assess the burden of disease, where one DALY represents the loss of the equivalent of 1 year of full health. This analysis found that the total number of DALYs for young people aged 10-24 years of age was about 236 million. This represented 15.5% of the total DALY burden for all age groups, but more importantly to note was the fact that 93% of these DALYs were in low- and middle-income countries and more than 50% of these were in Africa . Similarly, it is also estimated that 175,000 cases of cancer in children less than 15 years of age are diagnosed annually worldwide, and less than 40% of patients are from high-income countries where they could receive adequate diagnosis and treatment . In a less-developed country, not only is a child’s probability of surviving cancer poorer, but they may also not have access to palliative care when required, and thus, they may experience extreme discomfort in this setting.

Malignant tumours of the lower genital tract

These are rare tumours and include rhabdomyosarcomas, germ cell tumours and clear cell adenocarcinoma.

  • Rhabdomysarcoma

Incidence

Rhabdomysarcomas are the most common soft tissue cancers in children and adolescents accounting for 4-6% of all malignancies in this age group . Sarcoma Botyroides occurs from infancy to early childhood (mean of 3 years), whereas cervical rhabdomyosarcomas peak in the second decade. Twenty percent of these occur in the lower genital tract with more than 50% being of the embryonal histological subtype .

The Intergroup Rhabdomyosarcoma Study Group (IRSG classified rhabdomyosarcomas into three histological subtypes):

  • Embryonal (commonest accounting for 58% of cases): these comprise the classic botyroides and the spindle cell variants

  • Alveolar

  • Undifferentiated subtypes

The alveolar and undifferentiated subtypes are the rarest and most aggressive with the poorest prognosis . The rarity of these tumours means that most information is based on case reports and short series. A report by Fernandez-Pineda et al. described their findings over a 30-year period (between 1970 and 2009). During this time, their solid tumour database at St Jude’s Children’s Research Hospital included 4485 paediatric cancers, of which only 18 patients were diagnosed with vaginal tumours and 13 of these 18 were diagnosed with rhabdomyosarcomas . Most rhabdomyosarcomas in children are in the vagina, and adolescents have predominantly cervical lesions.

Clinical presentation

Rhabdomyosarcoma of the lower genital tract is a rare tumour and the patients usually present with vaginal bleeding. Sarcoma botyroides often presents in the first few years of life with bleeding and nodular lesions filling and possibly protruding from the vagina (grape-like). In more advanced stages of disease, patients may present with abdominal pain, an abdominal mass or symptoms of distant metastases.

Treatment options

Treatment is based on the collection of case reports and case series due to the rarity of the tumour. There are no randomised control trials or evidence to suggest an optimum treatment. Previously, extensive radical surgery was the standard of care. There have been case series that suggest that in favourable cases, wide local excision and chemotherapy may prolong survival with good quality of life. Alternatively, neoadjuvant chemotherapy may be used primarily and followed by surgical resection. Unfavourable factors such as large size of the lesion, cervix as the primary site and extent of disease are associated with poor survival. In such cases, radical surgery (such as hysterectomy and exenteration) and/or chemotherapy is advocated . Radiotherapy treatment may have severe long-term side effects and should be avoided if possible. It is recommended that children and adolescents be referred to specialised units who have a multidisciplinary team and the necessary experience in treating this complex disease.

  • Clear cell adenocarcinoma

Incidence

This is even rarer than rhabdomyosarcomas. Historically, it is linked to intra-uterine diethylstilbestrol (DES) exposure, but clear cell carcinomas of the vagina and cervix can occur without exposure to DES.

Clinical presentation

The most common symptom at presentation is vaginal bleeding. It is very unusual for girls to present prior to adolescence, and age of presentation has varied from 7 to 34 years of age .

Treatment

Treatment depends on the stage of disease. Surgical resection and lymph node dissection play an important role in the treatment of this tumour in the early stage of disease. There are limited data on the role of neoadjuvant chemotherapy . Advanced disease has a poor prognosis, and expert palliative care is most likely the only intervention possible.

  • Germ cell tumour of vagina

Incidence

Malignant germ cell tumours of the vagina as the primary location are exceptionally rare (3-8% of all malignant germ cell tumours of the genital tract). The most common histological subtype is endodermal sinus tumour, and alpha-feto protein is a reliable tumour marker which assists with diagnosis, response assessment and remission .

Clinical presentation

Vaginal bleeding is the most common presentation, and this occurs usually in young girls (less than 3 years of age). Similarly to ovarian germ cell tumours, alpha-feto protein is a reliable tumour marker for diagnosis, response to treatment and regression.

Treatment

Mainstay of treatment is chemotherapy, but surgery may be possible in the early stage of disease that is confined to the vaginal epithelium.

Malignant Ovarian Germ Cell Tumours

Incidence

Ovarian germ cell tumours are the most common histological subtype in this age group (9–20 years), although the majority are benign. Malignant germ cell tumours only comprise 2-3% of all ovarian malignancies . The highest incidence is in the 15-19-year-old age group, but the range can vary from about 6 years of age to age 60 .

Clinical presentation

Clinical presentation may vary, but the presence of a large mass and a young patient should raise suspicion of a potential germ cell tumour. Adolescent girls most often present with an enlarging mass. This may be accompanied by amenorrhoea followed by irregular vaginal bleeding. The presence of a mass and amenorrhoea may mimic a pregnancy, but this is due to stromal hyperthecosis of the ovary which later results in anovulatory bleeding. Additional contributory may be the elevation in βHCG, which may occur with certain germ cell tumours. Vaginal bleeding is reported to be a presenting symptom in about 10% of cases, whereas 85% of adolescents present with a mass . Other rarer symptoms include abdominal distension with ascites, fever and symptoms secondary to a cyst accident such as rupture, torsion and haemorrhage (see Table 2 ).

Table 2
WHO Classification of Germ Cell Ovarian tumours (simplified).
  • Dysgerminoma

  • Endodermal sinus tumour

  • Embryonal carcinoma

  • Polyembroma

  • Choriocarcinoma

  • Teratoma

    • Immature

    • Mature

    • Monodermal (struma ovarii, carcinoid)

  • Mixed forms

  • Gonadoblastoma

Treatment options

Surgery is the recommended treatment initially as this is required to make a histological diagnosis, and it is a necessary part of staging as well as treatment. Surgery has traditionally been done via a laparotomy. Because of a paucity of data on laparoscopy in these cases, as well as the rarity of these malignant tumours, laparoscopic surgery cannot currently be recommended as the standard of care. It may be feasible only if the tumour can be removed completely without spillage, and if adequate staging can be performed.

An emphasis on fertility-sparing surgery should be placed in this age group (women below the age of 40 years). This would include removal of the ovarian tumour, washes, infracolic omental biopsy or omentectomy and biopsy of suspicious implants and enlarged nodes. If both ovaries are involved, an effort should be made to preserve the smaller ovary and biopsy or ovarian cystectomy may be more prudent. This is predominantly oncologically safe as malignant germ cell tumours are exceptionally chemosensitive with good survival after long-term follow-up . The uterus can be preserved as it is usually not involved, and this allows for the possibility of donor eggs and assisted reproduction if the patient can afford this at a later stage .

Chemotherapy treatment is based on the successes derived from the management of testicular cancers. The standard of care for patients with malignant ovarian germ cell tumours, when chemotherapy is recommended, is Bleomycin, Etoposide and Platinum (BEP). Patients with stage 1 dysgerminoma and stage 1A grade 1 immature teratoma can be managed with follow-up only. All other malignant ovarian germ cell tumours require three or four cycles of adjuvant BEP .

A small percentage of women will have persistent disease/progress during treatment or recur after treatment. Historically it is not routine to do imaging on follow-up, but patients at high risk of recurrence may benefit from periodic abdomino-pelvic imaging. Usually follow-up should include assessing for any new symptoms through physical and pelvic examination and relevant tumour markers periodically.

It is advisable to offer surgery for any resectable disease, if it is an isolated recurrence. This is because women who recur after primary chemotherapy do not have as favourable a prognosis as men . If surgery is not feasible, chemotherapy is offered. The agent/s used depends on whether the individual is categorised as platinum sensitive or insensitive.

Sex cord stromal ovarian malignancies

Incidence

Sex cord stromal tumours can occur in any age group; however, this histological subtype is more common in adults. It accounts for approximately 3-5% of ovarian malignancies . Sex cord stromal tumours may contain granulosa cells, thecal cells or Sertoli cells, and these tumours are usually hormonally active. Granulosa cell tumours generally secrete oestrogen, and Sertoli Leydig tumours generally secrete androgens.

Granulosa cell tumours (GCT), although rare, make up 70% of all malignant sex cord stromal tumours. GCT are subdivided into two types: the juvenile type (JGCT- 5% of cases) and the adult type (AGCT- 95% of cases) . The classification of the two histological subtypes is not based on age alone, but rather also on distinct histological features, as well as clinical behaviour. The majority of AGCT occur in postmenopausal women and less than 1% occurs in prepubescent girls, whereas 90% of JGCT occur in women below the 30 years of age and more than half of JGCT occurs in girls less than 10 years of age .

Clinical presentation

Prepubescent girls may present with isosexual precocious puberty. This includes bilateral breast development, irregular vaginal bleeding and secondary sexual characteristics (premature pubic and axillary hair development as well as skeletal growth). In addition, they may complain of abdominal pain and abdominal distension.

After puberty, there may be complaints of an irregular menstrual cycle, as well as abdominal pain, distension and a palpable mass.

GCT are exceptionally vascular tumours and may present with intra-abdominal rupture and haemorrhage. In the younger patient, this may resemble the clinical picture of a ruptured ectopic pregnancy .

It is important to note the clinical and pathological differences between JGCT and AGCT:

Histologically: JGCT have nodular/diffuse cellular growth with basophilic fluid in the lumens, round nucleoli without grooves and a high mitotic activity. This is in contrast to AGCT which has grooved nuclei.

Clinically: JGCT is rare, usually in the young patient, associated with precocious puberty and a good prognosis in comparison to AGCT, which is more common than JGCT and associated with hyperoestrogenism with the risk of endometrial hyperplasia and uterine cancer. There is also usually a high tumour mass .

Treatment options

Surgery is the standard of care for diagnosis and staging of GCT. In the prepubescent and adolescent patient, conservative surgery is acceptable as 70% of women will have stage 1 disease . This includes a unilateral salpingo-oophorectomy, infracolic omentectomy and biopsies of any suspicious or abnormal nodes. There is no evidence for routine systematic lymph node dissection .

Adjuvant chemotherapy is not required for the early stage disease. Some may suggest chemotherapy only for stage 1C disease with a high mitotic index or poorly differentiated cells . It is important to note the indolent course of malignant sex cord stromal tumours, and it is prudent to consider long-term follow-up as they may recur years later.

If there is a recurrence, it is important to identify whether the recurrence is isolated or disseminated. Isolated recurrences should be treated with aggressive surgery followed by radiation or chemotherapy as this has been shown to improve progression-free survival (PFS) . Disseminated disease requires chemotherapy, although response is limited. Hormonal treatment can also be offered for recurrent disease, although there are no randomised controlled trials. Smaller observational trials using progestogens and tamoxifen have shown some improvement in PFS .

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Nov 5, 2017 | Posted by in OBSTETRICS | Comments Off on Abnormal vaginal bleeding in women with gynaecological malignancies

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