Germ cell tumours, trophoblastic tumours, and neoplasms of gonads

Classification according to ICCC : X.

Definition

Germ cell tumours involve a heterogeneous group of tumour with a wide range of histological types and biological behaviour – from benign to highly malignant. They derive from pluripotent germ cells, which keep their ability to differentiate into various cell types; therefore, germ cell tumours can consist of cells and tissues often very strange for their location.

Location:

Germ cell tumours are usually located in the midline of the body, from the head down to the sacrococcygeal region. Their location corresponds to the migration of germ cells during the embryonal development of an individual. Germ cell tumours are classified as:

  • gonadal:
    • ovaries
    • testes
  • extragonadal:
    • brain, neck
    • mediastinum
    • retroperitoneum
    • sacrococcygeal region

The representation of histological types and location is age-specific. Clinical behaviour of the tumour depends on:

  • age at the time of diagnosis
  • sex
  • primary location
  • histological type

All of the above-mentioned factors have age-specific cytogenetic and molecular aberrations. Germ cell tumours can produce the following tumour markers:

  • AFP
  • beta HCG
  • LDH

Epidemiology

Germ cell tumours are classified as rare cancers:

  • 3–5% of all malignancies in patients under the age of 15
  • 14% of all malignancies in patients above the age of 15

Incidence rate: 3.9 cases per 1 million children under the age of 15:

  • gonadal germ cell tumours: 1.5 cases per 1 milion children
  • extragonadal germ cell tumours: 2.4 cases per 1 milion children

Bimodal distribution:

  • first peak in children under the age of 3:
    • extragonadal (S-C)
  • second peak in teenagers:
    • gonadal
    • mediastinal

The following table sums up the classification of germ cell tumours:

  Children under the age of 1 Children under the age of 5 Adolescents
Location extragonadal, S-C extragonadal gonadal
Histological type teratomas yolk sac tumours mixed tumours
Sex predominance female female male
Clinical behaviour benign with a malignant potential malignant malignant

 

Clinical symptoms

  • Clinical symptoms depend on:
    • tumour location
    • patient’s age
    • biological properties (histological type of tumour)
  • palpable or visible tumour mass is usually the first symptom
  • overall symptoms (fever, weight loss, general weakness) are rare
  • tumours can be hormonally active:
    • virilism
    • signs of precocious pseudopuberty
    • gynaecomastia
  • other symptoms depend on the tumour location (bowel obstruction, obstipation, abdominal pain, dyspnoea, dry cough, potential spinal cord compression when the tumour is located in the retroperitoneum)

Aetiology

The aetiology of most germ cell tumours has not yet been reliably clarified.

Genetic syndromes

  1. Klinefelter’s syndrome (47 XXY)
  2. gonadal dysgenesis:
    • Swyer syndrome (46, XY)
    • Turner’s syndrome (45, XO)

Anatomical anomalies of the urogenital system

  1. cryptorchidism
  2. genitourinary anomalies:
    • hydrocele
    • inguinal hernia
    • hypospadias

No environmental risk factors are known in relation to the development of germ cell tumours.

Diagnosis

  • Medical history:
    • duration of symptoms
    • onset of menarche / development of secondary sex characteristics
  • Clinical examination:
    • it is essential to evaluate the secondary sex characteristics according to the Tanner scale
    • virilism, signs of precocious pseudopuberty
    • gynaecomastia in boys
  • Imaging examination :
    • ultrasound
    • CT/MRI scan
    • scintigraphy
  • Functional examination:
    • DTPA renal scan
    • cardiology
    • spirometry
  • Tumour markers:
    • AFP
    • beta HCG
    • Ca 12_5
    • LDH
  • Hormone profile:
    • both in girls and boys
  • Gynaecological/urological examination in cases of gonadal location
  • Genetic examination in ovarian tumours and suspected intersex:
    • SRY
    • karyotype

Differential diagnosis

  • In differential diagnosis, one must take into account:
    • tumour location
    • patient’s age and sex
  • Sacrococcygeal tumours (mostly in newborns and infants):
    • other type of tumour (neuroblastoma, sarcoma) must be ruled out
  • Ovarian tumours (in pubescent and adolescent girls):
    • congenital anomalies (polycystic ovary syndrome, endometriosis)
    • inflammation
    • ovarian torsion
    • other pelvic tumours (sarcomas)
    • pregnancy
  • Testicular tumours (young boys under the age of 5 and adolescents):
    • varicocele, hydrocele
    • orchitis (inflammation of a testis)
    • testicular torsion
    • paratesticular tumour (rhabdomyosarcoma)
    • other malignancies (infiltrations in leukaemia/lymphoma patients, Leydig cell tumours)
  • Retroperitoneal tumours (mostly in children under the age of 5):
    • benign tumours
    • congenital anomalies (extensive hydronephrosis)
    • other malignancies (neuroblastoma, sarcoma, less usually lymphoma)
  • Mediastinal tumours (mostly in adolescents):
    • other malignancies (Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, thymoma, sarcoma)
    • benign tumours (neurofibroma, ganglioneuroma, mature teratoma)
    • benign lymphadenopathy
  • CNS tumours (preschool-age children, school-age children):
    • other types of CNS tumours (craniopharyngioma)

Treatment

The treatment strategy is influenced by:

  • biological characteristics of the tumour
  • primary location
  • clinical stage at the time of diagnosis
  • patient’s age
  • levels and dynamics of tumour markers

According to the above-mentioned parameters, patients are classified into risk groups (low, moderate and high risk).

Surgical treatment

  • radical resection of the tumour as well as operative staging are very important
  • efforts to preserve fertility should be made in patients with gonadal tumours
  • delayed surgery (after preceding chemotherapy) might be indicated for patients with initially inoperable tumours or those at risk of mutilation

Chemotherapy

  • chemotherapy plays a key role in the treatment of germ cell tumours
  • according to the degree of risk, chemotherapy combined with BEP (bleomycin, etoposide and cisplatin) might be indicated: the so-called compressed-BEP for low-risk and moderate-risk patients, C-BEP for high-risk patients
  • high-dose chemotherapy with an autologous transplantation of haematopoietic stem cells is not a standard treatment method in paediatric patients, and is not indicated as the first-line treatment

Radiotherapy

  • apart from dysgerminoma, germ cell tumours are resistant to radiotherapy; however, chemotherapy is preferred even for dysgerminoma due to the late effects of radiotherapy
  • seminomas do not occur in paediatric patients; however, they can be part of mixed germ cell tumours
  • radiotherapy is not used any more in extracranial germ cell tumours

Recurrent tumours

Recurrent tumours are very rare (less than 10% of all germ cell tumours). With respect to effectiveness of the first-line treatment and the rareness of recurrent tumours, there are no guidelines in terms of treatment strategy, and a personalised approach must be applied.

Factors influencing the decision on further treatment:

  1. type of recurrence:
    • local/locoregional
    • distant metastases
  2. time to progression (TTP): early or late relapse
  3. type of first-line treatment
  4. type of tumour, primary location
  5. location of the recurrent tumour (possibility of surgical resection)

Treatment options:

  1. surgery (biopsy or radical resection)
  2. second-line chemoterapy: VIP, VeIP, ICE , TIC
  3. treatment as part of clinical trials
  4. palliative treatment

Prognosis

  • in general, germ cell tumours are curable
  • long-term survival:
    • more than 95% of patients survive a localised disease (97% of patients diagnosed at stage I, 95.7% of patients diagnosed at stage II)
    • about 80% of patients survive an advanced disease (90% of patients diagnosed at stage III, 85% of patients diagnosed at stage IV)
  • recurrent germ cell tumours (10–15% of cases) are curable as well (75–80 %)

Literature

  1. Bajčiová, V., Štěrba, J., Kadlecová, V.: Extrakraniální germinální nádory u dětí a adolescentů. Současné názory a léčebná strategie. Postgraduální medicína 2005; 7(6): 598–604.
  2. Bajčiová, V.: Nádory varlat u dětí, adolescentů a mladých dospělých. Rozdíly v biologii napříč věkovým spektrem. Onkológia 2007; 2(6): 380–384.
  3. Bajčiová, V.: Germinální nádory u dětí. In: Adam, Z. a kol.: Speciální onkologie: Příznaky, diagnostika a léčba maligních chorob, Galen 2010. pp. 391–392. ISBN 978-80-7262-648-9.
  4. Bajčiová, V.: Riziko rozvoje germinálních nádorů u pacientů s gonadální dysgenezí. Onkológia 2010; 5(3): 152–155.

 

This chapter was authored by:
Viera Bajčiová, M.D., Ph.D.
Department of Paediatric Oncology
University Hospital Brno