Key words
uterine tumor - uterine sarcoma - embryonal rhabdomyosarcoma - sarcoma botryoides
Schlüsselwörter
Uterussarkom - embryonales Rhabdomyosarkom - maligne Uterustumoren - botryoides Rhabdomyosarkom
Introduction
Rhabdomyosarcomas (RMS) are malignant mesenchymal tumours originating from myogenic
progenitor cells. They represent the most common soft tissue tumour in childhood but
are rarely diagnosed in adults [1]. The head and neck region are the most affected tumour sites, followed by the genitourinary
tract [1], [2]. Approximately 3 % of rhabdomyosarcomas in adults originate in the female genitals
[2]. Three major histological subtypes can be differentiated according to the Intergroup
Rhabdomyosarcoma Study Group (IRSG) and the WHO classification: the embryonal (including
botryoides as most frequent variant [3]), the alveolar and the pleomorphic/undifferentiated type. The majority of RMSs originating
from the female genital tract are embryonal and botryoid types.
The botryoid type has a typical “grape-like” appearance due to a layer of spindle
cells pushing up beneath the mucosa in polypoid masses. It is usually found in the
infantile vagina but can also occur in the cervix. Cervical RMS is usually seen in
the second decade of life. Because skeletal muscle is not normally found in the genital
tract, RMS is a heterologous tumor. The mean age at diagnosis of patients suffering
from embryonal RMS arising in the cervix is higher than that of patients with vaginal
lesions [4], [5]. The clear differentiation of histological subtypes is important due to significant
discrepancy in clinical behaviour and prognosis. Especially embryonal RMS of the uterus
is suggested to represent an extreme rare and aggressive form associated with poor
prognosis [1], [2], [6], [7], [8].
Survival management has changed significantly over the past 20 years. Hilgers et al.
in 1970 recommended that vaginal RMS was best treated by pelvic exenteration [9]. The addition of adjuvant chemotherapy makes a substantial contribution to the improvement
in survival [10]. The preoperative chemotherapy with or without radiotherapy can allow preservation
of the bladder and rectum [11], [12], and even save the uterus for fertility with wide local excision of cervix [13], [14].
Unfortunately, no standard therapy regimen is established for treatment of RMS in
adults. Treatment is carried out according to the guideline for treatment in childhood
in most adult cases. It usually includes surgery, multiagent chemotherapy (vincristine,
cyclophosphamide, Adriamycin) and radiotherapy.
Up to now, 16 cases of uterine RMS in adults have been reported whereas no case appeared
in association with a tumour of the uterus in statu nascendi [2].
Case
Suffering from therapy resistant vaginal discharge and bleeding for 6 months an 18-year-old
woman (virgo intacta) was treated with antibiotic and antifungal drugs by her gynaecologist.
No improvement was notable. The first physical examination revealed a tumour filling
out the vagina. A small biopsy was performed and there was strong suspicion for a
malignant mesenchymal tumour without definitive diagnosis due to limited material.
Therefore the patient was referred to our centre.
Physical examination was not possible. Vulvar examination was extremely painful and
presented a fist-sized, bleeding tumour of the uterus in statu nascendi without signs
of an infection.
Subsequently we performed an examination during anesthesia and vaginal surgery. The
tumour and the stalk passing the cervical canal were removed. There were no pathological
findings in the parametric areas and the vagina. Histopathological examination confirmed
an embryonal rhabdomyosarcoma ([Fig. 1]).
Fig. 1 a to f a–c Histopathological examination. d–f Immunhistochemical staining: d MyoD1; e myogenin; f desmin.
The tumour was homogeneous with spindle and polygonal cells and scattered multinucleated
giant cells with polymorphic and hyperchromatic nuclei and perivascular growth ([Fig. 1 a–c]). There was no clear rhabdomyogenic differentiation or rhabdomyoblasts. There were
disseminated necrosis, focal chondroid differentiation and a very high proliferation
with 8 mitosis in one high-power field and a proliferation of 80 % in Ki-67 immunohistochemistry.
Immunohistochemical work-up showed that the tumor was strongly expressing Desmin and
MyoD1 in 50–60 % and Myogenin in 20 % of tumor cells ([Fig. 1 d–f]). Epithelial markers (CK, EMA), smooth muscle markers (smooth muscle actin, h-caldesmon),
neurogenic markers to exclude a malignant neurogenic sarcoma with rhabdomyoblastic
differentiation or malignant Triton tumour (S100) and PAX5 were all negative.
The tumour was classified as grade III (high grade) according to the FNCLCC grading
system with an overall score of 7.
The staging of patients with a rhabdomyosarcoma is relatively complex. The process
includes the following steps [15]:
-
assigning a stage (consider site, size, surgico-pathologic group, and presence/absence
of metastases),
-
assigning a local tumor surgico-pathologic group (status post-surgical resection/biopsy,
with pathologic assessment of the tumour margins), and
-
assigning a risk group (classified by stage, group, and histology).
Postoperative imaging by PET/CT scan presented a tumour rest in the uterine cavity
and one suspicious lymph node in the right pelvic area ([Fig. 2]) There was no further distant disease. According to the IRS Clinical grouping Classification
the diagnosis was a group IIB embryonal rhabdomyosarcoma of the uterus. Risk stratification
corresponding to the CWS guidance (dependent on IRSG age, node status, metastasis
and site) presented a high risk group and subgroup [15].
Fig. 2 a to f a, b MRI T2w before surgery: a intravaginal part of the tumour; b cavum uteri including tumour stalk. c–f 18F-FDG-PET/CT (after surgery): c, e residual tumour (arrow); d, f suspicious lymph node (arrow) and stimulated ovary (arrow head).
Therefore, a multiagent chemotherapy with ifosfamide (3000 mg/m2), d1 + 2, vincristine (1.5 mg/m2), d1 + 8 + 15, courses 1 and 2 + d1 of courses 3 + 4, and actinomycin D (1.5 mg/m2), d1, q21d, was recommended and started according to the CWS guidance. A cryoconservation
of ovarian tissue was performed before chemotherapy. After the initial three courses
of chemotherapy a re-staging by PET/CT scan was done which revealed a complete response.
Consequently another cycle of chemotherapy was given for consolidation.
Afterwards, secondary surgery was performed including laparoscopic dissection of regional
pelvic lymph nodes and endometrial and endocervical curettage. No residual tumour
was diagnosed intraoperatively ([Fig. 3]). Histopathological examination confirmed the complete response. Due to lack of
evidence based on guidelines for aftercare, follow-up visits were arranged every three
months including gynaecological ultrasound, complete CT scan every six months and
a nuclear bone scans every 12 months since July 2010. The patient started to menstruate
again 5 months after the last cycle of chemotherapy. The last follow-up examination,
which was performed in April 2012, revealed no abnormal findings ([Fig. 4]).
Fig. 3 a to d Intraoperative pictures final surgery after cycle 4. a Fundus uteri: Laparoscopic view from abdominal; b fundus uteri: hysteroscopic view cavum uteri; c, d ostium of fallopian tubes bilateral: hysteroscopic view cavum uteri.
Fig. 4 CT thorax/abdomen (2012-04-10). No organ or lymph node metastases.
Comment
RMS is a common soft tissue tumour in childhood but is rarely seen in adults. The
most common tumour site is usually the neck and head region, followed by the genitourinary
tract. Cervix and uterus are the most frequently affected tumour sites in adolescent
and postmenopausal women with tumours arising in the genitourinary tract, respectively.
RMS often occurs as an extremely heterologous tumour, because skeletal muscles are
naturally not found in the female genitals [16]. According to the histological examination three different subtypes of RMS can be
classified: the embryonal, the alveolar and the pleomorphic subtypes. Main differential
diagnoses are leiomyosarcoma, adenosarcoma, carcinomasarcoma and malignant neurogenic
sarcoma with rhabdomyoblastic differentiation (malignant Triton tumour) [1]. Therefore, histological findings like neoplastic pleomorphic skeletal muscle cells
of varying differentiation, sometimes
with myxoid stroma or cartilage diffentiation, have to be confirmed by immunhistochemical
staining with myogenin, desmin and MyoD1 ([Fig. 1]) [1], [2], [6], [15]. Furthermore any epithelial differentiation has to be excluded by extensive sampling
of the tumour and immunohistochemistry.
The treatment of patients with RMS is a multimodality challenge. Therapy strategy
includes systemic chemotherapy, in combination with either surgery, radiation therapy
(RT), or both modalities for local tumour control. Surgical resection should be performed,
if feasible without major functional/cosmetic impairment, followed by chemotherapy
and RT. Some patients with initially unresected tumours may undergo second-look surgery
to remove the residual tumour. Because RMS is sensitive to chemotherapy and RT, surgery
is delayed if disfigurement or interference with organ function is probable.
RT is indicated for patients with microscopic residual (Group II) disease, gross residual
(Group III) disease or Group I patients with alveolar histology. The discussion of
treatment options for children with RMS is therefore divided into separate sections
describing surgery, chemotherapy, and RT [17]. In most cases fertility-sparing surgery is impossible and usually hysterectomy,
bilateral adnexectomy and dissection of regional lymph nodes are performed.
Some authors suggested that embryonal RMS in adults have a poor prognosis, irrespective
of the selected therapy, whereas others reported an improved survival comparable to
the survival rates in childhood [2], [18]. Due to lack of prospective randomized studies it is difficult to specify the individual
prognosis.
We report a case of an 18-year-old patient (virgo intacta) suffering from a fist-sized
embryonal RMS of the uterus in statu nascendi. Because the main tumour mass was located
in the vagina (being in statu nascendi) it could easily be removed during the first
examination in anaesthesia. Regarding the suspect pelvine lymph node a multiagent
chemotherapy was performed according to the CWS guidance and secondary surgery was
performed afterwards. Re-staging visualized a complete response enabling a fertility-sparing
surgery which was favoured by the patient and her family. Up to now, follow-up examinations
showed no signs for distant metastasis or local recurrence.
To our knowledge, fertility-sparing surgery is not described for uterine embryonal
RMS up to now. Kayton et al. [18] reported a case of an anaplastic embryonal RMS involving the cervix uteri in a 12-year-old
girl. They performed a fertility-sparing surgery with radical abdominal trachelectomy
for local control and to avoid infertility. Subsequently adjuvant multiagent chemotherapy
was given. No local recurrence was diagnosed up to the date of publication.
Similarly, a case of a 19-year-old woman suffering from a botryoid RMS of the posterior
lip of the cervix was described by Bernal et al. [19]. The RMS was located to the vagina and was removed including the cervical part by
curettage. Postoperative imaging showed no evidence of distant disease. Secondary
surgery was carried out by conisation. No residual tumour was identified in histological
analysis. Adjuvant multiagent chemotherapy was given and no evidence of disease was
seen after a follow-up of 11 months.
A case of embryonal RMS of the uterus was described in a 15-year-old adolescent by
da Silva et al. [2]. The tumour was expelling through the cervix into the vagina comparable to the present
case, but also with inversio uteri. Origin of the tumour was the fundus uteri. The
reason for the inversion was thought to be the softening of the uterine wall caused
by the rapidly growing tumour. Uterus-conserving surgery was no reasonable option
for local tumour control although the tumour was classified as Group I tumour according
to the IRSG Grouping classification.
In the present case no inversio uteri was noticeable. The tumour did not affect the
uterine wall but expelled directly through the cervix into the vagina. Therefore resection
of the tumour with the stalk was possible and only a very small tumour rest was remaining
in situ. This was treated with combined chemotherapy.
In conclusion, embryonal RMS of the uterus is a rare neoplasia in adult women. A poor
prognosis is described in literature. Main symptoms are therapy resistant bleeding
and discharge. The histopathological diagnosis has to be confirmed by extensive tumour
sampling to exclude a carcinosarcoma and immunohistochemical l staining for MyoD1,
desmin and myogenin. Therapy usually includes fertility-compromising surgery, multiagent
chemotherapy and radiotherapy. Fertility-sparing surgery is described to be possible
in exceptional cases of RMS of the cervix.
The present case shows that in individual cases fertility-sparing surgery is possible
for young patients suffering from RMS of the uterus. Further studies are necessary
to evaluate the most effective treatments for adult patients.
