Key words
uterus - metastasis - hormone receptor - uterus sarcoma - benign uterus tumours
Schlüsselwörter
Uterus - Metastasierung - Hormonrezeptor - Uterussarkom - benigne Uterustumoren
Introduction
Although uterine leiomyomas represent the most frequent gynaecological tumours, clear histopathological
classification of these tumours is not possible if an atypical growth pattern, metastatic dissemination
or extra-uterine relapse is present. In particular, the distinction from a leiomyosarcoma may be
difficult in these cases. The classification of the dignity of extra-uterine manifestations of uterine
leiomyomas has been the subject of controversial discussion since the initial description of a “benign,
metastasising fibro leiomyoma” by Steiner [1] in 1939. Metastasis or a lower
mitosis index is not sufficient for assessment in these cases. According to the current WHO
recommendations on histological tumour classification [2], cell atypia as well
as coagulative necrosis must be considered when assessing the malignancy potential, whereby none of the
criteria alone is sufficient for a diagnosis. Despite this extended panel of criteria and broader
immunohistochemical marker profiles, a clear dignity classification of some of these neoplasias has not
been possible to date, so that a heterogeneous group of “smooth muscle tumour of unknown malignant
potential (STUMP) was created as a collection of these borderline cases, which also included benign,
metastasising leiomyomas (BML) [3]. The most frequent location is the uterus;
other smooth muscle structures, such as the diaphragm, vessel walls or ureter, are rarely described, and
no oestrogen receptors can be identified in these extra-uterine cases. [4]
([Table 1]).
Table 1 Histological criteria for diagnosis of smooth muscle uterus tumours in
accordance with [9].
|
Diagnosis
|
Necrosis
|
Atypia
|
Mitosis/10 hpf
|
|
Leiomyosarcoma
|
yes
|
diffuse, moderate to pronounced
|
any number
|
|
|
yes
|
not present to mild
|
≥ 10
|
|
|
no
|
diffuse, moderate to pronounced
|
≥ 10
|
|
STUMP
|
yes
|
none to low-grade
|
< 10
|
|
|
no
|
diffuse, moderate to pronounced
|
5–9
|
|
|
no
|
focal, moderate to pronounced
|
≥ 5
|
|
Atypical leiomyoma
|
no
|
moderate to pronounced
|
< 5
|
|
Leiomyoma
|
no
|
none to low-grade
|
< 5
|
Case Description
As part of a regular medical check-up of an otherwise healthy 59 year-old, childless woman, on whom an
abdominal hysterectomy with adnectomy was performed 4 years previous due to a symptomatic uterine
myomatosis, a large, retroperitoneal neoplasia was discovered, which had translocated the ureter and
iliac vessels and which, based on magnetic resonance imaging ([Fig. 1]),
appeared to be a sarcoma. The tumour was removed transabdominally and displayed an encircling of the
ureter which made a partial resection with ureterovesicostomy necessary. The iliac vessels had been
translocated but not infiltrated. The histological examination confirmed the R0 resection of an 11.5 m
smooth muscle tumour, which was suspiciously similar to a highly differentiated leiomyosarcoma
(Actin/Desmin/Vimentin positive, Ki67 5 %). The resected ureter section was tumour-free.
Fig. 1 a and b Retroperitoneal lower abdominal tumour, encircling the left ureter
(a) and translocation of the iliac vessels (b) in the MRI scan.
Subsequent computer tomographic staging showed multiple smooth parenchymal lesions, up to 8 mm in size,
in all pulmonary lobes, focussed on the right, and showing irregular contrast in the X-ray ([Fig. 2]). Conspicuous lymphomas or other pathological findings were not
evident. A wait-and-see approach was not possible due to the unclear genesis of the pulmonary lesions
and suspicion of a leiomyoscaroma; the patient was therefore admitted to surgical removal of the lesion
with further histological diagnostics. The patient was in a good general condition and was employed.
Regular medication in the form of an estradiol gel was prescribed for menopausal complaints.
Fig. 2 a and b Suspected round lesions in the CT, a histological intrapulmonary
lymph nodes, b STUMP metastasis in the medial lobe.
A right thoracic exploration took place via an anterolateral minor thoracotomy with extra-anatomical
resection of all ipsilateral lesions due to the small size of the pulmonary changes and the localisation
in the centre of the parenchyma. Macroscopically, they resembled typical, anthracotic intrapulmonary
lymph nodes, which was also confirmed histologically. Only a 5 mm medial lobe lesion with a glazed
surface and coarse consistency looked suspiciously malignant. Microscopically, this was a solitary,
partially necrotic, smooth muscle tumour lesion, which displayed no clear malignancy criteria ([Fig. 3]). Atypia or increased mitosis were not present (< 3 per 10 high
power fields [hpf]). Immunohistochemically, the tumour cells reacted positively to actin and desmin and
negatively to CD10, CD34 and S100. MIB1 stained only individual proliferating cells. Eighty-percent cell
nuclei positivity was present for the oestrogen and progesterone receptors (IRS 8/12). These findings
and a comparison to the sections of the previously resected retroperitoneal tumour resulted in the
classification of the lung lesion as a BML metastasis.
Fig. 3 a and b Histology of the lung metastasis in HE staining. a Solid,
intrapulmonary lesion with defined boundaries. b Typical smooth muscle cells in center of
metastasis, arranged in fascicles.
Additional reference pathology diagnostics of the retroperitoneal tumour described a mesenchymal, spindle
cell tumour, whose cells were arranged as fascicle bundles. Necrosis, nuclear atypia or mitosis were
absent (< 2/10 hpf). A similar immunohistochemical pattern was present and the hormone receptors were
also positive in this case. There was no accumulation of p53 protein. Classification was as a “smooth
muscle tumour of genital type with unclear malignancy potential” due to the clear smooth muscle
differentiation, the receptor positivity and the lack of clear malignancy criteria.
A comparison of the sections from the uterus myomatosis in 2008, which was also examined in consultation
with a reference pathologist at the time, also took place to better assess this finding. These specimens
also displayed no evidence of atypia or necrosis and showed only individual areas of increased mitotic
activity (< 10 mitoses/10 hpf). The diagnosis then referred to a “mitotically active, apoplectic
leiomyoma”.
In summary, in consideration of all the findings, the neoplasia described is a retroperitoneal and
pulmonary metastasised, well differentiated, primary uterine, smooth muscle tumour without traditional
malignancy criteria.
The patient recovered quickly and was able to be released from in-patient treatment seven days after the
operation. The additional abdominal sonographic and computer tomographic controls in the following 24
months to today, under medication with oestrogen receptor antagonists, showed no further changes, in
particular no progression in size of the residual left pulmonary lesions.
Discussion
The vast majority of smooth muscle uterine tumours can be definitively identified using a combination of
histological criteria. These criteria include the presence and type of necrosis (coagulative/hyaline),
the number and type of nuclear atypia, the miotic activity (mitoses per high power field, proliferation
marker) and an invasive proliferative behaviour. Beside this, there is a grey area of rare, smooth
muscle neoplasia that fulfil individual malignancy criteria, but which cannot be classified as a
leiomyosarcoma with any certainty and are therefore combined to form the heterogeneous STUMP group. The
incidence cannot currently be quantified due to the different pathological assessments and the
heterogeneity of this group; however, it seems to be much lower than that of the leiomyosarcoma [5], [6].
Tumour growth is generally slow, so that a PET/CT diagnosis without or with only a low 18F FDG signal can
potentially differentiate these STUMP from leiomyosarcoma or metastases, which display an increased
accumulation [7]. Pulmonary metastases are most common but can be observed in
almost all tissues. The lesions are mostly multi-focal on both sides of the lungs, however solitary
lesions may occur on rare occasions [8]. Without a histological confirmation
of the extrauterine lesion there is a risk of a false positive diagnosis, as frequently – as in the
above case – simultaneous, benign, reactive proliferations may be present.
STUMP diagnosis generally is achieved surgically, since biopsates are mostly insufficient for
histopathological and immunohistochemical analysis and as much tissue material as possible is required.
Individual interpretive difficulties also occasionally lead to different assessments of these
neoplasias, which is reflected in the reassessments by the reference pathologists in retrospective
studies [5], [6]. A mitosis rate of > 10 per hpf
is consistently viewed as a malignancy criteria; however, the range from 5–9 per hpf cannot be reliably
assessed. In addition, within tumours, areas of higher proliferation may occur next to areas without
increased mitosis rates, which also limits the diagnostic reliability. The evaluation of nuclear atypia
is also linked with uncertainties if the nuclei is condensed or artificially changed. For these reasons,
the surgical removal of a sufficient quantity of intact tissue is recommended [9].
Coagulative necroses, especially in the area of metastases, no longer necessarily lead to the diagnosis
of a leiomyosarcoma [10], as the dignity classification was originally based
on studies of uterine tumours and statements on extrauterine manifestations only apply to a limited
extent [3], [11]. As a result, additional
immunohistochemical criteria are included in order to improve the diagnostic reliability. These criteria
include the expression of progesterone receptors, which are more distinct for leiomyomas, and an
expression of p53, which is seen more frequently in leiomyosarcoma [12].
The formation of metastases is also still unclear. Haematogenic, peritoneal or retroperitoneal cell
spreading is often assumed, as a monoclonal origin of the smooth muscle cells can be observed at the
molecular and genetic levels and in almost all cases the patients had previously been pregnant or a
surgical intervention had taken place in the lower abdomen [13]. This
mechanism is primarily postulated for the BML and links well with the diffuse peritoneal leiomyomatosis
or the intravascular myomatosis, which have already been described in combination with the BML [14]. Of interest are comparisons with pulmonary lymphangioleiomyomatosis (LAM)
which displays striking similarities: a pathological proliferation of smooth muscle cells, with
haematogenic or lymphogenic migration to the lungs, a lack of pathological malignancy criteria, a
hormone sensitivity and a female gender specificity. This cannot be explained solely by
oestrogen/progesterone secretion, as these hormones are also produced by males; however, the uterus is
unique, so that patients with pulmonary LAM not only display leiomyomas, but 90 % of the patients also
display uterine LAM cells [15]. Estradiol, though not progesterone, promotes
the growth of LAM cells as well as BML, for which good results can be achieved with an antioestrogen
treatment and with which the progression slows after menopause or after an oophorectomy and can even be
reversed in some cases [4], [5], [16], [17]. A special feature of the LAM cells are
inactivating mutations of the tumour suppressor genes TSC1/TSC2, which lead to an activation of the
mTORC1 pathway and corresponding cell growth. However, as only about 40 % of patients with TSC1/TSC2
mutations develop pulmonary LAM lesions and antioestrogens have a blocking effect, mTOR activation does
not seem to be sufficient and estradiol stimulation is also required [17].
TSC1/TSC2 have not previously been investigated in BML; however, the striking similarities between LAM
and BML may offer an approach to better understand uterine, smooth muscle growth.
Recurrences with a latency of up to several decades occur in about 7 % of STUMP cases, which tends to
contradict the one-off cell spread model [18]. As a higher rate of necrosis
can also be observed for extrauterine metastases, in these cases it is possible that they are closer to
a leiomyosarcoma. However, most current publications are limited to the “good-natured” BML. Studies that
focus on STUMP with recurrences or investigate the long-term behaviour of different metastases have not
been published and could only refer to observations in individual cases or small case numbers due to the
rarity of these entities [19].
Due to the low incidence of these tumours, no generally accepted treatment recommendations currently
exist. A treatment indication exists for progress with parenchymal destruction or the obturation of
vascular structures. An aggressive treatment with radical resection and adjuvant
radiotherapy/chemotherapy, as is the case for leiomyosarcoma, is currently not indicated according to
the general consensus; however, some authors recommend a radical resection with hysterectomy, bilateral
oophorectomy and the removal of metastases in combination with an antihormonal treatment, especially for
premenopausal patients with high endogenous oestrogen secretion [9], [20]. In contrast, due to the hormone sensitivity and the generally benign
growth behaviour following menopause, most publications recommend a watch and wait approach following
histological identification or a medicinal, antioestrogen treatment regime. For BML with pulmonary
metastases, for which continued tumour growth could lead to respiratory failure, zero growth or even a
remission can be achieved by antihormonal treatment, even for extensive tumours. Oestrogen receptor
antagonists are less effective than GnRh agonists or aromatase inhibitors. Progesterone also leads to a
slow-down of the hypothalamic hypophyseal gonadal axis and inhibits the aromatase activity leading to
regression of the pulmonary BML lesions [4], [6], [18], [21]. The follow-up period
should consider the often slow growth behaviour and be at least 10 years, in our opinion. Alternatively,
surgical resectioning procedures are also available for preventing local organ complications [22].
The heterogeneity of the STUMP as a collective group of smooth muscle tumours that cannot be definitively
classified has not permitted any reliable treatment recommendations to date. After surgical tissue
removal a conservative approach or antioestrogen treatment is recommended, especially for postmenopausal
patients. It is possible that the BML will be able to be distinguished from other STUMP in
histopathology and clinical behaviour in the future, as they display striking similarities to other
smooth muscle proliferations, such as lymphangioleiomyomatosis. TSC1/TSC2 mutations could play a role in
this regard.
