Arch Gynecol Obstet (2008) 278:177–180 DOI 10.1007/s00404-008-0567-x
C A S E RE P O RT
Primary endometrial squamous cell carcinoma N. Thomakos · K. Galaal · K. A. Godfrey · D. Hemming · R. Naik · M. H. Hatem · A. Lopes
Received: 20 October 2007 / Accepted: 8 January 2008 / Published online: 31 January 2008 © Springer-Verlag 2008
Abstract Primary squamous cell carcinoma of the endometrium (PESCC) is rare and its pathogenesis is unclear. IdentiWcation of PESCC and its diVerentiation from endometrial involvement by squamous cell carcinoma is essential for correct patient management and is based on strict pathological criteria. We present a case of a 71-yearold patient satisfying the proposed diagnostic criteria for PESCC together with a review of the literature. Keywords
follows: there should be no co-existing adenocarcinoma of the endometrium, there should be no demonstrable connection between the tumour in the endometrium and the squamous epithelium of the cervix and there is no co-existing primary squamous cell carcinoma of the cervix. A more recent criterion included by the World Health Organisation is that the tumour must exhibit keratinisation and/or intercellular bridges.
Endometrial cancer · Primary · Squamous Case
Introduction Primary endometrial squamous cell carcinoma (PESCC) is an extremely rare entity. Since 1892, when Gebhard [1] reported the Wrst case of PESCC, only sporadic cases have been published in the literature. The prevalence of this neoplasm is about 0.1% of endometrial carcinomas [2] and its pathogenesis remains obscure. Histological identiWcation [3, 4] of PESCC is based on strict pathological and clinical criteria Wrst established by Fluhmann in 1928 [4]. There are three criteria proposed as N. Thomakos · K. Galaal · K. A. Godfrey · R. Naik · M. H. Hatem · A. Lopes Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, UK D. Hemming Department of Cyto-Histopathology, Gateshead Health NHS Trust, Queen Elizabeth Hospital, SheriV Hill, Gateshead NE9 6SX, UK N. Thomakos (&) 17 Eslin Street, 115 23 Ampelokipi, Athens, Greece e-mail:
[email protected]
A 71-year-old nulliparous woman, already 20 years postmenopausal, was referred to the Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, UK with a several months’ history of mild vaginal bleeding. The patient was generally Wt and healthy, although she had a history of hypertension and polymyalgia rheumatica. The smear history was negative with her last smear taken 10 years previously. There was no other signiWcant gynaecological history. Gynaecological examination revealed a normal cervix, an enlarged uterus, and non-palpable adnexae. A transvaginal ultrasound was performed and showed a bulky uterus with an abnormal endometrial thickness of 19.1 mm. The endometrium was of mixed echogenicity with small cystic areas throughout. The patient subsequently underwent hysteroscopy and endometrial biopsy. Hysteroscopy revealed a uterine cavity of 8 cm with some abnormal endometrium near the internal cervical os. Curettings obtained were reported as showing fragments of a squamous carcinoma with a papillary morphology, but it could not be determined whether this was arising from the endometrium or cervix, given the type of specimen.
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Arch Gynecol Obstet (2008) 278:177–180
An MRI scan disclosed a 3.7 £ 2 £ 2.8 cm mass occupying and expanding the uterine cavity, causing full thickness disruption of the myometrial junctional zone (Fig. 1). The serosal surface of the uterus was not disrupted and appeared smooth. The cervix, vagina and adnexae appeared normal. The patient underwent exploratory laparotomy; no extra uterine tumour was seen in the abdomen or pelvis. The uterus was larger than normal but no serosal involvement was observed in gross examination, tubes and ovaries appeared normal. There was no palpable pelvic or para-aortic lymphadenopathy. Total abdominal hysterectomy with bilateral salpingooophorectomy was performed and peritoneal washings taken for cytology.
Pathological Wndings
Fig. 2 High power view of tumour showing keratinisation with keratin pearl formations (H&E £200)
Macroscopically the uterus was distended by a tumour and measured 7 £ 4 £ 3 cm in maximum dimension. On sectioning the uterus, the uterine cavity was found to be distended by tumour measuring 3 £ 2 £ 2 cm invading the myometrium posteriorly at the fundus. The lower uterus and cervix appeared unremarkable and uninvolved by the tumour. Histology conWrmed the presence of a poorly diVerentiated invasive squamous cell carcinoma with focal keratinisation (Fig. 2) and necrosis with a papillary morphology superWcially (Fig. 3). None of the sections showed evidence of an adenocarcinoma. There was invasion of the
Fig. 3 Low power of the tumour showing a papillary appearance superWcially (H&E £100)
Fig. 1 Pelvic MRI scan showing tumour occupying uterine fundus and normal cervix
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inner half of the myometrium. Lymphovascular space involvement was not seen. The cervix was unremarkable with no evidence of in situ or invasive malignancy. The endometrium adjacent to the tumour was inactive and showed no evidence of squamous metaplasia. The tubes and ovaries were normal and washings (taken intra-operatively) were negative for malignant cells. Immunocytochemistry showed the tumour to be strongly pan-cytokeratin and vimentin positive with focal positivity for cytokeratin 7, Ca 125, CEA and P53. There was weak positivity for oestrogen and progesterone receptors. The tumour was negative for cytokeratin 20 and TTF 1 (thyroid transcription factor 1). This staining proWle suggests an endometrial origin for the tumour. Positive expression of TTF1 is useful in determining whether a tumour is of bronchogenic origin but negative TTF1 is unhelpful. Positive expression of oestrogen and progesterone receptors is
Arch Gynecol Obstet (2008) 278:177–180
usually seen in primary endometrial carcinoma but can also be seen in some endocervical carcinomas (usually adenocarcinoma) [5].
Discussion Primary endometrial squamous cell carcinoma is a rare entity. Most squamous cell carcinomas found in the endometrium are of primary cervical origin. To correctly identify PESCC, three criteria must be fulWlled [4]: (a) No co-existing primary adenocarcinoma of the endometrium (b) No connection between PESCC and cervical squamous epithelium and (c) No co-existing primary squamous cell carcinoma of the cervix. More recently, the WHO added that the tumour must have clear evidence of squamous diVerentiation such as intercellular bridges and/or keratin [3]. In order to fulWl these criteria the whole of the uterus and cervix should be sampled in order not to miss a small focus of primary endometrioid adenocarcinoma or a focus of squamous cell carcinoma in the cervix. One theory for the development of PESCC is by the transformation of reserve or “stem” cells located between the glandular basement membrane and the endometrial columnar epithelium [6, 7]. The relationship between squamous metaplasia of the endometrium and PESCC has been investigated and remains controversial. It has been demonstrated by some investigators that squamous metaplasia has the potential for malignant transformation and could be a precursor of PESCC, based on its frequent co-existence with PESCC [8–10]. Chronic inXammation, pyometra and radiation can all result in squamous metaplasia and these conditions are associated with PESCC [11]. However, in a review by Im et al. [12], there was no convincing evidence (other than co-existence of the two lesions) to suggest that endometrial squamous metaplasia is the precursor of PESCC. Based on single case reports, various controversial theories have been proposed to determine pathogenetic mechanisms responsible for PESCC. Based on immunohistochemical results with anti-all-cytokeratin (KLI), antiCEA and anti-vimentin, Horn and Bilek [13] suggest that PESCC may be the result of a bi-directional diVerentiation of pluripotent endometrial precursor cells. Yamamoto and co-workers [14] support the hypothesis that heterotopic cervical tissue in the endometrium could be a possible origin for PESCC. The staining pattern of this particular tumour in our case was in keeping with that of an endometrial origin, raising the possibility that this type of tumour may arise from an endometrial site, and could argu-
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ably represent an endometrial adenocarcinoma, in which the malignant squamous element has overgrown the glandular component. Other authors have tried to establish a link between human papilloma virus (HPV) infection and PESCC. It is well known that high-risk HPV subtypes are strongly associated with squamous neoplasms of the lower genital tract, if not the cause of these lesions. The relationship of HPV antigen or HPV DNA has been clearly demonstrated in the squamous component of endometrial adenoacanthoma [15, 16]. Kataoka et al. [17], by polymerase chain reaction (PCR) ampliWcation documented that HPV type 31 could be included as a possible factor in the development of PESCC. However, HPV analysis of PESCC in previously published case reports has failed to show the presence of HPV by a series of diVerent methods [8, 10]. More recently, other pathogenetic mechanisms, which cause a mutation of P53 tumour-suppression gene, may have been implicated in the development of PESCC [18]. The signiWcance of p53 positivity would suggest that the tumour probably arose by mutation of the p53 tumour suppression gene. In conclusion, we consider that our case fulWls the proposed strict criteria for establishing the diagnosis of PESCC as deWned by Fluhmann [4] and the WHO [3]. Survival data for PESCC are scanty. However, for stage 1 disease the prognosis is said to be much worse than the prognosis for endometrial adenocarcinoma despite similar treatment with surgery and adjuvant chemotherapy [19]. Adjuvant radiotherapy is suggested for local and regional control in PESCC despite limited data to support this. In our case adjuvant radiotherapy was given with the patient disease free at 6 weeks and 3-month follow-up. It is important that clinicians and pathologists are aware of this rare entity in their day-to-day practice. We suggest that it can be diYcult to determine with conWdence that the tumour is endometrial in origin even when the entire cervix is sampled and that in some cases a small area of adenocarcinoma may not be necessarily detected even on blocking out the whole specimen. Furthermore immunocytochemistry may not be discriminatory.
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