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Pathology – Research and Practice 203 (2007) 677–681 www.elsevier.de/prp
TEACHING CASES
Endometrial carcinoma recurring as carcinosarcoma: Report of two cases G. Ferrandinaa,c,, G.F. Zannonib, E. Martinellia, V. Velloneb, M.G. Priscoa, G. Scambiac a
Gynecologic Oncology Unit, Catholic University of Rome, Italy Institute of Human Pathology, Catholic University of Rome, Italy c Department of Oncology, Catholic University of Campobasso, Italy b
Received 18 February 2007; accepted 7 May 2007
Abstract Endometrial carcinosarcoma is a rare, aggressive disease, accounting for approximately 3% of all uterine neoplasms. The emergence of sarcomatous elements is considered the evolution of subclones arising from high grade endometrial carcinomas. Here, we report two cases of primary endometrial carcinomas recurring as carcinosarcoma. Case 1. a 58-year-old postmenopausal woman diagnosed to have a poorly differentiated endometrial endometrioid adenocarcinoma (FIGO stage IB) developed an intra-abdominal recurrence of disease after 17 months from diagnosis. Histopathological analysis documented a biphasic neoplasia consisting of an epithelial (grade 3 endometrial endometrioid adenocarcinoma) and a sarcomatous component. Salvage chemotherapy with cisplatin, ifosfamide, epirubicin, and then with taxotere was attempted. The patient died after 2 months. Case 2. A 56-year-old woman with a diagnosis of grade 3 endometrial adenosquamous carcinoma of the endometrium (FIGO stage IIIA) experienced pelvic recurrence after five months from completion of chemotherapy. Definitive histology was malignant mixed mesodermal tumor with focal areas of chondrosarcomatous elements. The patient was triaged to exclusive concomitant chemoradiotherapy and salvage chemotherapy. The patient died after 3 months. We describe two cases of high grade endometrial carcinomas recurring as carcinosarcoma, thus providing evidence that the metaplastic sarcomatous evolution is a very rare event which can occur in patients with anaplastic endometrial cancer. r 2007 Elsevier GmbH. All rights reserved. Keywords: Endometrial carcinomas; Carcinosarcoma; Recurrence
Introduction The term carcinosarcoma was first used by Virchow in 1864 to describe tumors with both carcinomatous and sarcomatous elements [15]. In gynecologic tumors, Corresponding author. Department of Oncology, Catholic University of Campobasso, Italy. Tel.: +39 06 35508736; fax: +39 06 35508736. E-mail address:
[email protected] (G. Ferrandina).
0344-0338/$ - see front matter r 2007 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2007.05.008
the carcinomatous component can include serous, endometrioid, clear cell, and squamous or mucinous differentiation, as well as undifferentiated elements, while the sarcomatous component may contain homologous (endometrial stromal sarcoma, fibrosarcoma, leiomyosarcoma) or heterologous elements, such as osseous, cartilaginous, and rhabdomyoblastic cells. Endometrial carcinosarcoma is a rare, highly aggressive disease, accounting for approximately 3% of all uterine neoplasms [4]. Although several hypotheses have
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been proposed to explain the histogenesis of carcinosarcomas, once thought to be independent neoplasms merging to form a biclonal tumor (‘‘collision theory’’) [8], recent studies have demonstrated that they are monoclonal and should be regarded as high grade carcinomas with metaplastic sarcomatous elements [8,13]. In this context, the emergence of sarcomatous elements would represent the evolution of subclones arising from high grade endometrial carcinomas [8,13,2]. To the best of our knowledge, no cases of recurrence of carcinosarcoma from primary endometrial adenocarcinoma have been documented in the literature. Here, we report two cases of primary endometrial carcinomas recurring as carcinosarcoma. The immunohistochemical analysis of several biologic parameters in primary endometrial cancer and recurrent carcinosarcomas has also been performed.
Case 1 A 58-year-old postmenopausal woman, gravida 2 para 2, was admitted to the Gynecologic Oncology Unit, Catholic University of Rome, complaining of pelvic pain and abnormal vaginal bleeding. US examination showed an 8-cm-long uterus with a 13-mm-thick endometrium, normal adnexa, and no lymphoadenopathies. Operative hysteroscopy was performed, documenting the presence of a suspicious lesion (maximum diameter ¼ 1.5 cm) macroscopically resembling a submucous fundic myoma, which was resected. Histopathology documented the presence of a poorly differentiated endometrial endometrioid adenocarcinoma (Fig. 1C). Abdomino-pelvic MRI showed a focal area of an altered signal located within the anterior uterine wall (maximum diameter ¼ 1.2 cm), and involving the inner third of myometrium. Uterine cervix and adnexa appeared uninvolved. No lymphoadenopathies were documented. She underwent abdominal hysterectomy (Piver II), plus bilateral salpingo-oophorectomy and pelvic lymphadenectomy. At definitive histopathology, the diagnosis was poorly differentiated endometrial endometrioid adenocarcinoma, with focal nests of clear cells. Uterine cervix, adnexa, and pelvic lymph nodes (n ¼ 24), as well as peritoneal washing were negative. The case was staged as FIGO stage IB. She refused to undergo adjuvant treatment, and was triaged to strict follow-up procedures. After 17 months from diagnosis, the patient started complaining of an abdominal nodule located superficially in the umbilical area: abdominal US examination revealed the presence of a solid mass (maximum diameter ¼ 4 cm) with heterogenous echogenicity, located within the abdominal wall and strictly adherent to the small intestine. Right
external iliac lymphoadenopathies (maximum diameter ¼ 1.5 cm) were observed. Ca125 levels were 106 U/ml. Exploratory laparotomy was performed, and the abdominal mass and an additional intraperitoneal small nodule suspicious of a neoplastic localization were removed. Histopathological analysis documented a biphasic neoplasia consisting of an epithelial (poorly differentiated endometrial endometrioid adenocarcinoma) and a sarcomatous component (Fig. 1D). A re-joint evaluation of the slides referring to the diagnosis of the primary tumor was planned confirming the initial diagnosis. A total body CT scan performed after 3 weeks documented multiple metastatic lesions in the lung, liver, and abdomen, as well as bulky bilateral pelvic lymphoadenopathies. Chemotherapy with cisplatin (50 mg/m2 d1), ifosfamide (1,500 mg/m2 d1-5), and epirubicin (90 mg/m2 d1) every 3 weeks was then started. After 4 cycles, progression of disease was documented, and chemotherapy with taxotere (100 mg/m2 d1) every three weeks was attempted. Rapid deterioration of the general conditions was observed, and the patient was triaged to only supportive and antalgic treatment. The patient died after 2 months.
Case 2 A 56-year-old gravida 2 para 1 woman was admitted to the Gynecologic Oncology Unit, Catholic University of Rome, complaining of abnormal vaginal bleeding. Her gynecological history was negative, with spontaneous menopause occurring at the age of 50 yrs. Uterine dilation and curettage were performed, and diagnosis was poorly differentiated endometrial endometrioid carcinoma. Work-up procedures were performed, documenting the presence of a large volume uterine mass infiltrating the outer half of the myometrium. There was no lymph node involvement. The patient underwent total abdominal hysterectomy plus bilateral salpingooophorectomy and pelvic lymph node sampling. Macroscopically, a mass of 7 cm in maximum diameter originating from the posterior uterine wall was found, showing areas of hemorrhage and necrosis. At least one sample for every 0.5 cm of tumor diameter (14 sections) was taken for histopathologic diagnosis, which revealed a poorly differentiated endometrial adenosquamous carcinoma of the endometrium (Fig. 1A), infiltrating the myometrium until the serosa. Neoplastic lymphovascular space involvement was documented. Peritoneal washing, adnexa, and lymph nodes were negative (FIGO stage IIIA). Four cycles of chemotherapy with carboplatin (AUC 5) and pegylated liposomal doxorubicin (30 mg/m2) every 3 weeks were then started.
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Fig. 1. Primary endometrial carcinoma (A, B) and recurrent carcinosarcoma (C, D). (A) Case 1: a poorly differentiated endometrial endometrioid carcinoma is shown (Hematoxylin and Eosin, 200). (B) Case 1: recurrent carcinosarcoma. A biphasic pattern of endometrial adenocarcinoma and malignant stromal elements are shown (Hematoxylin and Eosin, 200). (C) Case 2: a poorly differentiated endometrial endometrioid carcinoma is shown (Hematoxylin and Eosin, 100). (D) Case 2: recurrent carcinosarcoma. Carcinomatous micronodular foci are dispersed in the context of spindle-shaped cells. Areas of chondrosarcomatous morphology are evident (Hematoxylin and Eosin, 100).
Five months after completion of treatment, gynecological examination documented the presence of a solid nodule on the vaginal cuff (maximum diameter ¼ 2 cm), which resulted negative at the biopsy. CA125 levels were 20 U/ml. Further examinations were planned: abdomino-pelvic US examination revealed a hypoechogenic nodule (maximum diameter: 2.5 cm) without any signs of involvement of the surrounding tissues. Abdomino-pelvic CT scan and MRI were able to detect signs of initial infiltration of the anterior vaginal wall and bladder, while the rectum appeared uninvolved. No lymphoadenopathies were observed. Biopsy was again performed, and the definitive histology was malignant mixed mesodermal tumor: microscopically, the major component consisted of spindle-shaped pleomorphic cells with focal areas of chondrosarcomatous elements. In this context, epithelial cell nests were detected that consisted of foci of poorly differentiated endometrioid adenocarcinoma cells resembling the histopathologic features of the primary tumor (Fig. 1B). A re-joint evaluation of the slides referring to the diagnosis of primary tumor was carried out, confirming the initial diagnosis. The patient was triaged to exclusive concomitant chemoradiotherapy (5-fluorouracil, 1,000 mg/m2/d, 2 cycles, 96 h continuous infusion i.v., d1-4,; mitomycin
C, 10 mg/m2, bolus i.v., d1, and external beam radiation 4-week split course 23.4 Gy+23.4 Gy). Imaging evaluation documented no change of disease, and the patient was administered salvage chemotherapy with ifosfamide (2,400 mg/m2 d1-5) every three weeks. After 4 cycles, the patient experienced progression of disease (enlargement of the vaginal lesion, appearance of a new osteolytic lesion of the left ischium), and chemotherapy with the combination gemcitabine (800 mg/m2/d1, 8) and taxotere (75 mg/m2 d8) every three weeks was attempted. On progression after three cycles, treatment options were discussed with the patient and her family, and only supportive care (biphosphonates, antalgic therapy) was adopted. The patient died after 3 months.
Materials and methods Immunohistochemical analysis was performed on 4-mm formalin fixed, paraffin-embedded tumor samples. The following antibodies were used: anti-estrogen receptor (ER) monoclonal antibody (MoAb) (clone 1-D5 diluted 1:50), anti-progesterone receptor (PR) MoAb (clone 1-A6, dilution 1:50), anti-epithelial membrane antigen (EMA) MoAb (clone GP1.4, dilution 1:40),
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anti-vimentin MoAb (clone V9, dilution 1:200), anti S-100 polyclonal antibody (dilution 1:200), all purchased from Ylem, Rome, Italy, and anti p53 MoAb (clone DO-7, dilution 1:20) and anti-ki67 MoAb (clone Mib-1, dilution 1:100) from Dako, Glostrup, Denmark). Immunohistochemical characterization was made using a labeled streptavidin biotin peroxidase method (LSABPx). Visualization of the reaction was performed with the Dako LSAB 2 Kit peroxidase, containing labeled streptavidin biotin for primary rabbit/mouse antibody and diaminobenzidine (DAB). Sections were briefly counterstained with hematoxylin, dehydrated, cleared, and coverslipped.
Results The results of immunohistochemical staining of all biological markers examined are summarized in Table 1: Case 1 was found to be ER- and PR-negative both in the primary and in the recurrent tumor, while Case 2 was characterized by positive ER and PR immunoreactions in the vast majority of tumor cells of the primary tumor, and by complete loss of steroid hormone receptor expression in both carcinomatous and sarcomatous components of the recurrence. p53 was expressed in only 30% and 40% of tumor cells from primary tumor in Cases 1 and 2, respectively, while in recurrent carcinosarcoma, a higher percentage of epithelial tumor cells showed p53 positivity compared to the sarcomatous component. Overall, the proliferative rate, represented by the percentage of ki67-positive cells, was high in primary and recurrent tumor in both cases. EMA was, as expected, positive in a larger proportion of epithelial cells both in primary tumors and recurrent disease, and was also detectable in sarcomatous elements. As far as vimentin immunoreaction is concerned, the sarcomatous component of the recurrence showed positive immunostaining in the totality of cells, while the percentage of vimentin positivity in the carcinomatous component was low. Interestingly, positivity for vimentin showed a positive Table 1.
immunoreaction of up to 35% and 50% in the primary tumor in Cases 1 and 2, respectively. In both primary tumors, S-100 immunoreaction was negative, while it resulted positive in 100% of the sarcomatous component of the recurrent tumor only in Case 1.
Discussion Although carcinosarcomas of the uterus are relatively rare diseases, they exhibit a very aggressive behavior, and effective treatment still remains a clinical challenge [4,2]. Although the precise nature of the relationship between the carcinomatous and the sarcomatous components remains to be clarified, evidence has been accumulated over recent years that uterine carcinosarcoma should be regarded as metaplastic carcinomas: indeed, the carcinomatous component is considered the ‘‘driving force’’ of the disease, being the most frequently found element in tumor-involved lympho-vascular space, metastatic lesions, and representing, above all, the major determinant of clinical outcome [12,11]. Therefore, the emergence of sarcomatous elements would represent the evolution of subclones arising from high grade endometrial carcinomas [8,13]. To our knowledge, no evidence of patients showing progression from primary endometrial tumors to carcinomas with metaplastic sarcomatous features has been reported in the literature. We here report two cases of primary endometrial carcinomas recurring as carcinosarcoma. In this context, the critical issue is represented by the possible, unnoticed coexistence of carcinomatous and sarcomatous components in the primary tumor: although this cannot be excluded in principle, it has to be taken into account that two blocks for each cm of the largest diameter of the primary tumor is usually examined in our Pathology Institute, according to previous reports emphasizing the issue of sampling adequacy [14]; moreover, in both cases, a re-joint evaluation of the slides referring to the primary tumor was performed, confirming the initial diagnosis: indeed, in both cases, the primary
Immunohistochemical analysis of biological markers in primary endometrial cancer and recurrent carcinosarcoma Percentage of cells showing positive immunoreaction
Case 1 Primary tumor Recurrence Case 2 Primary tumor Recurrence
ER
PR
p53
Ki67
P27
EMA
Vimentin
S100
carcinomatous sarcomatous
5 0 0
0 0 0
30 70 10
80 80 20
60 30 10
60 100 10
35 10 100
0 0 100
carcinomatous sarcomatous
90 0 0
90 0 0
40 80 0
40 80 80
50 10 10
80 100 15
50 10 100
0 0
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tumor was represented by a poorly differentiated endometrial carcinoma, and the same histology was found in the carcinomatous component of the recurrence, suggesting the metaplastic sarcomatous evolution from high grade endometrial cancer. Although several efforts are being made to develop a comprehensive model of endometrial carcinogenesis, including carcinosarcomas as well [13,7,10], the molecular alterations responsible for the sarcomatous evolution remain unknown. The absence or loss of ER and PR as well as the high percentage of ki67-positive tumor cells might reflect the biological aggressiveness of carcinosarcomatous recurrence. It is also worth noting that p53 protein positivity was shown in a relatively low percentage of tumor cells in the primary tumor, while it increased up to 70–80% in the carcinomatous component of the carcinosarcomatous recurrence; indeed, the crucial role of p53 alterations in the pathogenetic pathways leading to the evolution from poorly differentiated endometrioid to serous endometrial carcinomas and, eventually, to uterine carcinosarcoma has already been proposed [13,7,10]. Indeed, three cases of adenocarcinoma of the ovary recurring as heterologous carcinosarcoma have also been reported [6,5,9]. Interestingly, we found in both cases a higher percentage of p27-positive cells in primary tumor compared to the epithelial and stromal components of the carcinosarcomatous recurrence. This data seems to contrast with the results reported by [1], who documented that p27 expression is more frequently reduced in endometrial cancer than in the epithelial component of carcinosarcoma. However, it has to be acknowledged that in the series by [1], primary endometrial tumors and carcinosarcomas were obviously from different patients, and, as emphasized by [3], no attention was paid to the histotype of the epithelial component of carcinosarcoma. In conclusion, we described two cases of high grade endometrial carcinomas recurring as carcinosarcoma, thus providing evidence that the metaplastic sarcomatous evolution is a very rare event which can occur in patients with anaplastic endometrial cancer.
Acknowledgments This work was financially supported by grants from Associazione Italiana per la Ricerca sul Cancro (A.I.R.C) and I.R.I.S-PCR-OG-ONLUS (www.iris-og.com).
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