Carcinosarcoma

Carcinosarcoma is an aggressive neoplasm of the female genital tract, which comprises 4% of malignancies of the uterine corpus. A population-based study (1976–1985) from Norway showed a trend of increasing incidence and mortality in carcinosarcoma over time, and a survey carried out by the SEER group between 1989 and 1999 from the USA, the incidence rates of carcinosarcoma were 1.71, 4.28 and 0.99 per 100,000 women-years in white, black and the other races. This malignancy has biphasic epithelial and mesenchymal components. The histogenesis is unclear, but recent immunohistochemical and molecular genetic studies have attributed carcinosarcoma to a metaplastic carcinoma.

The median age is around 58–67 years in various studies, but most women are of postmenopausal age. Thus, abnormal vaginal bleeding or postmenopausal bleeding is the most frequent presenting symptom occurring in more than 85% of women. In addition, pelvic discomfort, enlarged pelvic mass and profound foul-smelling vaginal discharge are also often associated with abnormal vaginal bleeding. The triad of painful postmenopausal bleeding in a woman with friable tissue that is prolapsing through a dilated cervix is highly indicative of a polypoid carcinosarcoma.

On the basis of the cancer registry from the SEER database of the National Cancer Institute between 1988 and 2003, the American Joint Committee on Cancer stage of 2662 women with carcinosarcoma was as follows: 65% Stage I, 14% Stage II and 21% Stage III. Clinical stage I or II carcinosarcoma (grossly confined to the uterus) were often upstaged (30–61%) at the time of comprehensive surgical staging. The rates of pelvic or para-aortic lymph-node metastasis ranged from 13.2–90% according to clinical stage. The prognosis was poor even in early stage (44–74% of 5-year overall survival in FIGO stage I–II), and 5-year overall survival ranged from 6–38% in stage I–IV. Uterine carcinosarcoma staging should use the same staging system applied to endometrial cancer, which was revised by the FIGO committee in 2009.

In a study of 55 women with carcinosarcoma immunostained with antibodies to epidermal growth factor receptor and epidermal growth factor receptor 2 (ERBB2), fluorescent in-situ hybridisation for ERBB2 gene amplification was carried out on all women showing 2+ or 3+ ERBB2 staining by immunohistochemistry. Epidermal growth factor receptor expression was identified in most of the tumours (45 out of 55, 82%). ERBB2 overexpression (3+) was seen in 14 out of 55 (25%) cases, and ERBB2 gene amplification was seen in 11 (20%) cases.

Leiomyosarcoma

Leiomyosarcoma represents about 1.3% of uterine malignancies and about one-third of uterine sarcomas. About one out of every 8000 smooth- muscle tumours of the uterus is an LMS, and less than 1% of women with clinical uterine leiomyoma have LMS. LMS constitutes 13% of all uterine sarcomas, second to mixed mesodermal sarcoma in a large prospective study of 453 women with clinical stage I or II uterine sarcoma. The age of women with LMS is about 10 years older than those with leiomyoma, most being aged over 40 years. The median age of the 1396 women with LMS was 52 years (range 18–92 years) from the SEER database between 1988 and 2003.

The most common symptoms were abdominal pain (35%), abnormal vaginal bleeding (53%) or palpable abdominal mass (14%). The pain is often a uterine colic associated with the passage of clots from the vagina, and the intensity of pain may account for the short interval from onset of symptoms to diagnosis. Uterine enlargement with rapidly growing uterine leiomyoma may be a malignant process requiring surgical removal. Most experts consider a leiomyoma that doubles in size within 3–6 months a matter for concern, but the precise definition of ‘rapidly growing’ remains controversial. According to our literature review, only 0.27–2.6% of women identified as the presenting sign of ‘rapidly growing uterus’ were confirmed as having LMS. Symptoms and signs resemble those of more common uterine leiomyomas, so preoperative distinction between benign and malignant uterine tumours has been a challenge for clinicians.

The histopathologic diagnosis of uterine LMS is usually straightforward: to meet at least two criteria of microscopic features, including severe nuclear atypia, significant mitotic count more than 10 per 10 high-power-fields and coagulative tumour cell necrosis. The findings of immunohistochemical analyses in LMS are summarised well in the study by Amand et al. Most uterine LMS express the platelet-derived growth factor receptor-alfa, Wilms’ tumour gene 1, aromatase, and gonadotropin-releasing hormone receptor. Expression profiles of oestrogen and progesterone receptor show wide variations. Androgen receptor positivity has been detected in 40% of uterine LMS. Studies on platelet-derived growth factor-beta reported conflicting findings. Uterine LMS almost always have absence of epidermal growth factor receptor and ERBB2 expression.

Estimates of outcome in uterine LMS vary widely according to different stage and other risk factors. Five-year survival rates ranged between 18.8% and 65% for all stages of disease, and between 52% and 85% in stage I disease. The reported risk of recurrence varies from 45 to 73%. A comparison between the American Joint Committee on Cancer and old FIGO staging systems found overlapping stages predictive of progression-free and overall survival for uterine LMS. The results indicated that low-grade and serosal involvement were significant prognostic factors. New classifications, however, have been developed for LMS ESS and adenosarcomas, respectively ( Table 1 ). They were approved by FIGO committee in 2009.

Endometrial stromal sarcomas

According to the latest World Health Organization classification, the term ‘endometrial stromal sarcoma’ is applied to the neoplasms typically composed of cells that resemble endometrial stromal cells of the proliferative endometrium. The tumour is classified into a low-grade and high-grade variety divided at the cut-off point of mitotic count less than or more than 10 mitoses per 10 high-power-fields. The ESS is frequently associated with varying degrees of permeation of the myometrium, including worm-like plus from the tumour that fill and distend myometrial veins, even further extending into parametrial veins and lymphatics. The old classification of high-grade ESS, however, has been replaced by undifferentiated endometrial sarcoma caused by its exhibition of extensive myometrial invasion, severe nuclear pleomorphism, high mitotic activity, tumour cell necrosis, or all, and lack of smooth muscle or endometrial stromal differentiation. Expression profiles frequently contain the oestrogen and progesterone receptors, platelet-derived growth factor receptor-alfa, aromatase, GnRH-R, and Wilms’ tumour gene 1. CD117 (KIT) was positive in only 11% of investigated ESS (six out of 53). The two studies on platelet-derived growth factor receptor-beta show opposite findings.

The most common symptom of ESS is irregular vaginal bleeding. Asymptomatic uterine enlargement, pelvic pain or palpable mass are also common symptoms. The mean age at diagnosis of all 831 women with ESS was 52 years (range, 17–96 years) from the SEER database of the National Cancer Institute from 1988 to 2003. In total, 65% belonged to Stage I and II, and 35% Stage III and IV. The 5-year disease-specific survival in women with stage I and II compared with III and IV is 89.3% and 50.3%, respectively.

Carcinosarcoma

Carcinosarcoma is an aggressive neoplasm of the female genital tract, which comprises 4% of malignancies of the uterine corpus. A population-based study (1976–1985) from Norway showed a trend of increasing incidence and mortality in carcinosarcoma over time, and a survey carried out by the SEER group between 1989 and 1999 from the USA, the incidence rates of carcinosarcoma were 1.71, 4.28 and 0.99 per 100,000 women-years in white, black and the other races. This malignancy has biphasic epithelial and mesenchymal components. The histogenesis is unclear, but recent immunohistochemical and molecular genetic studies have attributed carcinosarcoma to a metaplastic carcinoma.

The median age is around 58–67 years in various studies, but most women are of postmenopausal age. Thus, abnormal vaginal bleeding or postmenopausal bleeding is the most frequent presenting symptom occurring in more than 85% of women. In addition, pelvic discomfort, enlarged pelvic mass and profound foul-smelling vaginal discharge are also often associated with abnormal vaginal bleeding. The triad of painful postmenopausal bleeding in a woman with friable tissue that is prolapsing through a dilated cervix is highly indicative of a polypoid carcinosarcoma.

On the basis of the cancer registry from the SEER database of the National Cancer Institute between 1988 and 2003, the American Joint Committee on Cancer stage of 2662 women with carcinosarcoma was as follows: 65% Stage I, 14% Stage II and 21% Stage III. Clinical stage I or II carcinosarcoma (grossly confined to the uterus) were often upstaged (30–61%) at the time of comprehensive surgical staging. The rates of pelvic or para-aortic lymph-node metastasis ranged from 13.2–90% according to clinical stage. The prognosis was poor even in early stage (44–74% of 5-year overall survival in FIGO stage I–II), and 5-year overall survival ranged from 6–38% in stage I–IV. Uterine carcinosarcoma staging should use the same staging system applied to endometrial cancer, which was revised by the FIGO committee in 2009.

In a study of 55 women with carcinosarcoma immunostained with antibodies to epidermal growth factor receptor and epidermal growth factor receptor 2 (ERBB2), fluorescent in-situ hybridisation for ERBB2 gene amplification was carried out on all women showing 2+ or 3+ ERBB2 staining by immunohistochemistry. Epidermal growth factor receptor expression was identified in most of the tumours (45 out of 55, 82%). ERBB2 overexpression (3+) was seen in 14 out of 55 (25%) cases, and ERBB2 gene amplification was seen in 11 (20%) cases.

Leiomyosarcoma

Leiomyosarcoma represents about 1.3% of uterine malignancies and about one-third of uterine sarcomas. About one out of every 8000 smooth- muscle tumours of the uterus is an LMS, and less than 1% of women with clinical uterine leiomyoma have LMS. LMS constitutes 13% of all uterine sarcomas, second to mixed mesodermal sarcoma in a large prospective study of 453 women with clinical stage I or II uterine sarcoma. The age of women with LMS is about 10 years older than those with leiomyoma, most being aged over 40 years. The median age of the 1396 women with LMS was 52 years (range 18–92 years) from the SEER database between 1988 and 2003.

The most common symptoms were abdominal pain (35%), abnormal vaginal bleeding (53%) or palpable abdominal mass (14%). The pain is often a uterine colic associated with the passage of clots from the vagina, and the intensity of pain may account for the short interval from onset of symptoms to diagnosis. Uterine enlargement with rapidly growing uterine leiomyoma may be a malignant process requiring surgical removal. Most experts consider a leiomyoma that doubles in size within 3–6 months a matter for concern, but the precise definition of ‘rapidly growing’ remains controversial. According to our literature review, only 0.27–2.6% of women identified as the presenting sign of ‘rapidly growing uterus’ were confirmed as having LMS. Symptoms and signs resemble those of more common uterine leiomyomas, so preoperative distinction between benign and malignant uterine tumours has been a challenge for clinicians.

The histopathologic diagnosis of uterine LMS is usually straightforward: to meet at least two criteria of microscopic features, including severe nuclear atypia, significant mitotic count more than 10 per 10 high-power-fields and coagulative tumour cell necrosis. The findings of immunohistochemical analyses in LMS are summarised well in the study by Amand et al. Most uterine LMS express the platelet-derived growth factor receptor-alfa, Wilms’ tumour gene 1, aromatase, and gonadotropin-releasing hormone receptor. Expression profiles of oestrogen and progesterone receptor show wide variations. Androgen receptor positivity has been detected in 40% of uterine LMS. Studies on platelet-derived growth factor-beta reported conflicting findings. Uterine LMS almost always have absence of epidermal growth factor receptor and ERBB2 expression.

Estimates of outcome in uterine LMS vary widely according to different stage and other risk factors. Five-year survival rates ranged between 18.8% and 65% for all stages of disease, and between 52% and 85% in stage I disease. The reported risk of recurrence varies from 45 to 73%. A comparison between the American Joint Committee on Cancer and old FIGO staging systems found overlapping stages predictive of progression-free and overall survival for uterine LMS. The results indicated that low-grade and serosal involvement were significant prognostic factors. New classifications, however, have been developed for LMS ESS and adenosarcomas, respectively ( Table 1 ). They were approved by FIGO committee in 2009.

Endometrial stromal sarcomas

According to the latest World Health Organization classification, the term ‘endometrial stromal sarcoma’ is applied to the neoplasms typically composed of cells that resemble endometrial stromal cells of the proliferative endometrium. The tumour is classified into a low-grade and high-grade variety divided at the cut-off point of mitotic count less than or more than 10 mitoses per 10 high-power-fields. The ESS is frequently associated with varying degrees of permeation of the myometrium, including worm-like plus from the tumour that fill and distend myometrial veins, even further extending into parametrial veins and lymphatics. The old classification of high-grade ESS, however, has been replaced by undifferentiated endometrial sarcoma caused by its exhibition of extensive myometrial invasion, severe nuclear pleomorphism, high mitotic activity, tumour cell necrosis, or all, and lack of smooth muscle or endometrial stromal differentiation. Expression profiles frequently contain the oestrogen and progesterone receptors, platelet-derived growth factor receptor-alfa, aromatase, GnRH-R, and Wilms’ tumour gene 1. CD117 (KIT) was positive in only 11% of investigated ESS (six out of 53). The two studies on platelet-derived growth factor receptor-beta show opposite findings.

The most common symptom of ESS is irregular vaginal bleeding. Asymptomatic uterine enlargement, pelvic pain or palpable mass are also common symptoms. The mean age at diagnosis of all 831 women with ESS was 52 years (range, 17–96 years) from the SEER database of the National Cancer Institute from 1988 to 2003. In total, 65% belonged to Stage I and II, and 35% Stage III and IV. The 5-year disease-specific survival in women with stage I and II compared with III and IV is 89.3% and 50.3%, respectively.