Type II carcinomas

T hese generally occur in women a decade later than type I carcinoma, and in contrast to type I carcinoma they usually arise in the setting of endometrial atrophy (Fig. 22-29). Type II tumors are by definition poorly differentiated (grade 3) tumors and account for approximately 15% of cases of endometrial carcinoma. The most common subtype is serous carcinoma, referred to as such because of morphologic and biologic overlap with ovarian serous carcinoma. There are less common histologic subtypes (clear cell carcinoma and malignant mixed müllerian tumor) within this category, but very little is known about their pathogenesis. The most frequent alteration described thus far in serous endometrial carcinoma is mutation of the p53 tumor suppressor gene. Alterations in other genes have been described, but at much lower frequency. Mutations in p53 are present in at least 90% of serous endometrial carcinoma.57 The majority of mutations are missense mutations that result in an accumulation of the altered protein that can be detected with immunohistochemistry as strong, diffuse staining of the tumor cell nuclei (Fig. 22-30B and D).

The precursor of serous carcinoma, endometrial intraepithelial carcinoma (EIC), consists of cells identical to those of serous carcinoma but lacks identifiable stromal invasion. Mutations in p53 are found in approximately 75% of these lesions, suggesting that mutation of p53 is an early event in serous endometrial carcinoma. Thus, serous carcinoma presumably begins as a surface epithelial neoplasm that extends into adjacent gland structures and later invades endometrial stroma. Their generally poorer prognosis is thought to be a consequence of a propensity to exfoliate, undergo transtubal spread, and implant on peritoneal surfaces like their ovarian counterparts. They have often spread outside of the uterus at the time of diagnosis.

Morphology. Generally, serous carcinomas arise in small atrophic uteri and are often large bulky tumors or deeply invasive into the myometrium. The precursor lesion, endometrial intraepithelial carcinoma, consists of malignant cells identical to those of serous carcinoma but they remain contained to the gland surface without identifiable stromal invasion (see Fig. 22-30A and B). The invasive lesions may have a papillary growth pattern composed of cells with marked cytologic atypia including high nuclear-to-cytoplasmic ratio, atypical mitotic figures, heterochromasia, and prominent nucleoli (see Fig. 22-30C and D). However, they can also have a predominantly glandular growth pattern that can be distinguished from endometroid carcinoma by the marked cytologic atypia. All of the non-endometrioid carcinomas are classified as grade 3 irrespective of histologic pattern. Serous carcinoma, despite relatively superficial endometrial involvement, may be associated with extensive peritoneal disease, suggesting spread by routes (i.e., tubal or lymphatic transmission) other than direct invasion.

Malignant mixed müllerian tumors

MMMTs (previously referred to as carcinosarcomas) consist of endometrial adenocarcinomas with malignant changes in the stroma.61 The stroma tends to differentiate into a variety of malignant mesodermal components, including muscle, cartilage, and even osteoid. The epithelial and stromal components are presumably derived from the same cell, a concept supported by immunohistochemical and molecular studies.62 Both clinicopathologic and molecular studies suggest that the vast majority of these tumors are carcinomas with sarcomatous differentiation. The mechanisms underlying the sarcomatous transformation are unknown. MMMTs occur in postmenopausal women and present with postmenopausal bleeding.

Morphology. In gross appearance, MMMTs are fleshier than adenocarcinomas, may be bulky and polypoid, and sometimes protrude through the cervical os. On histology, the tumors consist of adenocarcinoma (endometrioid, serous, or clear cell) mixed with the malignant mesenchymal (sarcoma) elements (Fig. 22-31A); alternatively, the tumor may contain two distinct and separate epithelial and mesenchymal components. Sarcomatous components may also mimic extrauterine tissues (e.g., striated muscle, cartilage, adipose tissue, and bone). Metastases usually contain only epithelial components (Fig. 22-31B).

Outcome of MMMTs is determined primarily by depth of invasion and stage. As with endometrial carcinomas, the prognosis is influenced by the grade and type of the adenocarcinoma, being poorest with serous differentiation. These tumors are highly malignant, with 5-year survival rate of 25% to 30%.61

Stage I.	Carcinoma is confined to the corpus uteri itself.
Stage II.	Carcinoma involves the corpus and the cervix.
Stage III.	Carcinoma extends outside the uterus but not outside the true pelvis.
Stage IV.	Carcinoma extends outside the true pelvis or involves the mucosa of the bladder or the rectum.

S taging of types I and II of endometrial adenocarcinoma and MMMTs is as follows :

Tumors of the Myometrium