Joanne Rutgers

This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.

Forty-three patients with the androgen insensitivity syndrome (AIS), ages 14 to 83 (average 27) years, were studied. Forty patients had complete AIS and three patients had incomplete AIS. Microscopic examination of the testes revealed immature tubules, which contained rare spermatogonia in 28% of the cases. Prominent Leydig cells and a spindle-cell stroma resembling ovarian stroma were found in a majority of cases. The organization of the testicular parenchyma could be classified into one of four patterns: diffuse tubulostromal, lobular tubulostromal, mixed tubulostromal, or stromal-predominant. Hamartomas were present in 63% and Sertoli cell adenomas in 23% of the cases. Malignant tumors developed in 9% of the patients and comprised two seminomas, one intratubular germ cell neoplasm with early stromal invasion, and a malignant sex cord tumor. At least one fallopian tube was present in 35% of the cases.

BACKGROUND: The purpose of this study was to evaluate the clinical and pathologic factors associated with survival in patients with neuroendocrine (NE) cervical carcinoma. METHODS: All patients with NE cervical carcinoma diagnosed between 1979-2001 were identified from tumor registry databases at two hospitals. Data were collected from hospital charts, office records, and tumor registry files. The impact of clinical and pathologic risk factors on the survival of patients with small cell NE carcinoma of the cervix was evaluated using Kaplan-Meier life table analyses and log-rank tests. The independent prognostic factors found to be predictive of survival in univariate analysis were evaluated using Cox regression. All tests were two-tailed with P values < 0.05 considered significant. RESULTS: Thirty-four patients (median age, 42 years) were diagnosed with neuroendocrine cervical carcinoma, which included 21 with International Federation of Gynecology and Obstetrics (FIGO) Stage I disease, 6 with FIGO Stage II disease, 5 with FIGO Stage III disease, and 2 with FIGO Stage IV disease. Seventeen patients underwent a radical and 6 patients underwent a simple hysterectomy. Fourteen women received adjuvant therapy with pelvic radiation and/or cisplatin-based chemotherapy. Ten women received primary radiotherapy with (n = 5) or without (n = 4) chemotherapy and the remaining patient refused therapy. Women with early-stage (Stage I-IIA) disease had median survival rates of 31 months compared with 10 months in the advanced-stage (Stage IIB-IVB) group (P = 0.002). In univariate analysis, advanced stage (P = 0.002), tumor size >2 cm (P = 0.02), margin involvement (P = 0.016), pure versus a mixed histologic pattern (P = 0.04), margin status (P = 0.016), and smoking (P = 0.04) were considered poor prognostic factors. In multivariate analysis, smoking for early-stage patients and stage of disease in the overall population remained as independent prognostic factors of survival. CONCLUSIONS: Smoking and advanced stage are reported to be poor prognostic factors for survival in patients with NE small cell carcinoma of the cervix. Only those with early lesions amenable to extirpation are cured. The role of primary or postoperative radiation with or without chemotherapy is unclear and yields uniformly poor results, particularly in patients with advanced lesions. Clinical trials are needed.

The management of endocervical adenocarcinoma is largely based on tumor size and depth of invasion (DOI); however, DOI is difficult to measure accurately. The surgical treatment includes resection of regional lymph nodes, even though most lymph nodes are negative and lymphadenectomies can cause significant morbidity. We have investigated alternative parameters to better identify patients at risk of node metastases. Cases of invasive endocervical adenocarcinoma from 12 institutions were reviewed, and clinical/pathologic features assessed: patients' age, tumor size, DOI, differentiation, lymph-vascular invasion, lymph node metastases, recurrences, and stage. Cases were classified according to a new pattern-based system into Pattern A (well-demarcated glands), B (early destructive stromal invasion arising from well-demarcated glands), and C (diffuse destructive invasion). In total, 352 cases (FIGO Stages I-IV) were identified. Patients' age ranged from 20 to 83 years (mean 45), DOI ranged from 0.2 to 27 mm (mean 6.73), and lymph-vascular invasion was present in 141 cases. Forty-nine (13.9%) demonstrated lymph node metastases. Using this new system, 73 patients (20.7%) with Pattern A tumors (all Stage I) were identified. None had lymph node metastases and/or recurrences. Ninety patients (25.6%) had Pattern B tumors, of which 4 (4.4%) had positive nodes; whereas 189 (53.7%) had Pattern C tumors, of which 45 (23.8%) had metastatic nodes. The proposed classification system can spare 20.7% of patients (Pattern A) of unnecessary lymphadenectomy. Patients with Pattern B rarely present with positive nodes. An aggressive approach is justified in patients with Pattern C. This classification system is simple, easy to apply, and clinically significant.