Vinita Parkash

Low-grade endometrial stromal sarcoma: hormonal aspects☆

OBJECTIVE The goal of this work was to determine whether exposure to estrogen following treatment of low-grade endometrial stromal sarcomas affects clinical outcome. METHODS Twenty-two patients with low-grade endometrial stromal sarcomas were reviewed to determine whether they were exposed to exogenous or endogenous estrogen and/or progestins following their diagnosis and whether exposure to these hormones might have influenced their prognosis. Estrogen receptor (ER) alpha and beta and progestin receptor (PR) status were analyzed from paraffin-embedded tissue by immunohistochemistry and ER mRNA was measured in fresh tissue by reverse transcription polymerase chain reaction (RT-PCR). RESULTS Ten of the twenty-two patients with low-grade endometrial stromal sarcomas developed recurrent disease. Four of five patients (80%) who received estrogen replacement therapy (ERT) recurred. Four of eight patients (50%) with retained ovaries recurred. Eight of the ten specimens available for analysis were positive for ERalpha, none were positive for ERbeta, and 9 of 10 were positive for PR. Four of thirteen patients who received progestins as adjuvant therapy recurred, compared with 6 of 9 patients who did not receive progestins (31% vs 67%). Eight recurrences were treated with progestin therapy and 7 (88%) of them had either stable disease (3/8, 38%) or complete response (4/8, 50%). CONCLUSIONS Our results suggest that ERT may be detrimental in patients with low-grade endometrial stromal sarcoma. Retention of normally functioning ovaries, on the other hand, may not significantly affect the recurrence rate following hysterectomy alone in Stage I patients. The lack of ERbeta expression in endometrial stromal sarcomas compared with normal endometrial stromal cells suggests that loss of ERbeta may be a marker for malignancy. Progestin therapy should be routinely considered for adjuvant therapy and for the treatment of recurrent endometrial stromal sarcomas.

Desmoplastic small round cell tumor of the pleura.

Three cases of desmoplastic small round cell tumor (DSRCT) with multiphenotypic differentiation, primary in the pleura, are presented. This is a previously unrecognized site for this tumor type. Two patients were male and one female aged 29, 24, and 17 years. All presented with chest pain and were found to have pleural-based tumors associated with pleural effusion. Abdominal involvement was not present in any of the cases. Histologically, the tumor showed the characteristic features of intra-abdominal DSRCT, including angulated nests of small cells embedded in a vascular fibroblastic stroma, focal rhabdoid phenotype, and areas of central necrosis. The neoplastic cells showed evidence of epithelial, mesenchymal, and neural differentiation with characteristic dot-like positivity for vimentin and desmin topographically corresponding to perinuclear aggregates of intermediate filaments identified on electron microscopy in one case. Two patients died of disease 2 years and 15 months after presentation, respectively, and one patient is alive with disease 18 months after presentation. The histogenesis of DSRCT is unknown. Most previously reported cases involved the peritoneum or tunica vaginalis, suggesting a histogenetic relationship to the mesothelium. The occurrence of these tumors in the pleura lends further support to this theory.

Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma

PURPOSE Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a rare type of T-cell lymphoma that arises around breast implants. The optimal management of this disease has not been established. The goal of this study is to evaluate the efficacy of different therapies used in patients with BI-ALCL to determine an optimal treatment approach. PATIENTS AND METHODS In this study, we applied strict criteria to pathologic findings, assessed therapies used, and conducted a clinical follow-up of 87 patients with BI-ALCL, including 50 previously reported in the literature and 37 unreported. A Prentice, Williams, and Peterson model was used to assess the rate of events for each therapeutic intervention. RESULTS The median and mean follow-up times were 45 and 30 months, respectively (range, 3 to 217 months). The median overall survival (OS) time after diagnosis of BI-ALCL was 13 years, and the OS rate was 93% and 89% at 3 and 5 years, respectively. Patients with lymphoma confined by the fibrous capsule surrounding the implant had better event-free survival (EFS) and OS than did patients with lymphoma that had spread beyond the capsule (P = .03). Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014) than did patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. CONCLUSION Surgical management with complete surgical excision is essential to achieve optimal EFS in patients with BI-ALCL.

Benign mesothelial cells in mediastinal lymph nodes.

Inclusions of benign tissues in lymph nodes are most often aberrant glandular tissue, including endosalpingiosis, the thyroid, parotid, breast, and pancreas. Nonglandular inclusions are rare and include nevus cells and decidua. Mesothelial cells in lymph nodes are exceedingly rare; only eight cases have been reported in mediastinal lymph nodes and three cases in abdominal lymph nodes. The incidence of benign mesothelial cells in mediastinal lymph nodes in patients with a history of pericarditis or pleuritis is reported in this study. A retrospective search showed eight cases with removal of mediastinal lymph nodes in the absence of neoplasm. Hematoxylin and eosin-stained sections were examined in all cases. Immunohistochemical stains for CAM 5.2 were performed in all cases, and stains for AE1/AE3, Ber-EP4, carcinoembryonic antigen, Leu-M1, B72.3, and S-100 were performed in one case. CAM 5.2-positive cells with features of mesothelial cells were present in five of eight cases. In all cases, the cells were present in nodal sinuses and appeared as single cells or small clusters. The cells were missed on routine hematoxylin and eosin sections in all cases but one, in which they were numerous and mimicked metastatic carcinoma. Malignancy was not found in any of the cases preoperatively, at the time of surgery, or during the follow-up period. Benign mesothelial cells may embolize to regional lymph nodes in pleuritis or pericarditis. In most cases, these cells are few and undetectable on routine sections. Rarely, hyperplastic mesothelial cells may be present and must be distinguished from metastatic carcinoma, mesothelioma, and melanoma.

Quantitative analysis of follicle-stimulating hormone receptor in ovarian epithelial tumors: A novel approach to explain the field effect of ovarian cancer development in secondary mullerian systems

The role of FSHR expression in ovarian cancer development is not clear. We examined quantitative expression of FSHR in different types of OET, presumed precursor lesions and peritoneal implants and further discussed FSH as a key growth‐promotion factor for the process of ovarian epithelial tumorigenesis. Thirty‐five primary OET specimens, including 5 serous cystadenomas, 4 papillary serous cystadenomas, 9 SBTs and 17 serous carcinomas, were examined for quantitative FSHR expression. Ten paired samples (3 benign cystadenomas, 5 SBTs and 2 carcinomas) were obtained from several morphologically different areas, including benign‐looking, borderline and cancerous areas in the same OETs, and from the remaining ovarian tissue and contralateral ovaries. Competitive RT‐PCR was performed to measure the quantitative expression of FSHR in each tissue sample. FSHR expression levels were compared among nonpaired samples and within paired samples. We found that OSE had the lowest FSHR expression, whereas antral follicles had the highest level. Within benign OETs, papillary serous cystadenomas have 4.9‐fold higher FSHR levels than nonpapillary serous cystadenomas. SBTs had the highest level of FSHR expression, which was 12.8‐fold, 2.7‐fold and 2.4‐fold higher than that of serous cystadenomas, papillary serous cystadenomas and grade 1 carcinomas, respectively. A similarly high level of FSHR mRNA was found in peritoneal implants, which were associated with SBTs. FSHR levels among serous carcinomas decreased with an increase in carcinoma grade. Grade 3 carcinomas had the lowest FSHR level, which was similar to that of serous cystadenomas, while grade 1 carcinomas had 6.5‐fold higher FSHR levels than those in serous cystadenomas. Our results suggest that not only serum FSH but also FSHR in ovarian epithelium may play important roles in ovarian OET development. Both the receptor and ligand may act in a synergistic way to promote tumor growth. The observation that high FSHR levels are present in peritoneal implants suggests that FSH may also play a similar role in the development of peritoneal serous tumors. From this perspective, circulating FSH may be considered a driving force in the field effect theory for the development of both ovarian neoplasms and their associated peritoneal implants. However, the exact role of FSH and/or FSHR in the development of epithelial tumors arising in both the ovary and peritoneum needs further investigation.

Frequent expression of napsin a in clear cell carcinoma of the endometrium: Potential diagnostic utility

The histotyping of high-grade endometrial carcinomas with clear cells may be subject to significant interobserver variability, which suggests that a biomarker that can distinguish endometrial clear cell carcinoma (CCC) from its mimics would be of diagnostic utility. This study assessed the usefulness of napsin A immunohistochemistry in the diagnosis of CCC, on the basis of an analysis of 77 cases diagnosed as such at 9 institutions. After being independently reviewed by a subset of 3 pathologists, cases for which there was diagnostic consensus among all 3 reviewers in agreement with the primary contributor (n=60) were used to establish a “consensus group” that served as a gold standard relative to which napsin A performance was assessed. Duplicate, 1.0-mm-core tissue microarrays were constructed from the 54 cases in the consensus group for which requisite materials were available, as well as from 49 endometrial endometrioid carcinomas (all grades) and 17 endometrial serous carcinomas. Napsin A immunohistochemical analysis was performed on the microarrays and on the 17 cases for which there was no diagnostic consensus, with scoring based on the proportion of immunoreactive cells (0, 1+, 2+, and 3+ indicative of 0, 1% to 25%, 26% to 49%, and ≥50% immunoreactive cells, respectively). The distribution of scores for the 49 CCC cases with evaluable cores was as follows: 0, n=6; 1+, n=6; 2+, n=8; 3+, n=29. Among the evaluable cases, the frequency of ≥1+ napsin A immunoreactivity was significantly higher in CCCs (43/49, 88%) than in endometrial serous carcinomas (1/13, 7.7%; P<0.0001) and endometrial endometrioid carcinomas (0/49, 0%; P<0.0001). The sensitivity, specificity, negative predictive value, and positive predictive value of ≥1+ napsin A expression in predicting the consensus clear cell histotype were 0.88 (95% confidence interval [CI], 0.75-0.95), 0.98 (95% CI, 0.9-1), 0.91 (95% CI, 0.86-0.96), and 0.98 (95% CI, 0.86-1), respectively. Napsin A expression was not associated with survival or clinicopathologic factors. In the group of cases without diagnostic consensus for CCC, 50% showed ≥1+ napsin A expression; all napsin A-negative cases had previously been classified as non-CCC by ≥2 reviewers, whereas only 37.5% of the napsin A-positive cases had been classified as CCC by 2 of the 3 reviewers. In conclusion, napsin A is a sensitive and specific biomarker of the clear cell histotype in endometrial carcinomas and accordingly may have diagnostic utility in their histotyping.

Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement.

We report on the clinical and histological features of five cases of epithelioid trophoblastic tumor, with an emphasis on its involvement of the uterine cervix. All five patients were of reproductive age (median age 38.4 years) and all, except one, presented with vaginal bleeding 3 to 18 years after the most recent pregnancy. One patient presented with amenorrhea. Elevation of serum human chorionic gonadotropin (hCG) was seen in four cases. Pathologically, the tumor involved endocervix in three cases and involved uterine corpus in another two. All five tumors were invasive, nodular lesions consisting of epithelioid intermediate trophoblastic cells that were mononuclear with abundant eosinophilic cytoplasm, along with zones of hyaline material and necrotic debris. In three cases of cervical involvement, the neoplastic cells focally replaced endocervical surface and glandular epithelium, simulating high-grade squamous intraepithelial lesions. Immunohistochemically, all five tumors displayed focal positivity for human placental lactogen and hCG. Positive nuclear staining of p63 was seen in all five cases. All patients received total hysterectomy and various regimes of adjuvant chemotherapy. Three patients survived the tumor with no recurrences or metastases with follow-up periods of 3, 7 and 16 years. One patient is currently alive with lung metastasis 1 month after the surgery. One patient died of tumor metastasis 8 months after the diagnosis. In summary, with its unusual ability to simulate an invasive squamous cell carcinoma and other epithelioid neoplasms, epithelioid trophoblastic tumor frequently poses a diagnostic challenge, especially when involving the uterine cervix. High index of suspicion and an awareness of elevation of serum chorionic gonadotropin are crucial in reaching a correct diagnosis.

The clinicopathologic significance of p53 and BAF-250a (ARID1A) expression in clear cell carcinoma of the endometrium.

TP53 mutation (and associated p53 protein overexpression) is probably a negative prognostic marker in endometrial cancers, but its relevance in the rarer histologic subtypes, including clear cell carcinomas, has not been delineated. Preclinical studies suggest functional interactions between p53 and the BAF250a protein, the product of a tumor suppressor gene ARID1A (adenine-thymine (AT)-rich interactive domain containing protein 1A) that is frequently mutated in ovarian clear cell carcinoma. In this study, we evaluated the significance of p53 and BAF250a expression, as assessed by immunohistochemistry, in a group of 50 endometrial clear cell carcinomas. Of 50 cases, 17 (34%) were p53+, and the remaining 33 cases had a p53 wild-type (p53-wt) immunophenotype. Of the 11 relapses/recurrences in the entire data set, 73% were in the p53+ group (P=0.008). On univariate analyses, the median overall survival for the p53-wt patients (83 months) was longer than the p53+ patients (63 months) (P=0.07), and the median progression-free survival for the p53-wt group (88 months) was significantly longer than the p53+ group (56 months) (P=0.01). On multivariate analyses, p53 expression was not associated with reduced overall or progression-free survival. In addition, p53 status was not significantly associated with pathologic stage or morphologic patterns. Of the 50 cases, 10 (20%) showed a complete loss of BAF250a expression. There was no significant correlation between p53 and BAF250a expression. The p53+/BAF250a−, p53+/BAF250a+, p53-wt/BAF250a+ and p53-wt/BAF250a− composite immunophenotypes were identified in 8%, 26%, 54% and 12% of cases, respectively, and neither loss of BAF250a expression nor composite p53/BAF250a expression patterns were associated with reduced overall or progression-free survival. In conclusion, a significant subset of CCC express p53, and these cases are apparently not definable by their morphologic features. P53 expression may be a negative prognostic factor in this histotype, and warrants additional studies. Loss of BAF250a expression has no prognostic significance in endometrial clear cell carcinomas.

The diagnosis of endometrial carcinomas with clear cells by gynecologic pathologists: An assessment of interobserver variability and associated morphologic features

The purposes of this study are to assess the level of interobserver variability in the diagnosis of endometrial carcinomas with clear cells by gynecologic pathologists based purely on their morphologic features and to comparatively describe the cases of putative clear cell carcinoma (CCC) with and without significant interobserver variability. A total of 35 endometrial carcinomas (1 slide per case) were reviewed by 11 gynecologic pathologists (median experience: 10 y) from 11 North American institutions. The cases were selected from the files of 3 institutions on the basis of the presence of at least focal clear cells and had previously been classified as a variety of histotypes at these institutions. Diagnoses were rendered in a blinded manner and without predetermined diagnostic criteria or categories. The &kgr; values between any pair of observers ranged from 0.18 to 0.69 (combined 0.46), which was indicative of a “moderate” level of interobserver agreement for the group. Subgroups of “confirmed CCC” [cases diagnosed as such by at least 8 (73%) of the 11 observers, n=14] and “possible CCC” (cases diagnosed as CCC by ≥1 but <8 observers, n=13) were compared with regard to a variety of semiquantified morphologic features. By combining selected morphologic features that displayed statistically significant differences between the 2 groups on univariate analyses, the following approximate morphologic profile emerged for the confirmed CCC group: papillae with hyalinized cores in ≥33% of the lesion, clear cells in ≥33% of the lesion, hyperchromasia in ≥33% of the lesion, the absence of nuclear pseudostratification in >3 cells on the papillae, the absence of nuclear pseudostratification in glands in ≥33% of the lesion, the absence of diffuse grade 3 nuclei, the absence of long and slender papillae in ≥33% of the lesion, and glands and papillae lined by cuboidal to flat, noncolumnar cells. In a backward stepwise logistic regression analysis, features from the profile that predicted the confirmed CCC group included: (1) absence or minimality of diffuse sheets of grade 3 nuclei [P=0.025; 95% confidence interval (CI), 0.0266-0.363]; (2) absence or minimality of nuclear stratification in glands and papillae (P=0.040; 95% CI, −0.228 to −0.0054); and (3) glands and papillae lined by cuboidal to flat, noncolumnar cells (P=0.008; 95% CI, 0.0911-0.566). The 2 groups displayed significant overlap regarding a wide variety of features, and no single case displayed a full complement of potentially diagnostic features. Morphologic patterns associated with cases with very high levels of interobserver variability (defined as cases with ≥4 different diagnoses rendered for them, n=9) included the near-exclusive or exclusively solid pattern of clear cells (3/9) and glandular/papillary proliferations whose only CCC-like feature was the presence of clear cells (2/9). In conclusion, the diagnosis of endometrial carcinomas with clear cells by gynecologic pathologists is associated with a moderate level of interobserver variability. However, there is a morphologic profile that characterizes cases that gynecologic pathologists more uniformly classify as CCC, and the presence of these features is supportive of a CCC diagnosis in an endometrial carcinoma with clear cells. Cases that display broad and significant qualitative deviations from the aforementioned profile should prompt the consideration of a diagnosis other than CCC.

Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor With Unusual Metastatic Patterns and Poor Prognosis.

Gastric-type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of 3 institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (1 Li-Fraumeni, 1 Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II to IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least 1 site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 mo); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease-specific survival at 5 years was 42% for GAS versus 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon.