Role of Lymphovascular Invasion in Pattern C Invasive Endocervical Adenocarcinoma.

Lymphovascular invasion (LVI) has been reported as an independent predictor of patient outcome in cervical carcinoma. However, not all studies support independent significance, especially in multivariable analyses. A risk stratification system recently introduced for endocervical adenocarcinoma was reported to better predict risk of lymph node (LN) metastasis. A subset of patients with tumors with pattern C features had LN metastasis and died of disease. In this study, we determined whether LVI had any additional significance in this subset of tumors. A total of 127 patients with pattern C tumors and at least 12-month follow-up were included. Tumors were separated into 3 subgroups. Those with no LVI and negative LNs represented 41 cases; most patients (36, 88%) were alive with no evidence of disease at last follow-up, whereas 4 (10%) died of disease, all after tumor recurrence/metastasis. Tumors with LVI, but negative LNs, represented 55 cases; recurrences were seen in 10 (18%) patients, of which 5 (50%) of them died of disease; remaining 5 patients are alive with persistent disease. Tumors with both LVI and positive LNs represented 31 cases; recurrences were seen in 13 (42%) patients; 11 (85%) patients died of disease and 2 are alive with persistent disease. One additional patient who presented with advanced stage also died of disease. Tumor size, horizontal spread, and LN status were significantly associated with outcome in univariate, but not in multivariable analysis; depth of invasion was not a predictor of outcome. Tumors with no LVI and negative LNs behaved significantly less aggressively than tumors with both LVI and positive LNs (P<0.01). LVI status (independent of LN status) was not significantly associated with patient outcome, although approached significance (P=0.06). In conclusion, LVI is a prerequisite for LN metastasis; however, by itself is not sufficient to predict tumor aggressiveness, whereas over 50% of patients with positive LNs died of disease. Stratifying pattern C tumors into subgroups based on LVI and LN status could further determine treatment in patients with pattern C tumors.

New pattern-based personalized risk stratification system for endocervical adenocarcinoma with important clinical implications and surgical outcome.

We present a recently introduced three tier pattern-based histopathologic system to stratify endocervical adenocarcinoma (EAC) that better correlates with lymph node (LN) metastases than FIGO staging alone, and has the advantage of safely predicting node-negative disease in a large proportion of EAC patients. The system consists of stratifying EAC into one of three patterns: pattern A tumors characterized by well-demarcated glands frequently forming clusters or groups with relative lobular architecture and lacking destructive stromal invasion or lymphovascular invasion (LVI), pattern B tumors demonstrating localized destructive invasion (small clusters or individual tumor cells within desmoplastic stroma often arising from pattern A glands), and pattern C tumors with diffusely infiltrative glands and associated desmoplastic response. Three hundred and fifty-two cases were included; mean follow-up 52.8 months. Seventy-three patients (21%) had pattern A tumors; all were stage I and there were no LN metastases or recurrences. Pattern B was seen in 90 tumors (26%); all were stage I and LVI was seen in 24 cases (26.6%). Nodal disease was found in only 4 (4.4%) pattern B tumors (one IA2, two IB1, one IB not further specified (NOS)), each of which showed LVI. Pattern C was found in 189 cases (54%), 117 had LVI (61.9%) and 17% were stage II or greater. Forty-five (23.8%) patients showed LN metastases (one IA1, 14 IB1, 5 IB2, 5 IB NOS, 11 II, 5 III and 4 IV) and recurrences were recorded in 41 (21.7%) patients. This new risk stratification system identifies a subset of stage I patients with essentially no risk of nodal disease, suggesting that patients with pattern A tumors can be spared lymphadenectomy. Patients with pattern B tumors rarely present with LN metastases, and sentinel LN examination could potentially identify these patients. Surgical treatment with nodal resection is justified in patients with pattern C tumors.

Vascular invasion in uterine sarcomas and its significance. A multi-institutional study.

Although metastases and high-mortality are frequent in high-grade endometrial sarcomas (HGSs), these findings are less commonly seen in low-grade endometrial stromal sarcomas (LGESSs), even in cases with lymphovascular invasion (LVI). We hypothesized that the "bulging plugs" of tumor characteristic of LVI in LGESS are fundamentally different from LVI seen in HGS. We reviewed 70 uterine sarcomas: 42 HGSs (high-grade endometrial stromal sarcomas, undifferentiated uterine sarcoma, and leiomyosarcoma) and 28 LGESSs. All cases had LVI documented on the histologic slides. Immunostains for CD31, ERG, and D2-40 were performed. LGESS harbored cohesive intravascular tumor foci with direct communication from the main tumor and attached to the vessel wall. The intravascular foci included tumor cells and small arteriole-type vessels and were surrounded by a thin fibrous band. Vascular markers confirmed the LVI and highlighted positively stained endothelial cells separating intravascular tumor foci from the blood itself. In contrast, intravascular tumor foci in HGS were composed of discohesive cells clusters, lacking the features described in LGESS. Only 8 (30.8%) patients with LGESS had recurrence/metastases (6 with lung metastasis); only 1 patient died of disease. Thirty (77%) patients with HGS had recurrence/metastases, 27 (69%) patients had lung metastases, and 22 (56.4%) patients died of disease. We propose that in most LGESSs, LVI represents vascular intrusion; manipulation or trauma is potentially responsible for tumor cell detachment into the circulation increasing the chances of recurrence/metastases. Classic LVI features were identified in HGS. This important distinction may allow for better management of patients and avoid unnecessary treatment in LGESS, reducing morbidity.

Risk factor analysis of recurrence in low-grade endometrial adenocarcinoma.

Prognosis of endometrial adenocarcinoma is favorable; however, the risk of recurrence ranges from 7% to 13%. Recurrence has been related to age, tumor type, International Federation of Gynecology and Obstetrics grade, depth of invasion, and lymphovascular invasion (LVI); however, morphologic features that would predict the site of recurrence have not been established. In this multi-institutional study, we reviewed 589 patients with International Federation of Gynecology and Obstetrics grades 1 or 2 endometrial adenocarcinoma, endometrioid type. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for recurrence and survival. Univariate analysis revealed features of tumors that recurred only in the vagina: low nuclear grade; superficial myoinvasion; minimal to no LVI; and minimal myoinvasion with microcystic, elongated, and fragmented (MELF) pattern; low nuclear grade and superficial myoinvasion persisted on multivariate analysis. Features of tumors that recurred at other sites included large size, deep myoinvasion, tumor necrosis, 1 or more LVI foci, LVI foci distant/deeper than invasive tumor front, MELF myoinvasion pattern, lower uterine segment and cervical stromal involvement, pelvic and/or paraaortic lymph node metastases at presentation, and higher grade of tumor in the metastatic foci, whereas increased percentage of solid component and lower percentage of mucinous features were marginally associated. Tumors with recurrences only in vagina had different features than tumors that recurred at other sites. The presence of tumor necrosis, MELF foci at the invasive tumor front, and the percentage of solid component and mucinous features could be helpful in grading endometrioid adenocarcinomas, if a 2-tier rather than a 3-tier grading system is accepted in the future.

Invasive endocervical adenocarcinoma: a new pattern-based classification system with important clinical significance.

A new 3-tier pattern-based system to classify endocervical adenocarcinoma was recently presented. In short, pattern A tumors were characterized by well-demarcated glands frequently forming clusters or groups with relative lobular architecture. Pattern B tumors demonstrated localized destructive invasion defined as desmoplastic stroma surrounding glands with irregular and/or ill-defined borders or incomplete glands and associated tumor cells (individual or small clusters) within the stroma. Tumors with pattern C showed diffusely infiltrative glands with associated extensive desmoplastic response. In total, 352 cases (all FIGO stages) from 12 institutions were identified. Mean patient age was 45 years (range, 20 to 83 y). Forty-nine (13.9%) cases demonstrated lymph nodes (LNs) with metastatic endocervical carcinoma. Using this new system, 73 patients (20.7%) were identified with pattern A tumors (all stage I); none had LN metastases and/or recurrences. Ninety patients (25.6%) were identified with pattern B tumors (all stage I); only 4 (4.4%) had LN metastases; 1 had vaginal recurrence. The 189 (53.7%) remaining patients had pattern C tumors; 45 (23.8%) of them had LN metastases. This new classification system demonstrated 20.7% of patients (pattern A) with negative LNs, and patients with pattern A tumors can be spared of lymphadenectomy. Patients with pattern B tumors rarely presented with metastatic LNs, and sentinel LN examination could potentially identify these patients. Aggressive treatment is justified in patients with pattern C tumors.

A cautious view of putative precursors of serous carcinomas in the fallopian tubes of BRCA mutation carriers.

OBJECTIVE: To compare the frequency and distribution of candidate precursors of serous carcinoma in the fallopian tubes of BRCA mutation carriers to BRCA non-mutation carriers (controls) at risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: 78 BRCA carriers (52 BRCA1, 26 BRCA2) and 23 controls underwent RRSO. Fallopian tubes were serially cross-sectioned, and adnexa were entirely submitted and examined by two gynecologic pathologists blinded to BRCA mutation status. The presence and location of serous tubal intraepithelial carcinoma (STIC), p53 overexpression (≥ 6 consecutively stained nuclei), Ki67 overexpression, atypia/low grade dysplasia and epithelial hyperplasia were compared between BRCA carriers and controls. Patient age was dichotomized: ≤ 50 and >50 years. RESULTS: 9 (12%) BRCA carriers had occult carcinoma: 8 STIC and 1 stage IC tubal carcinoma with STIC. No occult carcinomas or STIC was seen in controls. STIC involved the distal tube in all cases and was multifocal in three cases. STIC was more common in women >50 (p=0.06). P53 overexpression was common in BRCA carriers (30%) and controls (43%) (p=0.5) and did not correlate with age. Only 5/9 (55%) of STIC exhibited p53 overexpression. 2 patients had Ki67 overexpression: both BRCA1 carriers with STIC. No difference in the frequency of atypia/low grade dysplasia or hyperplasia was observed between BRCA carriers and controls. CONCLUSIONS: STIC is the dominant precursor of serous fallopian tube carcinoma in BRCA carriers. There is insufficient evidence to support p53 overexpression alone as a putative precursor. Atypia/low grade dysplasia and epithelial hyperplasia are not pre-neoplastic lesions of serous fallopian tube carcinoma.

Risk factors for recurrence and prognosis of low-grade endometrial adenocarcinoma; vaginal versus other sites.

Endometrial adenocarcinoma is the most common gynecologic cancer in the United States. The prognosis is generally favorable, however, a significant number of patients do develop local or distant recurrence. The most common site of recurrence is vaginal. Our aim was to better characterize patients with vaginal recurrence of low-grade endometrioid adenocarcinoma with respect to associated tumor parameters and clinical outcome. We compiled 255 cases of low-grade (FIGO Grade I or II) endometrioid adenocarcinoma on hysterectomy specimens with lymph node dissection. A total of 113 cases with positive lymph nodes or recurrent disease were included in our study group. Seventy-three cases (13 Grade 1, 60 Grade 2) developed extravaginal recurrence and 40 cases (7 Grade 1, 33 Grade 2) developed vaginal recurrence. We evaluated numerous tumor parameters including: percentage myoinvasion, presence of microcystic, elongated, and fragmented pattern of myoinvasion, lymphovascular space invasion, and cervical involvement. Clinical follow-up showed that 30% (34/113) of all patients with recurrent disease died as a result of their disease during our follow-up period, including 31 (42.5%) with extravaginal recurrence and 3 (7.5%) with primary vaginal recurrence (P=0.001). The 3 patients with vaginal recurrence developed subsequent extravaginal recurrence before death. Vaginal recurrence patients show increased cervical involvement by tumor, but lack other risk factors associated with recurrent disease at other sites. There were no deaths among patients with isolated vaginal recurrence, suggesting that vaginal recurrence is not a marker of aggressive tumor biology.

Invasive endocervical adenocarcinoma: proposal for a new pattern-based classification system with significant clinical implications: a multi-institutional study.

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.

The pattern of myometrial invasion as a predictor of lymph node metastasis or extrauterine disease in low-grade endometrial carcinoma.

The purpose of this study was to examine predictors of lymph node (LN) metastases or extrauterine disease (ED) in low-grade (FIGO grade 1 or 2) endometrioid carcinoma (LGEC) in a multi-institutional setting. For LGEC with and without LN metastasis or ED, each of the 9 participating institutions evaluated patients' age, tumor size, myometrial invasion (MI), FIGO grade, % solid component, the presence or absence of papillary architecture, microcystic, elongated, and fragmented glands (MELF), single-cell/cell-cluster invasion (SCI), lymphovascular invasion (LVI), lower uterine segment (LUS) and cervical stromal (CX) involvement, and numbers of pelvic and para-aortic LNs sampled. A total of 304 cases were reviewed: LN(+) or ED(+), 96; LN(-)/ED(-), 208. Patients' ages ranged from 23 to 91 years (median 61 y). Table 1 summarizes the histopathologic variables that were noted for the LN(+) or ED(+) group: tumor size ≥2 cm, 93/96 (97%); MI>50%, 54/96 (56%); MELF, 67/96 (70%); SCI, 33/96 (34%); LVI, 79/96 (82%); >20% solid, 65/96 (68%); papillary architecture present, 68/96 (72%); LUS involved, 64/96 (67%); and CX involved, 41/96 (43%). For the LN(-)/ED(-) group, the results were as follows: tumor size ≥2 cm, 152/208 (73%); MI>50%, 56/208 (27%); MELF, 79/208 (38%); SCI, 19/208 (9%); LVI, 56/208 (27%); >20% solid, 160/208 (77%); papillary architecture present, 122/208 (59%); LUS involved, 77/208 (37%); CX involved, 24/208 (12%). There was no evidence of a difference in the number of pelvic or para-aortic LNs sampled between groups (P=0.9 and 0.1, respectively). After multivariate analysis, the depth of MI, CX involvement, LVI, and SCI emerged as significant predictors of advanced-stage disease. Although univariate analysis pointed to LUS involvement, MELF pattern of invasion, and papillary architecture as possible predictors of advanced-stage disease, these were not shown to be significant by multivariate analysis. This study validates MI, CX involvement, and LVI as significant predictors of LN(+) or ED(+). The association of SCI pattern with advanced-stage LGEC is a novel finding.

Mucinous metaplasia of the fallopian tube: a diagnostic pitfall mimicking metastasis.

Interpretation of the mucinous change in the fallopian tubes has been difficult because several reports consider this mucinous change as a metastasis from a mucinous tumor. To clarify this issue, we decided to retrospectively review salpingectomies from 3 institutions looking for mucinous change in the fallopian tubes and documented the clinical history of these patients. Twenty-three cases of fallopian tubes with mucinous changes were found, including 11 patients without evidence of malignancy, 4 patients with mucinous ovarian tumors, 5 patients with nonmucinous gynecologic tumors, 2 patients with mucinous appendiceal neoplasm, and 1 patient with colon carcinoma. As mucinous changes are seen in several patients who do not have a malignant tumor, we believe that these changes represent a metaplastic process. The mucinous changes are frequently seen with chronic inflammation and/or other metaplastic changes and without cytologic evidence of malignancy.

Ovarian preservation in stage I low-grade endometrial stromal sarcomas.

OBJECTIVE: To examine the impact of ovarian preservation in a case-control study of women with stage I low-grade endometrial stromal sarcomas. METHODS: Patients with low-grade endometrial stromal sarcomas were identified at 5 institutions from 1976 to 2002. Cases were defined as patients who retained ovarian function; each case was matched to 2 control patients who underwent bilateral salpingo-oophorectomy (BSO). Immunostaining for estrogen and progesterone receptors was performed. Data were examined with Student t, chi(2), Cox regression, and Kaplan-Meier analyses. RESULTS: Twelve premenopausal patients with low-grade endometrial stromal sarcomas who did not undergo BSO were matched to 24 controls. Of the 36 patients in the entire cohort, disease recurred in 14 (39%). Recurrences were identified in the pelvis, abdomen, lung, or lymphatics in both cases and controls. Disease recurred in 4/12 (33%) case patients, compared with 10/24 (42%) control patients (P = .63). When case patients were compared with controls, no differences in progression-free (91.3 months versus 68.6 months, P = .44) or overall survival (median survival not yet reached versus 406 months, P = .82) were identified. This study had 13% power to detect the observed difference in median disease-free survival. After controlling for use of adjuvant therapy and BSO, older age remained the only independent poor prognostic factor for progression-free survival (P = .008). Twenty-two available tumors demonstrated positivity for both estrogen and progesterone receptors. CONCLUSION: Bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas.

BRCA-mutation-associated fallopian tube carcinoma: a distinct clinical phenotype?

OBJECTIVE: To compare clinical and histologic features between fallopian tube cancers in women with germline BRCA mutations and sporadic cases. METHODS: Twenty-eight patients with fallopian tube cancer had BRCA mutation testing using multiplex polymerase chain reaction and protein truncation testing. Histologic slides were reviewed by 2 pathologists, and immunohistochemical staining for p53, ki67, estrogen receptor, and progesterone receptor was performed on carcinomas and dysplastic and benign tubal epithelia. RESULTS: Twelve of 28 (43%) women had BRCA mutations: 11 BRCA1, 1 BRCA2. Excluding 4 cases found at prophylactic surgery, the median age of diagnosis of BRCA mutation carriers was 57 years compared with 65 years among sporadic cases (P = .09). Patients with BRCA-associated fallopian tube cancer had a median survival time of 68 months compared with 37 months when compared with sporadic cases (P = .14). Both groups had predominantly advanced stage, high grade, serous fallopian tube cancers. No patient had exclusively proximal disease. Occult fallopian tube cancer diagnosed at prophylactic surgery in BRCA mutation carriers was exclusively distal. "Skip" areas of high-grade dysplasia were only seen in 2 patients, both of whom were BRCA mutation carriers. There were no differences in the immunohistochemical staining for p53, ki67, estrogen receptor or progesterone receptor in carcinomas and dysplastic or benign epithelia of patients with or without BRCA mutations. Overexpression of p53 was commonly seen in fallopian tube cancers and dysplastic epithelium, but rarely noted in benign epithelium. CONCLUSION: Fallopian tube cancer is part of the BRCA mutation phenotype and seems to share many clinical features with sporadic fallopian tube cancers, including no exclusively proximal disease. The presentation of BRCA-associated fallopian tube cancers may, however, occur at a younger age and have an improved survival.