Andres A. Roma

Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma

Lymphangiogenesis, detected by antibodies specific for lymphatic endothelial cells, has been associated with regional lymph node metastases and poor prognosis in carcinomas of head and neck, breast and uterine cervix, but remains largely uninvestigated in prostate adenocarcinoma. We evaluated the lymphatic vessel density and lymphatic vessel invasion by prostate cancer cells in the intratumoral, peritumoral and normal prostate tissue compartments in cancer-bearing prostate glands and correlated them with lymph node metastases, Gleason score and other pathological parameters. Lymphatic vessels were detected by immunohistochemical stain using an antibody specific for the lymphatic endothelial cells (clone D2-40) on 33 radical prostatectomies. In all, 26 patients had lymph node dissection, and 14 of them had lymph node metastasis. The lymphatic vessel density and lymphatic vessel invasion were then recorded for each of the three compartments microscopically. Lymphatic vessel density in the intratumoral, peritumoral and normal prostate compartments was 0.91±0.80, 1.54±0.68 and 1.58±0.96/mm2, respectively. The intratumoral lymphatic vessel density was significantly lower than that of the peritumoral and normal prostate compartments, and the latter two were not significantly different. The lymphatic vessel density of the three compartments was not significantly different between cases with and without lymph node metastasis. The peritumoral lymphatic vessel density correlated inversely with the Gleason score. Lymphatic vessel invasion was present in significantly higher percentage of cases with lymph node metastasis (9/14, 62.3%), as compared to those without lymph node metastasis (1/12, 8.3%, P<0.01). The peritumoral lymphatic vessel invasion had a better correlation with the presence of lymph node metastases than intratumoral lymphatic vessel invasion. There is no evidence of lymphangiogenesis in prostate adenocarcinoma. Peritumoral lymphatic vessel invasion correlates with regional lymph node metastases, suggesting that the peritumoral lymphatic vessels are functionally important and identification of lymphatic vessel invasion in this compartment implies a high probability of regional lymph node metastases.

Implementation of tumor testing for lynch syndrome in endometrial cancers at a large academic medical center

OBJECTIVES Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. Recognizing women at risk for LS based on personal/family history is burdensome and imprecise. Tumor testing using microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair protein expression can be an effective strategy for identifying potential LS in patients presenting with colorectal or endometrial cancer. Here we describe our experience implementing a screening program for endometrial cancers. METHODS Endometrial cancers diagnosed ≤50 years or those with suspicious personal history or histopathologic features were screened with MSI/IHC, June 2009-June 2011. Criteria were later (July 2011-July 2012) expanded to patients diagnosed <60 years, or at any age with suspicious features, and finally (after August 2012) universal screening was implemented. Screening techniques began with both MSI and IHC for every tumor, and later converted to IHC for two proteins, and MLH1 promoter methylation analysis when indicated. A genetic counselor contacted patients directly to offer genetic counseling appointments. RESULTS Two hundred and forty-five endometrial cancers (average age, 57 years) were screened. Sixty-two patients (25%) had abnormal results, and 42 patients were referred for genetic counseling. Of the 42 patients, 34 underwent genetic counseling, 28 pursued genetic testing, and 11 were diagnosed with LS. When age and pathology criteria were used, 27 eligible cases were overlooked for screening and 3 cases of LS were found only because a clinician requested screening. CONCLUSIONS Universal screening of endometrial cancers for LS is practical and successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

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.

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.

Differential expression of melanocytic markers in myoid, lipomatous, and vascular components of renal angiomyolipomas.

CONTEXT Renal angiomyolipoma is a tumor composed of varying amounts of fat, smooth muscle, and blood vessels. Characteristically, tumor cells express melanocytic markers such as HMB-45 and Melan-A. Recently, several other markers have been described as having excellent diagnostic sensitivity in cutaneous melanocytic lesions. OBJECTIVES To compare the sensitivities of 5 melanocytic markers in renal angiomyolipoma and to study the expression patterns of these markers in the 3 different components of angiomyolipoma. DESIGN A tissue microarray of 20 renal angiomyolipomas was constructed. For each case, 3 cores containing fat, blood vessels, and smooth muscle were taken. The tissue microarray was then stained for HMB-45, Melan-A, tyrosinase, NK1-C3, and CD117. RESULTS HMB-45 was positive in 95%, Melan-A in 85%, NK1-C3 in 70%, tyrosinase in 50%, and CD117 in 40% of the cases. All (20/20) were positive for HMB-45 and Melan-A combined. These 5 markers had different sensitivities in the 3 components. HMB-45 was positive in 90%, 85%, and 80% of fat, smooth muscle, and blood vessel components, respectively; Melan-A in 70%, 60%, and 40%; NK1-C3 in 55%, 55%, and 45%; tyrosinase in 30%, 40%, and 10%; and CD117 in 20%, 40%, and 10%, respectively, of these 3 components. CONCLUSIONS HMB-45 and Melan-A combined were positive in 100% of the renal angiomyolipomas. We recommend the use of these 2 markers in the workup of this entity, including those with predominantly 1 component. Other melanocytic markers are of limited use. A tissue block comprising predominantly fat or smooth muscle components should be used when performing melanocytic marker immunostain.

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.

The impact of chemotherapy and radiation therapy on the remodeling of acellular dermal matrices in staged, prosthetic breast reconstruction

Background: An acellular dermal matrix will typically incorporate, in time, with the overlying mastectomy skin flap. This remodeling process may be adversely impacted in patients who require chemotherapy and radiation, which influence neovascularization and cellular proliferation. Methods: Multiple biopsy specimens were procured from 86 women (n = 94 breasts) undergoing exchange of a tissue expander for a breast implant. These were divided by biopsy location: submuscular capsule (control) as well as superiorly, centrally, and inferiorly along the paramedian acellular dermis. Specimens were assessed for cellular infiltration, cell type, fibrous encapsulation, scaffold degradation, extracellular matrix deposition, neovascularization, mean composite remodeling score, and type I and III collagen. Patients were compared based on five oncologic treatment groups: no adjuvant therapy (untreated), neoadjuvant chemotherapy with or without radiation, and chemotherapy with or without radiation. Results: Biopsy specimens were procured 45 to 1805 days after implantation and demonstrated a significant reduction in type I collagen over time. Chemotherapy adversely impacted fibrous encapsulation (p = 0.03). Chemotherapy with or without radiation adversely impacted type I collagen (p = 0.02), cellular infiltration (p < 0.01), extracellular matrix deposition (p < 0.04), and neovascularization (p < 0.01). Radiation exacerbated the adverse impact of chemotherapy for several remodeling parameters. Neoadjuvant chemotherapy also caused a reduction in type I (p = 0.01) and III collagen (p = 0.05), extracellular matrix deposition (p = 0.03), and scaffold degradation (p = 0.02). Conclusion: Chemotherapy and radiation therapy limit acellular dermal matrix remodeling. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

HER-2/neu expression in glioblastoma multiforme.

BackgroundThe HER-2/neu oncogene encodes for a transmembrane glycoprotein with intracellular tyrosine kinase activity. The HER-2/neu receptor belongs to the family of epidermal growth factor receptors that are crucial in the activation of subcellular signal transduction pathways controlling epithelial cell growth and differentiation. Overexpression of HER-2/neu is observed in 20% to 40% of breast cancers and other solid tumors. Although information is limited, one study suggested that 15% of glioblastoma multiforme (GBM) express HER-2/neu by immunohistochemistry (IHC); gene amplification by fluorescence in situ hybridization (FISH) was not investigated. Studies in this area are potentially significant owing to the role of recombinant monoclonal anti-HER-2/neu antibody traztuzumab (Herceptin) in the treatment of tumors. DesignA retrospective clinicopathologic review of 49 patients with GBM with HER-2/neu IHC staining and HER-2/neu gene amplification by FISH was performed. ResultsThe study included 44 patients (17 women, 27 men; age range 20 to 79 y, mean 57.9 y). Initial surgery involved tumor debulking or subtotal resection in 34 patients. Thirty-six patients received adjuvant radiation therapy and 19 patients received adjuvant chemotherapy. At follow-up (range 1.0 to 49.5 mo, mean 10.5 mo), 40 patients died with tumor and 4 patients were lost to follow-up. All tumors were negative for HER-2/neu protein by IHC and for HER-2/neu gene amplification by FISH. ConclusionsNo GBM demonstrates HER-2/neu protein by IHC or amplification of the HER-2/neu gene by FISH. The HER-2/neu oncogene does not seem to play a role in the pathogenesis of GBM.

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.

Mesonephric carcinosarcoma involving uterine cervix and vagina: report of 2 cases with immunohistochemical positivity For PAX2, PAX8, and GATA-3.

Mesonephric carcinomas are rare tumors predominantly arising in the uterine cervix from mesonephric remnants. Although the tumor has classic morphologic features, some cases can mimic Müllerian adenocarcinoma and be misdiagnosed, especially those with significant ductal pattern. Moreover, there is an overlap in immunohistochemical results with endometrial and endocervical carcinomas. In this study, we report 2 cases of mesonephric carcinosarcoma, originally diagnosed as Müllerian carcinomas, 1 presenting in the vagina; review immunohistochemical results including positivity for GATA-3, not previously reported and comment on the proposed panel of PAX8, p16, and estrogen receptors as discriminators of Müllerian adenocarcinoma (endocervical or endometrial) versus mesonephric carcinoma.