Melissa P. Murray

Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes

OBJECTIVE To compare the incidence of metastatic cancer cells in sentinel lymph nodes (SLN) vs. non-sentinel nodes in patients who had lymphatic mapping for endometrial cancer and to determine the contribution of metastases detected on ultrastaging to the overall nodal metastasis rate. METHODS All patients who underwent lymphatic mapping for endometrial cancer were reviewed. Cervical injection of blue dye was used in all cases. Sentinel nodes were examined by routine hematoxylin and eosin (H&E), and if negative, by standardized institutional pathology protocol that included additional sections and immunohistochemistry (IHC). RESULTS Between 09/2005 and 03/2010, 266 patients with endometrial cancer underwent lymphatic mapping. Sentinel node identification was successful in 223 (84%) cases. Positive nodes were diagnosed in 32/266 (12%) patients. Of those, 8/266 patients (3%) had the metastasis detected only by additional section or IHC as part of SLN ultrastaging. Excluding the 8 cases with positive SLN on ultrastaging only, 24/801 (2.99%) SLN and 30/2698 (1.11%) non-SLN were positive for metastatic disease (p=0.0003). CONCLUSION Using a cervical injection for mapping, metastatic cells from endometrial cancer are three times as likely to be detected in SLN than in the non-sentinel nodes. This finding strongly supports the concept of lymphatic mapping in endometrial cancer to fine tune the nodal dissection topography. By adding SLN mapping to our current surgical staging procedures we may increase the likelihood of detecting metastatic cancer cells in regional lymph nodes. An additional benefit of incorporating pathologic ultrastaging of SLN is the detection of micrometastasis, which may be the only evidence of extrauterine spread.

Underestimation of Atypical Ductal Hyperplasia at MRI-Guided 9-Gauge Vacuum-Assisted Breast Biopsy

OBJECTIVE The purposes of this study were to determine the frequency of diagnosis of atypical ductal hyperplasia (ADH) at MRI-guided 9-gauge vacuum-assisted breast biopsy and to assess the rate of underestimation of ADH at subsequent surgical excision. MATERIALS AND METHODS We conducted a retrospective review of medical records of 237 lesions consecutively detected with MRI and then subjected to MRI-guided 9-gauge vacuum-assisted breast biopsy during a 33-month period. Underestimated ADH was defined as a lesion yielding ADH at vacuum-assisted biopsy and cancer at surgery. Scientific tables were used to calculate 95% CI. RESULTS Histologic analysis of MRI-guided vacuum-assisted breast biopsy specimens yielded ADH without cancer in 15 (6%) of 237 lesions. Among 15 patients in whom vacuum-assisted breast biopsy yielded ADH, the median age was 52 years (range, 46-68 years). The median number of specimens obtained was nine (range, 8-18 lesions). Median MRI lesion diameter was 1.3 cm (range, 0.7-7.0 cm). Among 15 MRI lesions, 10 (67%) were nonmasslike enhancement and five (33%) were masses. Surgical excision was performed on 13 lesions. Surgical histologic findings were malignancy in five (38%) of the cases, all ductal carcinoma in situ; high-risk lesion in six (46%) of the cases, including ADH without other high-risk lesions (n = 2), ADH and lobular carcinoma in situ (LCIS) (n = 1), ADH, LCIS, and papilloma (n =1), ADH and papilloma (n = 1), and LCIS (n = 1); and benign in two (15%) of the cases. These data indicated an ADH underestimation rate of 38% (95% CI, 14-68%). CONCLUSION ADH without cancer was encountered in 6% of MRI-guided 9-gauge vacuum-assisted breast biopsies. ADH at MRI-guided vacuum-assisted breast biopsy is an indication for surgical excision because of the high (38%) frequency of underestimation of these lesions.

Classic lobular carcinoma in situ and atypical lobular hyperplasia at percutaneous breast core biopsy: outcomes of prospective excision.

No consensus exists on the need to excise breast lesions that yield classic lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH) (known together as classic lobular neoplasia [LN]) as the highest risk lesion at percutaneous core‐needle biopsy (CNB). Here, the authors report findings from 72 consecutive lesions with LN at CNB and prospective surgical excision (EXB).

Imaging–Histologic Discordance at MRI-Guided 9-Gauge Vacuum-Assisted Breast Biopsy

OBJECTIVE The purpose of this study was to determine the frequency of discordance at MRI-guided vacuum-assisted biopsy and to assess the cancer rate in discordant lesions. MATERIALS AND METHODS With institutional review board approval, retrospective review was performed of a database of 342 lesions that had MRI-guided vacuum-assisted biopsy during a 39-month period. Biopsy samples were obtained in a 1.5-T magnet using a 9-gauge MRI-compatible vacuum-assisted biopsy device. Medical and pathology records were reviewed to determine the number of discordant lesions and surgical outcome. Statistical analysis was performed. RESULTS Among 342 lesions that had MRI-guided vacuum-assisted biopsy, results were discordant in 24 (7% [95% CI, 3-14%]) lesions. The discordance rate was significantly (p < 0.001) higher among MRI target lesions that were possibly missed rather than sampled. A trend was seen (p < 0.06) toward a higher discordance rate in MRI lesions that were sampled rather than excised at MRI-guided vacuum-assisted biopsy. Subsequent surgery in 20 discordant lesions yielded cancer in six (30% [12-54%]), including ductal carcinoma in situ (DCIS) in two and invasive carcinoma in four (three ductal and one lobular, all with DCIS). The cancer rate among discordant lesions was significantly higher in postmenopausal women than in premenopausal women (p <0.05). CONCLUSION Imaging-histologic discordance was found in 7% of lesions that had MRI-guided vacuum-assisted biopsy. Among discordant lesions, surgical excision revealed cancer in 30%. Imaging-histologic correlation is essential after MRI-guided vacuum-assisted biopsy to avoid delay in the diagnosis of breast cancer.

Is pleomorphic lobular carcinoma really a distinct clinical entity

Attempts to define the clinical behavior of pleomorphic lobular carcinoma (PLC) have been limited to small series, and clinical management strategies have yet to be established. We describe our experience with PLC as compared to classic ILC and invasive ductal carcinoma (IDC).

Sentinel lymph node biopsy in the management of early-stage cervical carcinoma.

OBJECTIVES We aimed to determine the sentinel lymph node detection rates, accuracy in predicting the status of lymph node metastasis, and if pathologic ultrastaging improves the detection of micrometastases and isolated tumor cells at the time of primary surgery for cervical cancer. METHODS A prospective, non-randomized study of women with early-stage (FIGO stage IA1 with lymphovascular space involvement--IIA) cervical carcinoma was conducted from June 2003 to August 2009. All patients underwent an intraoperative intracervical blue dye injection. Patients who underwent a preoperative lymphoscintigraphy received a 99m Tc sulfur colloid injection in addition. All patients underwent sentinel lymph node (SLN) identification followed by a complete pelvic node and parametrial dissection. SLN were evaluated using our institutional protocol that included pathologic ultrastaging. RESULTS SLN mapping was successful in 77 (95%) of 81 patients. A total of 316 SLN were identified, with a median of 3 SLN per patient (range, 0-10 SLN). The majority (85%) of SLN were located at three main sites: the external iliac (35%); internal iliac (30%); and obturator (20%). Positive lymph nodes (LN) were identified in 26 (32%) patients, including 21 patients with positive SLN. Fifteen of 21 patients (71%) had SLN metastasis detected on routine processing. SLN ultrastaging detected metastasis in an additional 6/21 patients (29%). Two patients had grossly positive LN at exploration, and mapping was abandoned. Three of 26 (12%) patients had successful SLN mapping; however, the SLN failed to identify the metastatic LN. Of these 3 false negative cases, 2 patients had a metastatic parametrial node as the only positive LN with multiple negative pelvic nodes including negative SLN. One patient with stage IA1 disease and lymphovascular invasion had unilateral SLN mapping and a metastatic common iliac LN identified on completion lymphadenectomy of the contralateral side that did not map. The 4 (5%) patients with unsuccessful mapping included 1 who had grossly positive nodes identified at the time of laparotomy; the remaining 3 occurred during each surgeons initial SLN mapping learning phase. CONCLUSION SLN mapping in early-stage cervical carcinoma yields high detection rates. Ultrastaging improves micrometastasis detection. Parametrectomy and side-specific lymphadenectomy (in cases of failed mapping) remain important components of the surgical management of selected cases.

Underestimation of DCIS at MRI-Guided Vacuum-Assisted Breast Biopsy

OBJECTIVE The study objective was to assess the rate of underestimation of ductal carcinoma in situ (DCIS) at MRI-guided 9-gauge vacuum-assisted breast biopsy. MATERIALS AND METHODS An institutional review board-approved retrospective review was performed of 373 consecutive lesions that had undergone MRI vacuum-assisted breast biopsy. In 34 lesions with subsequent surgery, vacuum-assisted breast biopsy yielded DCIS without frank microinvasion or invasion. DCIS underestimates were lesions for which vacuum-assisted breast biopsy yielded DCIS without frank microinvasion or invasion at biopsy and surgery yielded invasive cancer. Records and pathology findings were reviewed. RESULTS Among 34 lesions, vacuum-assisted breast biopsy histology was DCIS in 29 and DCIS with possible microinvasion in five. Of 29 lesions yielding DCIS at MRI vacuum-assisted breast biopsy, surgical excision revealed invasive cancer in five (17%; 95% CI, 6-36%). The DCIS underestimation rate was significantly higher in lesions 6 cm or larger versus smaller lesions (60% vs 8%, p = 0.02). MRI lesion type, kinetics, number of specimens, menopausal status, and target sampling versus excision did not significantly affect underestimation. Of five lesions yielding DCIS with possible microinvasion at MRI vacuum-assisted breast biopsy, surgery revealed invasive carcinoma in four (80%; 95% CI, 28-99%). DCIS underestimation was significantly more likely if MRI vacuum-assisted breast biopsy showed possible microinvasion than if it did not (80% vs 17%, p =0.01). CONCLUSION Underestimation occurred in 17% of lesions yielding DCIS and in 80% of lesions yielding DCIS with possible microinvasion at MRI vacuum-assisted breast biopsy. DCIS underestimation was significantly more likely in lesions measuring 6 cm or larger. No other patient or lesion factors significantly affected DCIS underestimation at MRI vacuum-assisted breast biopsy.

Metastatic colorectal cancer cells induce matrix metalloproteinase release by human monocytes

Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) facilitate tumor invasion and metastasis via basement membrane degradation. In colorectal cancer (CRC) specimens, MMP production is largely stromal in origin, implicating monocytes (Mϕs) and fibroblasts. We hypothesize that CRC cells induce stromal cell MMP production. This study examines the differential effect of metastatic and non-metastatic CRC cells on Mϕ MMP production. The human Mϕ line THP-1 was co-cultured with either a non-metastatic human CRC cell line (SW620-P) or a metastatic clone (SW620-S5) established by serial cecal transplantation of SW620-P in nude mice. Conditioned medium MMP activity and cellular MMP mRNA expression were assessed by gelatinase zymography and Northern blot analysis, respectively. Neither CRC line released MMP-2 or MMP-9. Isolated THP-1 Mϕs produced basal levels of both MMP-2 and MMP-9. The level of MMP-9 activity was increased moderately by co-culture of Mϕs with the metastatic SW620-S5 clone, but decreased by the non-metastatic SW620-P cells. MMP-2 activity was greatly augmented by co-culturing Mϕs with SW620-S5 cells, but was not affected by SW620-P cells. The stimulatory effect of SW620-S5 cells on MMP-2 secretion was confirmed by Western blot analysis. Both isolated and co-cultured (Mϕs) expressed MMP-2 mRNA while SW620-S5 cells under similar conditions did not, implicating Mϕs as the source of increased MMP-2 activity. Since the induction of MMP-2 activity was not associated with a parallel increase in Mϕ MMP-2 mRNA, the modulation of Mϕ MMP-2 release appears to be post-transcriptionally regulated. Metastatic CRC cells are distinct from non-metastatic cells in their ability to induce Mϕ MMP release. This observation emphasizes the role of Mϕ-derived MMPs in facilitating CRC invasion and metastasis and suggests modulation of stromal cell MMP production by CRC cells in a paracrine fashion.

The Genomic Landscape of Male Breast Cancers

Purpose: Male breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers. Experimental Design: All male breast cancers were estrogen receptor–positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor–normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers. Results: Twenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A–like or luminal B–like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair–related genes. Conclusions: Male breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045–56. ©2016 AACR.

Varying Features of Early Age-of-Onset "Sporadic" and Hereditary Nonpolyposis Colorectal Cancer Patients

PURPOSE: Although the criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer are not fully agreed on, young age seems to be a common trait. The purpose of this study is to identify clinicopathologic features of hereditary nonpolyposis colorectal cancer in early age-of-onset colorectal cancer patients stratified as a function of family cancer history. METHODS: Two hundred thirty consecutive colorectal cancer patients 40 years or older at time of diagnosis were registered into an ongoing database during a ten-year period. Accurate family history was obtainedvia medical records, telephone calls, and questionnaires on 146 patients. According to extent of family history of cancer, patients were stratified into seven groups: 1) fulfilling Amsterdam criteria, 2) fulfilling less strict criteria, 3) having at least one first-degree relative with colorectal cancer, 4) having at least one distant relative with colorectal cancer, 5) having at least one first-degree relative with any cancer, 6) having at least one distant relative with any cancer, 7) having no family history of cancer. RESULTS: Twenty-two of 146 patients fulfilled Amsterdam and less strict hereditary nonpolyposis colorectal cancer criteria (15 percent). These hereditary nonpolyposis colorectal cancer patients were significantly younger (31vs. 35 years;P=0.0003) and had more metachronous colorectal cancer (27 percentvs. 2 percent;P=0.007) and less colorectal cancer with nodal or metastatic spread than the non-hereditary nonpolyposis colorectal cancer patients (35 percentvs. 65 percent;P=0.01). CONCLUSION: Precise familial cancer assessment in early age-of-onset colorectal cancer increases the yield of hereditary nonpolyposis colorectal cancer diagnosis. Because of the frequent development of metachronous colorectal cancer and favorable prognosis, extensive rather than segmental surgery should be considered in early age-of-onset colorectal cancer patients belonging to hereditary nonpolyposis colorectal cancer families.