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  Anatomic Abstracts

 

 

 

 

October 2009

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

Stromal gene signatures in large B-cell lymphomas
Clinical significance of signet-ring cells in colorectal mucinous adenocarcinoma
Secretory breast carcinomas with ETV6-NTRK3 fusion gene
Significance of sentinel node gradient in breast cancer
Detecting carcinoma in cavity margin performed at breast lumpectomy
Histogenesis of ovarian mucinous and transitional cell neoplasms
Value of Vienna classification to classify dysplasia in Barrett’s oesophagus

Stromal gene signatures in large B-cell lymphomas Stromal gene signatures in large B-cell lymphomas

The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), known as R-CHOP, has significantly improved the survival of patients with diffuse large B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of the disease is unclear. The authors conducted a study of gene-expression signatures in large B-cell lymphomas in which they profiled gene expression in pretreatment biopsy specimens from 181 patients with the disease who received CHOP and 233 patients with the disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. The authors found that a multivariate model created from three gene-expression signatures—termed germinal-center B-cell, stromal-1, and stromal-2—predicted survival in patients who received CHOP and those who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. The authors concluded that survival after treatment of diffuse large B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359:2313–2323.

Correspondence: Dr. L. M. Staudt at lstaudt@mail.nih.gov
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Clinical significance of signet-ring cells in colorectal mucinous adenocarcinoma Clinical significance of signet-ring cells in colorectal mucinous adenocarcinoma

Mucin occasionally accumulates intracellularly in colorectal mucinous adenocarcinomas, resulting in signet-ring cell morphology. There is no definitive rule on how to report a minor component of signet-ring cells in colorectal mucinous adenocarcinomas. The authors hypothesized that the absence of signet-ring cell component might have a favorable effect on the survival rate for mucinous adenocarcinoma patients. To assess the biological characteristics of colorectal mucinous adenocarcinoma, they analyzed its clinicopathological features, microsatellite instability status, and survival outcomes and compared them with those of colorectal signet-ring cell carcinoma. The authors’ analysis involved 266 consecutive colorectal mucinous adenocarcinoma patients and 65 signet-ring cell carcinoma patients. Mucinous adenocarcinomas, by comparison with signet-ring cell carcinomas, were characterized by development at an older age, less frequent vascular invasion and lymph node metasta-sis, and lower tumornodemetastasis (TNM) stage at presentation. A total of 21 of 95 (22 percent) mucinous adenocarcinomas and 12 of 63 (19 percent) signet-ring cell carcinomas exhibited high-frequency microsatellite instability. Patients with mucinous adenocarcinoma had signifi-cantly higher survival rates than those with signet-ring cell carcinoma (P<.0001) and those with signet-ring cell carcinoma showing more than 50 percent extracellular mucin by volume (P<.0001). In univariate analysis, absence of both signet-ring cell component (P=.0197) and vascular invasion, decreased invasion depth, no lymph node metastasis, and lower TNM stage had a favorable effect on survival rates for mucinous adenocarcinoma patients. Absence of vascular invasion, no lymph node metastasis, and lower TNM stage had a favorable effect on survival of signet-ring cell carcinoma patients. Multivariate analysis showed that higher TNM stage and T stage 4 were independent predictors of poor out-come in patients with mucinous adenocarcinoma. The authors’ observations strongly suggest that pathologists should report the percentage of signet-ring cell com-ponent in colorectal mucinous adenocarcinomas. It also indicates that mucinous adenocarcinoma exhibits different biologic behavior than signet-ring cell carcinoma.

Sung CO, Seo JW, Kim KM, et al. Clinical sig-nificance of signet-ring cells in colorectal mu-cinous adenocarcinoma. Mod Pathol. 2008;21:1533–1541.

Correspondence: Dr. C. K. Park at ckpark@skku.edu
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Secretory breast carcinomas with ETV6-NTRK3 fusion gene Secretory breast carcinomas with ETV6-NTRK3 fusion gene

Secretory breast carcinomas are associated with a characteristic morphology and a favorable prognosis. This entity, which represents fewer than .15 percent of breast tumors, is the only epithelial tumor of the breast with a balanced translocation, t(12;15) that creates an ETV6-NTRK3 gene fusion encoding chimeric tyrosine kinase, which is also encountered in cellular mesoblastic nephroma and infantile fibrosarcoma. The authors conducted a study to determine the phenotypic class (luminal A/B, ERBB2, basal like) of secretory breast carcinoma. They identified a series of six secretory breast carcinomas from their files. The ETV6 rearrangement was confirmed in all cases by fluorescence in situ hybridization. Immunophenotype was assessed with anti-ER, PR, ERBB2, KIT, EGFR, E-cadherin, vimentin, PS100, smooth muscle actin, basal (CK 5/6 and 14) and luminal (CK 8/18) cytokeratins, and p63 antibodies. In situ and invasive components shared the same immunoprofile and were ER, PR, ERBB2 negative with expression of basal cytokeratins. ETV6 gene alterations were present in invasive and in situ components, highlighting their genetic similarities. The immunoprofile data (triple negative with expression of basal markers) showed that secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the phenotypic basal-like spectrum of breast carcinomas. These results support the hypothesis that secretory breast carcinomas have immunohistochemical and genetic features that distinguish them from other basal-like tumors of the breast.

Lae M, Freneaux P, Sastre-Garau X, et al. Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. Mod Pathol. 2009;22:291–298.

Correspondence: Dr. A. Vincent-Salomon at anne.salomon@curie.net
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Significance of sentinel node gradient in breast cancer Significance of sentinel node gradient in breast cancer

Sentinel lymph node biopsy is standard for breast cancer staging, but SN dye gradients and their significance have not been characterized. If predictive of sentinel lymph node (SN) metastasis location, the use of SN dye gradients for focused pathology examination might improve intraoperative imprint cytology sensitivity. The authors conducted a prospective trial of clinically lymph node-negative patients with invasive breast cancer who were not receiving neoadjuvant chemotherapy. Surgeons marked SN gradients at their bluest end. Nodal halves were examined separately by imprint cytology, and the marked SN half was correlated with metastasis location. Demographic, pathologic, and prognostic features were recorded. Mean patient age and tumor size for the 102 patients was 59.6 years and 2.2 cm, respectively. Of 169 SNs, 159 (94.1 percent) had dye gradients, which varied by tumor quadrant but not by histology, diagnosis method, grade, or stage. Among 41 marked SNs with metastases, 92.7 percent were present in the halves marked by the surgeon. Fourteen were confined to one nodal half, with 11 on the marked side and three on the unmarked side (P=.029). Metastases were smaller when confined to one versus both SN halves (0.14 versus 0.75 cm; P=.005) and smaller when missed intraoperatively (0.87 versus 0.13 cm; P<.0001). The authors concluded that dye gradients occur in most SNs and predict metastasis location. The smallest metastases are hardest to detect intraoperatively and are usually confined to the marked SN half. This suggests that marking an SN’s bluest half warrants further study to explore whether its correlation to metastasis location may be exploited to focus pathologic examination and decrease the reoperative axillary dissection rate.

Bleicher RJ, O’Sullivan MJ, Ciocca V, et al. A prospective feasibility trial to determine the significance of the sentinel node gradient in breast cancer: a predictor of nodal metastasis location. Cancer. 2008;113:3100–3107.

Correspondence: Dr. Richard J. Bleicher at richard.bleicher@fccc.edu
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Detecting carcinoma in cavity margin performed at breast lumpectomy Detecting carcinoma in cavity margin performed at breast lumpectomy

Margin resection status is a major risk factor for developing local recurrence in breast conservation therapy for carcinoma. Tumor bed excision sent as separate orientated cavity margins can verify the completeness of the carcinoma resection. The authors conducted a study to determine the prevalence of positive cavity margins and how they influence subsequent surgical treatment as well as to identify potential predictive factors for positive cavity margins. The authors selected 107 consecutive patients (57 years; 30–88) who underwent a lumpectomy for carcinoma from 2003 to 2006 and who had four orientated cavity margins for carcinoma. The authors recorded preoperative clinical, radiological, and histological data, perioperative macroscopic characteristics, and definitive histological analysis results. Lumpectomy or cavity margins were considered to be positive when the distance from carcinoma to the margin was no more than 3 mm. Histological examination of cavity margins showed carcinoma in 38 patients (35 percent), leading to modification of subsequent surgical therapy in 33 cases. Examination of the cavity margins led to the decision to avoid surgical reexcision in 20 cases (lumpectomy margins positive and cavity margins negative) and to perform a mastectomy or reexcision in 13 cases (carcinoma in cavity margins although the lumpectomy margins were negative or tumor size was greater than 3 cm). The authors found that between preoperative and perioperative parameters, ultrasonographic scan and macroscopic size of the tumor were predictive factors for positive cavity margin, whereas characteristics of the carcinoma determined on biopsy samples and macroscopic status of the lumpectomy margins were not. They concluded that their study confirms that the systematic practice of cavity margin resection avoids surgical reexcision and reduces the likelihood of underestimating the extent of the tumor.

Tengher-Barna I, Hequet D, Reboul-Marty J, et al. Prevalence and predictive factors for the detection of carcinoma in cavity margin performed at the time of breast lumpectomy. Mod Pathol. 2009;22:299–305.

Correspondence: Dr. M. Ziol at marianne.ziol@jvr.aphp.fr
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Histogenesis of ovarian mucinous and transitional cell neoplasms Histogenesis of ovarian mucinous and transitional cell neoplasms

The origins of ovarian mucinous and transitional cell, or Brenner, neoplasms and the relationship between the tumors are enigmatic. The reported association ranges from one percent to 16 percent, and it is not known whether the tumors are associated with Walthard cell nests. The authors conducted a study to clarify the histologic relationship between mucinous and Brenner tumors. They studied 40 mucinous cystadenomas, 67 Brenner tumors, and 13 combined tumors. They examined peritoneal surfaces for Walthard nests in 83 patients compared with 272 controls. The authors found that 25 percent of tumors with a mucinous component contained a Brenner component, and 16 percent of tumors with a Brenner com-ponent contained a mucinous component. Most calcifications were spiculated (non-psammomatous). In six combined tumors, the relative volume of the two components was less than 1:3,000 (transitional mucinous). Walthard nests were found in 50 percent of patients with Brenner tumors and 59 percent of patients with mucinous tumors. This was significantly higher than the 28 percent found in controls (P=.002 and P<.001, respectively). The number of fallopian tube blocks examined was correlated with the likelihood of finding Walthard nests, and, accordingly, sampling accounted for 39 percent of the increase with Brenner tumors but strengthened the association with mucinous tumors. The authors concluded that the strong association of mucinous and transitional cell components, similar type of calcification, complementary size distributions, and frequent identification of a transitional component in the face of an exceedingly small estimated proportion of that component suggest that this association has been underestimated. The association of Brenner tumors with Walthard nests, although significant, appears weak and does not strongly support a histogenetic relationship. The stronger association of Walthard nests with mucinous tumors remains unexplained.

Seidman J, Khedmati F. Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neoplasms and their relationship with Walthard cell nests: a study of 120 tumors. Arch Pathol Lab Med. 2008;132:1753–1760.

Correspondence: Dr. Jeffrey D. Seidman at jdseidman@hotmail.com
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Value of Vienna classification to classify dysplasia in Barrett’s oesophagus Value of Vienna classification to classify dysplasia in Barrett’s oesophagus

The Vienna classification is used to classify dysplasia in Barrett’s oesophagus, but its reproducibility and the value of diagnosing lower grades, in particular, are often questioned. The authors conducted a study to test its diagnostic variability and correlation with patient outcome and to define histological features causing discrepant diagnoses, as well as to test the impact of p53 immunohistochemistry on reproducibility and prediction of outcome in Barrett’s dysplasia. The authors retrieved the pathology records of 143 patients with 154 sets of biopsy specimens originally diagnosed with Barrett’s dysplasia from Nottingham University Hospital, Nottingham, United Kingdom. They added to their study 32 Barrett’s patients without dysplasia. Five pathologists independently graded anonymized slides with and without p53-stained slides. Interobserver variation, correlation with outcome, and diagnostic accuracy were determined. The study found that weighted kappa scores between pairs of pathologists showed substantial agreement and improved after p53 immunohistochemistry. Agreement with the original diagnosis was substantially lower. Fourteen of 34 low-grade dysplasias and 27 of 30 high-grade dysplasias on consensus progressed within 10 years, compared with 18 of 94 and 28 of 39 for original diagnoses. Progression correlated with p53 positivity. The authors concluded that the Vienna classification is useful and reproducible in Barrett’s oesophagus. Consensus diagnoses by gastrointestinal pathologists produce high specificity and predictive value, even for low-grade dysplasias. P53 immunohistochemistry helps diagnose difficult cases and predicts progression.

Kaye PV, Haider SA, Ilyas M, et al. Barrett’’s dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry. Histopathology. 2009;54(6):699–712.

Correspondence: Dr. Philip Victor Kaye at philip.kaye@nuh.nhs.uk
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco.