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  Anatomic Abstracts

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January 2007

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Michael Bissell, MD, PhD, MPH

Detection of malignant hematopoietic cells in atypical or suspicious CSF
Sentinel-node biopsy or nodal observation in melanoma
Occult sentinel lymph node micrometastases in breast cancer
Characteristics of metastasizing SCC of the skin and lips
Role of BCL6 expression in patient prognosis

bullet Detection of malignant hematopoietic cells in atypical or suspicious CSF

It may be difficult to document involvement of the cerebrospinal fluid by hematopoietic malignancies using only morphology. In cases with low numbers of cells or ambiguous morphology, diagnoses of atypical or suspicious may be used. The significance of these diagnostic terms in this clinical scenario has not been well established. To that end, the authors conducted a study in which they identified 32 patients with known lymphoma or leukemia and an initial cerebrospinal fluid (CSF) diagnosis of atypical or suspicious by morphologic criteria. They evaluated subsequent flow cytometry and cytologic data from these patients. The authors found that of the 32 patients, 40.6 percent (n=13) had negative first and subsequent flow cytometry as well as negative subsequent morphologic evaluations with followup to one year. Nineteen patients (59.4 percent) had malignant hematopoietic cells identified in subsequent CSF samples by morphology or flow cytometry, or both. (Cytologic identification in 28 percent of cases increased to 59.4 percent with use of flow cytometry.) Further, malignancy was diagnosed by cytology approximately 79 days after the first CSF sample was submitted, while malignant cells were found by flow cytometry approximately 32 days after the first CSF sample was submitted. The authors concluded that in patients with a history of hematolymphoid malignancy, a majority of patients with an atypical or suspicious diagnosis on initial CSF examination will have malignant cells identified in CSF by cytology or flow cytometry, or both. Many of these patients can be identified more expediently by using flow cytometry concurrently.

Schinstine M, Filie AC, Wilson W, et al. Detection of malignant hematopoietic cells in cerebrospinal fluid previously diagnosed as atypical or suspicious. Cancer. 2006;108:157–162.

Reprints: Dr. Andrea Abati, Laboratory of Pathology, National Cancer Institute, NIH, Building 10, Room 2A19, 10 Center Drive, Bethesda, MD 20892-1500

bullet Sentinel-node biopsy or nodal observation in melanoma

The authors evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. Among 1,269 patients with an intermediate-thickness primary melanoma, the mean estimated five-year disease-free survival rate for the population was 78.3±1.6 percent in the biopsy group and 73.1±2.1 percent in the observation group (hazard ratio for death, 0.74; 95 percent confidence interval [CI], 0.59– 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1 ± 1.3 percent and 86.6 ±1.6 percent, respectively). In the biopsy group, metastases in the sentinel node was the most important prognostic factor; the five-year survival rate was 72.3 ±4.6 percent among patients with tumor-positive sentinel nodes and 90.2 ± 1.3 percent among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95 percent CI, 1.54– 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.9 percent (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6 percent (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the five-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3 ± 4.6 percent versus 52.4 ± 5.9 percent; hazard ratio for death, 0.51; 95 percent CI, 0.32– 0.81; P=0.004). The authors concluded that the staging of intermediate-thickness (1.2– 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy.

Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307–1317.

Reprints: Dr. D.L. Morton, John Wayne Cancer Institute, Saint John’s Health Center, 2200 Santa Monica Blvd., Santa Monica, CA 90404; mortond@jwci.org

bullet Occult sentinel lymph node micrometastases in breast cancer

Occult metastases, by definition, are not detected on initial examination. They may be present on slides but missed during screening or may be present in paraffin-embedded tissue blocks and undetected without additional levels. Anticytokeratin immunohistochemistry (CK IHC) enhances detection of occult metastases, particularly micrometastases greater than 0.2 mm but not larger than 2.0 mm or isolated tumor cell clusters of 0.2 mm or less. The authors conducted a study to define the rate at which pathologists miss metastases on CK IHC of sentinel lymph nodes. CK IHC sections 0.5 and 1.0 mm from the original surface of sentinel lymph node tissue blocks were screened by pathologists using standard bright field light microscopes (LM) and by supervised computer-assisted cell detection (CACD). All blocks were from breast cancer patients and initially classified as node negative on review of routinely stained sections from the surface of each block. Cases missed by LM screening but detected by CACD defined false-negative screens. Of 236 cases screened, LM detected 34 (14.4 percent; 95 percent confidence interval [CI], 9.6–20.2) cases and, in the 202 cases negative by LM, CACD detected an additional 30 (14.9 percent; 95 percent CI, 9.6–21.2 percent) cases with occult metastases. Occult metastases missed by LM screening ranged from 0.01 to 0.1 mm in greatest dimension. The probability of missing an occult metastasis of 0.02 mm or less, 0.05 mm or less, and 0.10 mm or less was 75 percent, 69.2 percent, and 61.2 percent, respectively. No occult metastases larger than 0.10 mm were missed by LM screening. The authors concluded that pathologists screening CK IHC-stained slides may frequently miss detecting metastases of less than 0.10 mm.

Weaver DL, Krag DN, Manna EA, et al. Detection of occult sentinel lymph node micrometastases by immunohistochemistry in breast cancer: an NSABP protocol B-32 quality assurance study. Cancer. 2006;107:661–667.

Reprints: Dr. Donald L. Weaver, University of Vermont College of Medicine, Dept. of Pathology, Given E-203, Health Science Complex, 89 Beaumont Ave., Burlington, VT 05405-0068; donald.weaver@uvm.edu

bullet Characteristics of metastasizing SCC of the skin and lips

The reported incidence of metastasis from squamous cell carcinoma of the skin and lips is between 0.5 percent and 16 percent. Clinical and histopathological criteria have been proposed to identify tumors that may have an increased risk of metastasis. The authors conducted a study to define such high-risk tumors in the wake of an increase in the incidence of squamous cell carcinoma (SCC) of the skin. They reassessed histopathological features of metastasized skin and lip tumors and a matched group of non-metastasizing tumors. They studied tumor width, excision margins, histological subtype, Clark level, Breslow depth, tumor differentiation, inflammation, perineural and angio-invasive growth, ulceration, and desmoplasia. The authors statistically analyzed data separately for skin and labial lesions. They found that desmoplasia, Clark level, Breslow depth, maximum diameter, angio-invasion, grading, perineural invasion, plasma cells, and eosinophilic inflammatory response were statistically significantly related to metastasis of skin tumors. Breslow depth, plasma cells, and grading appeared to be statistically significantly related to metastasis of SCC of the lips. The authors concluded that typical metastatic SCC showed tumor width of at least 15 mm, vertical tumor thickness of at least 2 mm, less differentiation, presence of desmoplasia, inflammatory response with eosinophils, and plasma cells.

Quaedvlieg PJ, Creytens DH, Epping GG, et al. Histopathological characteristics of metastasizing squamous cell carcinoma of the skin and lips. Histopathology. 2006;49:256–264.

Reprints available from P.J. Quaedvlieg at pqua@sder.azm.nl

bullet Role of BCL6 expression in patient prognosis

The authors investigated the role of BCL6 in the pathogenesis of gastric lymphoma. They analyzed the BCL6 promoter region for BCL6 translocations, somatic hypermutations, and deregulating mutations in 43 gastric lymphomas, including four extranodal marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas), 33 diffuse large B-cell lymphomas (DLBCLs), and six composite DLBCLs with residual MALT lymphoma (DLCLMLs). They found that BCL6 promoter substitutions by immunoglobulin (Ig) and non-Ig translocation partners, resulting in its deregulation, were frequently involved in DLBCL (36.4 percent) and DLCLML (50 percent). They also identified two novel BCL6 translocation partner genes, 28S rRNA and DMRTI, and a new BCL6 translocation breakpoint in intron 2. Deregulating mutations were found only in DLBCL (24.2 percent), which correlated significantly with high BCL6 protein expression as assessed by immunohistochemistry using a scoring system based on percentage of positive tumor cells. Significantly high BCL6 expression correlated strongly with longer overall survival, independent of mechanism in gastric DLBCL and DLCLML. Gastric DLBCLs were further subclassified into germinal center B-cell-like (GCB) and non-GCB subgroups immunohistochemically. High BCL6 expression was detected in all GCB cases, irrespective of BCL6 genetic alterations. In the non-GCB subgroup, BCL6-deregulating mutations correlated significantly with high BCL6 expression level. No significant correlation was found between BCL6 expression level and overall survival in the non-GCB subgroup, which had significantly poorer prognosis than the GCB subgroup.

Chen YW, Hu XT, Liang AC, et al. High BCL6 expression predicts better prognosis, independent of BCL6 translocation status, translocation partner, or BCL6-deregulating mutations in gastric lymphoma. Blood. 2006;108:2373–2383.

Reprints: Gopesh Srivastava, University Pathology Building, Queen Mary Hospital Compound, 102 Pokfulam Rd., Hong Kong; gopesh@pathology.hku.hk


Dr. Cibull is professor of pathology and laboratory medicine and direct of surgical pathology, University of Kentucky Medical Center, Lexington. Dr. Lele is assistant professor of pathology and laboratory medicine, University of Kentucky Medical Center. Dr. Kesler is hematopathology fellow, University of Texas Southwestern Medical Center at Dallas.