How reliable is Ki-67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss Working Group of Breast- and Gynecopathologists.

UNLABELLED: Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. METHODS: Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. RESULTS: The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56-0.72). However, we found very high inter-observer variabilities (Kappa 0.04-0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01-0.04) and intra-observer agreement was likewise poor (Kappa 0.00-0.35). CONCLUSION: Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas.

Incidence of small lymph node metastases with evidence of extracapsular extension: clinical implications in patients with head and neck squamous cell carcinoma.

PURPOSE: Small lymph nodes (LN) show evidence of extracapsular extension (ECE) in a significant number of patients. This study was performed to determine the impact of ECE in LN ≤7 mm as compared with ECE in larger LN. METHODS AND MATERIALS: All tumor-positive LN of 74 head and neck squamous cell carcinoma (HNSCC) patients with at least one ECE positive LN were analyzed retrospectively for the LN diameter and the extent of ECE. Clinical endpoints were regional relapse-free survival, distant metastasis-free survival, and overall survival. The median follow-up for the surviving patients was 2.1 years (range, 0.3-9.2 years). RESULTS: Forty-four of 74 patients (60%) had at least one ECE positive LN ≤10 mm. These small ECE positive LN had a median diameter of 7 mm, which was used as a cutoff. Thirty patients (41%) had at least one ECE positive LN ≤7 mm. In both univariate and multivariate Cox regression analyses, the incidence of at least one ECE positive LN ≤7 mm was a statistically significant prognostic factor for decreased regional relapse-free survival (adjusted hazard ratio [HR]: 2.7, p = 0.03, 95% confidence interval [CI]: 1.1-6.4), distant metastasis-free survival (HR: 2.6, p = 0.04, 95% CI: 1.0-6.6), and overall survival (HR: 2.5, p = 0.03, 95% CI: 1.1-5.8). CONCLUSIONS: The incidence of small ECE positive LN metastases is a significant prognostic factor in HNSCC patients. Small ECE positive LN may represent more invasive tumor biology and could be used as prognostic markers.

Quantitative analysis of extracapsular extension of metastatic lymph nodes and its significance in radiotherapy planning in head and neck squamous cell carcinoma.

PURPOSE: We performed a histopathologic analysis to assess the extent of the extracapsular extension (ECE) beyond the capsule of metastatic lymph nodes (LN) in head and neck cancer to determine appropriate clinical target volume (CTV) expansions. METHODS AND MATERIALS: All tumor-positive LN of 98 patients who underwent a neck dissection with evidence of ECE in at least one LN were analyzed by a single pathologist. The largest diameters of all LN, and in the case of ECE, the maximal linear distance, from the capsule to the farthest extent of tumor or tumoral reaction were recorded. RESULTS: A total of 231 LN with ECE and 200 tumor-positive LN without ECE were analyzed. The incidence of ECE was associated with larger LN size (p < 0.001). Of all tumor-positive LN with a diameter of < 10 mm or < 5 mm, 105/220 (48%) nodes or 17/59 (29%) nodes, respectively, showed evidence of ECE. The mean and median extent values of ECE were 2 and 1 mm (range, 1-10 mm) and the ECE was < or = 5 mm in 97% and < or = 3 mm in 91% of the LN, respectively. Overall, the extent of ECE was significantly correlated with larger LN size (Spearman's correlation coefficient = 0.21; p = 0.001). CONCLUSIONS: The incidence of ECE is associated with larger LN size. However, ECE is found in a substantial number of LN with a diameter of < 10 mm. The use of 10-mm CTV margins around the gross tumor volume seems appropriate to account for ECE in radiotherapy planning of head and neck cancer.

"Exterritorial" lymphocytic hypophysitis within an ovarian teratoma during pregnancy: a possible sentinel lesion?

Pituitary tissue is rarely to be found among the constituents of ovarian teratomas (dermoid cysts). In some exceptional cases, however, such ectopic pituitary anlagen may even give rise to secondary organ-specific pathologies. Akin to those of the pituitary in its natural location, these tend to be adenomas. We describe a unique example of lymphocytic hypophysitis incidentally encountered in a mature left ovarian teratoma from a 30-year-old woman in the 19th week of pregnancy. Amidst various fully differentiated derivatives of all three embryonic layers, the cyst wall also included a miniature replica of the anterior pituitary lobe 0.5 cm in diameter. While a full set of adenohypophyseal hormone-producing cell types could be identified, there was characteristic pregnancy-related hyperplasia of lactotrophs. This was further overlaid by prominent mononuclear inflammation, including infiltration by T lymphocytes, follicular aggregates of B cells, and attendant destruction of parenchyma. There was no significant inflammatory reaction elsewhere. Discounting the non-standard location, the ensemble of the clinical setting and histology were felt to be indistinguishable from the classical paradigm of lymphocytic hypophysitis complicating pregnancy. To date, lymphocytic thyroiditis is the sole form of organ-specific inflammatory process within an ovarian teratoma on record. By analogy, we hypothesize that this ectopic manifestation of immune-mediated inflammation of pituitary parenchyma may possibly be read as a preclinical sentinel lesion of lymphocytic hypophysitis.

Primary monophasic synovial sarcoma of the duodenum with SYT/SSX2 type of translocation.

Recent findings on the molecular background of synovial sarcoma with the description of the specific translocation t(X;18) led to the incorporation of this particular genetic aberration into the definition of this tumor type. Synovial sarcomas with proven diagnostic translocation are being described with increasing frequency in unsuspected locations not related to joints, such as lung, pleura, heart, or pharynx. The gastrointestinal tract has been rarely reported as a primary site of synovial sarcomas with rare cases in the esophagus and stomach. We report a case of a primary synovial sarcoma of the distal duodenum with SYT/SSX2 type of the t(X;18) translocation. Primary spindle cell neoplasms of the duodenum are rare and consist mostly of gastrointestinal stromal tumors, which are amenable to the therapy with Gleevec. Synovial sarcoma widens the differential diagnosis of mesenchymal tumors of the intestine.