Background The Ki‐67 proliferation marker has multiple diagnostic and prognostic applications. Although several clones to the Ki‐67 antigen are commercially available, the MIB1 clone is widely recommended in the surgical pathology literature for neuroendocrine tumors. In our cytopathology practice, we have encountered unexpectedly low MIB1 immunoreactivity in CytoLyt‐fixed cell blocks (CBs). The current study evaluated the impact of fixatives, CB processing, and immunocytochemical (ICC) procedures on Ki‐67 immunoreactivity. Methods Test CBs were prepared from freshly resected tumors, and multiple variables in the MIB1 ICC procedure were tested, including CytoLyt versus formalin collection media, MIB1 versus other Ki‐67 clones including 30‐9, and other variables. MIB1 versus Ki‐67 30‐9 clones were tested in parallel on CytoLyt‐fixed CBs from clinical samples of small cell lung carcinoma (SCLC). Results In the test CBs (n = 10), the mean MIB1 labeling index was 10% in CytoLyt versus 47% in formalin (P = .0116), with a mean loss of reactivity in matched CBs of 37% (up to 70%). None of the procedure modifications tested in 223 individual ICC reactions recovered MIB1 reactivity in CytoLyt except for switching to the Ki‐67 30‐9 antibody. In CytoLyt‐fixed SCLC samples (n = 14), the Ki‐67 30‐9 antibody demonstrated expected ranges of reactivity (mean, 83%; range, 60%‐100%), whereas MIB1 demonstrated markedly inhibited labeling (mean, 60%; range, 10%‐95%) (P = .0058). Conclusions CytoLyt fixation substantially inhibits MIB1 immunoreactivity, whereas the Ki‐67 30‐9 clone is not susceptible to inhibition. Markedly discrepant MIB1 reactivity may present a pitfall in the diagnosis of SCLC and may lead to the incorrect prognostic stratification of other tumor types. For laboratories using CytoLyt, we recommend using the Ki‐67 30‐9 antibody rather than the MIB1 antibody.
BACKGROUND Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. METHODS We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. RESULTS We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). CONCLUSION The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.
Proximal femoral focal deficiency (PFFD) represents CASE REPORTA 39-year-old woman, gravida 5, para 1-0-3-1, was referred from genetic counseling to our high-risk obstetric clinic at 19 weeks' gestation for a second opinion on a unilateral short femur. The patient had a history of three first-trimester miscarriages, and one prior pregnancy had resulted in the full-term delivery of a healthy infant. The pregnancy was unremarkable up to this point and previous amniocentesis had revealed a normal karyotype.Detailed two-dimensional (2D) and three-dimensional (3D) ultrasound examination using a Voluson 730 E8 machine (GE Healthcare, Zipf, Austria) at 18 + 3 weeks' gestation was performed. Gray-scale 2D examination showed a markedly asymmetrical shortening of the left femur, which measured 11.9 mm in length (consistent with a gestational age of 13 + 4 weeks) and a normal right femur measuring 29.3 mm in length (consistent with a gestational age of 19 + 0 weeks) (Figure 1a,b). 3D surface rendering clearly demonstrated the discrepancy between the length, position and appearance of the lower limbs (Figure 1c). The left thigh was laterally rotated and had a restricted range of motion compared with the contralateral limb (Videoclip S1). Using maximum mode (X-ray) display we had the impression that the upper end of the femur as well as part of the acetabulum appeared to be hypoplastic. The upper limbs and the right lower limb were within the normal range for this gestational age with no evidence of bowing or demineralization. Biparietal diameter and abdominal circumference were all consistent with menstrual dates. The facial profile was normal and no other associated structural abnormalities were observed. In addition to proximal femoral focal deficiency (PFFD), congenital hypoplasia of the femur is a principal sign of three other rare malformations, and a differential diagnosis had to be made between femur-fibula-ulna complex, femoral hypoplasia/unusual facies syndrome and limb/pelvis-hypoplasia/aplasia syndrome 1 . On the basis of the ultrasound findings PFFD was felt to be the probable diagnosis.
Estrogen receptor-α (ER-α), encoded by ESR1, is detected by immunohistochemistry in approximately 70% of invasive breast cancers and serves as a strong predictive biomarker. ESR1-activating mutations in the ligand-binding domain have been reported in up to 35-40% of ER-positive metastatic breast cancers and are associated with endocrine therapy resistance and disease progression. At present, it is unclear whether ESR1 mutations alter the immunohistochemical detection of ER performed in routine clinical practice. In this study, ESR1 mutations in breast cancer were identified utilizing Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a Food and Drug Administration-approved hybridization capture-based next-generation sequencing assay. Five hundred and eighty-six breast cancers from patients with locally advanced or metastatic disease were analyzed using MSK-IMPACT in the study period. ESR1 somatic alterations were identified in 67 breast cancer samples from 66 patients. Immunohistochemical analysis of ER, progesterone receptor, and human epidermal growth factor receptor 2 was performed on the primary and treated breast cancers from these patients at the time of diagnosis. Twenty unique ESR1 mutations were identified involving the ligand-binding domain, all in breast cancer samples from patients previously treated with endocrine therapy. The most frequent mutations were D538G (n = 22), Y537S (n = 7), and E380Q (n = 7). All breast cancer samples with an ESR1 mutation were ER-positive by immunohistochemistry. Review of the ER immunohistochemistry in the paired untreated primary tumor and treated tumor from 34 patients showed no detectable change in the ER-positive immunohistochemical status (median percentage of invasive tumor cells with nuclear staining: untreated primary tumor 90%, treated tumor 95%). We conclude that ESR1 mutations do not appreciably diminish ER-positive staining by immunohistochemistry. In addition to standard biomarker testing by immunohistochemistry, the assessment of ESR1 mutations by molecular testing can help guide the clinical management of patients with ER-positive breast cancer in the setting of endocrine resistance and progression of disease.
Papillary carcinoma of the breast consists of 3 morphologically distinct established subtypes: encapsulated papillary carcinoma, solid papillary carcinoma, and invasive papillary carcinoma. Papillary carcinoma is one of the special types of breast cancer and, as such, carries a more favorable prognosis. We sought to identify primary breast tumors with tubulopapillary morphology and correlate this finding with predictors of adverse prognosis. We investigated our pathology files for breast tumors exhibiting tubulopapillary features. The dominant morphology consisted of infiltrating gaping tubules with intratubular papillary projections. The study group consisted of 12 cases of papillary carcinoma with tubulopapillary features. A control group of 17 cases of papillary carcinoma were selected consisting of 4 encapsulated papillary carcinomas, 3 solid papillary carcinomas, and 10 invasive papillary carcinomas. The study group showed significantly higher mitotic rate, ki67 proliferation index, nuclear grade 3, lymphovascular invasion, p53 overexpression, unfavorable biomarker signature, and axillary nodal involvement compared to the control group (P = .01, .01, .04, .01, .007, .0001, .03, respectively). Invasive breast carcinomas with tubulopapillary features demonstrate significant correlation with predictors of adverse prognosis compared to ordinary papillary carcinomas. Larger studies with survival analysis are required to confirm aggressiveness in this group of breast cancers.
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