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Aims‘HER2-low’ breast cancer is an emerging issue as the clinical trials for anti-HER2 antibody–drug conjugates (trastuzumab deruxtecan) are making progress. A reliable method to identify HER2-low cancers is needed. This study aimed to evaluate immunohistochemistry (IHC) and in situ hybridisation (ISH) in detecting HER2-low status.MethodsWe evaluated the HER2 ISH data grouped by the IHC consensus in proficiency tests (PTs), and compared the HER2 ISH results between HER2 IHC scored 0 (IHC-0) and IHC scored 1+ (IHC-1+) tumours from in-house tissue microarrays (TMAs). Since benign/normal glands have HER2 expression and ideally should not be affected by targeted therapy, we evaluated HER2 ISH results in peritumoural benign glands of 52 breast cancers as reference values.ResultsNone of the 565 tissue cores in PTs achieved an 80% participant agreement of IHC-1+. In PTs and in-house TMAs, HER2signals of the IHC-1+cores (median: 2.6 and 2.0, respectively) were significantly higher than those of IHC-0 cores (median: 2.0 and 1.7, respectively). But the ranges of HER2signals had a considerable overlap between IHC-1+and IHC-0 cores. The HER2signals and HER2:CEP17 ratios of peritumoural benign glands exhibited normal distributions, and their upper bounds of the 95% reference intervals were 2.10 and 1.30, respectively.ConclusionsCurrent HER2 testing algorithms are unsatisfactory in detecting HER2-low cases. Using ISH to detect tumour with HER2signals and HER2:CEP17 ratio higher than the upper bound of the benign glands can be an alternative method.

To report a case and review literature of bowel metastases from cervical squamous cell carcinoma.

The blast percentage in bone marrow (BM) can be evaluated through biopsy and aspiration, which is essential for diagnosing myeloid neoplasms especially for dividing myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). However, methods for integrating the results of biopsy and smear have yet to be developed, particularly for cases in which the results fall on both sides of the cut-off value (10% or 20%). We studied 188 cases of MDS/AML initially diagnosed during 2011–2015 by using concomitant BM biopsy and aspiration and used different methods to compare the estimated blast percentages. A linear relationship was noted between the blast percentages estimated through biopsy and smear (R2=0.765). When the blast percentage was classified into four relevant clinical categories (<5%, 5–9%, 10–19%, and ≥20%), the total concordance between the results of the biopsy and smear was 76.1%. Although the prognostic values obtained through biopsy and smear were not significantly different, using the higher blast percentage estimation by biopsy and smear fared better in classifying patients into categories of 10–19% and ≥20% and demonstrated survival significance in both univariate and multivariate analyses. Subgroup analyses demonstrated that BM blast percentages had no prognostic significance when patients underwent intensive chemotherapy. However, blast percentages of ≥10% indicated poor prognosis for patients receiving only supportive care. In conclusion, most of the clinically relevant categories of blast percentages estimated through concomitant BM biopsy and smear were concordant. When the categories were different, the best prognostic prediction method was to select the higher blast percentage determined through biopsy and smear to diagnose MDS/AML.

The criteria for primary bone marrow large B-cell lymphoma (PBMLBCL) have not yet been clearly established. We aimed to investigate the clinicopathological features of PBMLBCLs (27 cases) and large B-cell lymphomas (LBCLs) with secondary marrow involvement (55 cases). PBMLBCL was defined as LBCLs presenting initially in bone marrow without lymphadenopathy, extramedullary tumour or localised bone tumour, and no evidence of transformation from low grade B-cell lymphoma. Compared with the patients in the secondary group, more patients in the primary group had haemophagocytic lymphohistiocytosis, cytogenetic aberrations, cytopenias, and atypical lymphocytes in peripheral blood. The most common chromosome abnormality in both groups was 6q deletion. The primary group had additional chromosome 10, 2, and 3 abnormalities. The acquired chromosome 10 aberration was associated with the risk of haemophagocytic lymphohistiocytosis. The 1-year survival rate was lower in the primary group than in the secondary group; however, the difference was not significant when the cases without chemotherapy plus rituximab were excluded. Moreover, multivariate analysis revealed that relatively high white blood cell count, not receiving chemotherapy plus rituximab, and cytogenetic aberrations were poor prognostic factors in the secondary group, but only not receiving chemotherapy plus rituximab was retained in the primary group. In conclusion, PBMLBCL is genetically and clinically distinct. Although patients with PBMLBCL generally have a poor outcome, the disease is treatable and some patients become long-term survivors.

AimsAlthough Ki67 labelling index (LI) is a prognostic and predictive marker in breast cancer, its accuracy and reproducibility must be validated before its clinical application. We aimed to evaluate the agreement of Ki67 LI in clinical practice in Taiwan.MethodsWe conducted a Ki67 immunohistochemistry (IHC) proficiency test. The participants performed the Ki67 IHC test and measured the Ki67 LI of 10 cases of breast cancer tissue on a microarray slide. The staining quality was centrally reviewed based on the Ki67 staining of the tonsil surface epithelium.ResultsKi67 staining and counting methods are diverse in Taiwan. The reproducibility of Ki67 LI was poor to good (intraclass correlation coefficient: 0.581, 95% CI 0.354 to 0.802). The reproducibility and agreement in the high staining quality group were significantly higher than those in the low staining quality group. The majority of the Ki67 LIs derived from the low staining quality group were underestimated. Different counting methods did not reveal significant differences when determining Ki67 LI with microarray sections.ConclusionsWe suggest using the surface epithelium of the tonsil as external control and achieving optimal staining results that consist of a high positive parabasal layer, a low positive intermediate layer and a negative superficial layer. Good Ki67 staining quality can minimise the staining variations among different laboratories, and it is essential for the reproducibility of Ki67 LI.

BLS-type diffuse large B-cell lymphoma (DLBCL) denotes an uncommon, aggressive variant of DLBCL presenting initially in bone marrow, liver and spleen without lymphadenopathy or mass lesion. Patients with BLS-type DLBCL present frequently with haemophagocytic syndrome which often leads to early patient demise. Programmed death ligand 1 (PD-L1) plays a negative regulatory role on effector T cells and is an important target of immunotherapy. Assessment of PD-L1 expression in BLS-type DLBCL may carry therapeutic implications and provide mechanistic insights. Standard immunohistochemical analysis for PD-L1 was performed in seven cohorts for this study: (1) DLBCL-not otherwise specified (NOS) (n=201); (2) Epstein–Barr virus (EBV)-positive DLBCL (n=26); (3) thymic (primary mediastinal) DLBCL (n=12); (4) intravascular LBCL (n=3); (5) high-grade B-cell lymphoma, NOS (n=12); (6) BLS-type DLBCL (n=37); and (7) systemic DLBCL involving bone marrow (n=28). We found that PD-L1 was positive in 12.9% of DLBCL-NOS cases, 46.2% of EBV-positive DLBCL, 91.7% of thymic LBCL, none of intravascular LBCL, 8.3% of high-grade B-cell lymphoma-NOS, and 56.8% of BLS-type DLBCL. By comparison, only 14.3% of bone marrow cases involved by systemic DLBCL were positive for PD-L1 (p<0.001). Interestingly, BLS-type DLBCL more frequently showed activated B-cell phenotype (86.5% vs 65.2%, p=0.010), a high Ki-67 proliferative index (97.1% vs 63.3%, p<0.001), MYC overexpression (90.9% vs 56.2%, p=0.023), presence of haemophagocytic syndrome (86.5% vs 4.0%, p<0.001), and poorer overall survival (p<0.001) than DLBCL-NOS. These data suggest that the poor prognosis of BLS-type DLBCL may be explained by both extrinsic tumour microenvironment factors and intrinsic genetic factors of tumour cells, such as PD-L1-associated inactivation of anti-tumour immunity for the former, and MYC pathway activation-related aggressiveness for the latter.

Supplemental Digital Content is available in the text.The O6-methylguanine-DNA-methyltranferase (MGMT) status is a powerful predictor of response to temozolomide for newly diagnosed glioblastoma (GBM) patients, and it is commonly assessed by immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP), quantitative real-time MSP (qMSP), and/or pyrosequencing (PSQ). This study was to compare their predictive power of prognosis in 121 newly diagnosed GBM patients using multivariate Cox regression with bootstrapping. MGMTstatus tested by IHC, MSP, qMSP, or PSQ all showed significant correlation with the progression-free survival and overall survival of GBM patients. The predictive power of IHC for progression-free survival and overall survival was lower than those of the methylation assays, but their differences were not significant. Performing additional methylation assay, especially PSQ, could better predict the prognosis of patients with IHC− tumors. MGMTstatus tested by IHC, MSP, qMSP, or PSQ all showed prognostic significance. An additional MGMTmethylation assay, of which PSQ appeared to be the best, could improve the predictive power for GBM patients with MGMT IHC− tumors.

Subependymal giant cell astrocytoma is a benign brain tumor mostly associated with tuberous sclerosis complex. However, it may be misinterpreted as other high-grade brain tumors due to the presence of large tumor cells with conspicuous pleomorphism and occasional atypical features, such as tumor necrosis and endothelial proliferation. In this study, we first investigated thyroid transcription factor-1 (TTF-1) expression in a large series of subependymal giant cell astrocytomas and other histologic and locational mimics to validate the diagnostic utility of this marker. We then examined TTF-1 expression in non-neoplastic brain tissue to determine the cell origin of subependymal giant cell astrocytoma. Twenty-four subependymal giant cell astrocytoma specimens were subjected to tissue microarray construction. For comparison, a selection of tumors, including histologic mimics (21 gemistocytic astrocytomas and 24 gangliogliomas), tumors predominantly occurring at the ventricular system (50 ependymomas, 19 neurocytomas, and 7 subependymomas), and 134 astrocytomas (3 pleomorphic xanthoastrocytomas, 45 diffuse astrocytomas, 46 anaplastic astrocytomas, and 40 glioblastomas) were used. Immunohistochemical stain for TTF-1 was positive in all 24 subependymal giant cell astrocytomas, whereas negative in all astrocytomas, gangliogliomas, ependymomas, and subependymomas. Neurocytomas were positive for TTF-1 in 4/19 (21%) of cases using clone 8G7G3/1 and in 9/19 (47%) of cases using clone SPT24. In the three fetal brains that we examined, TTF-1 expression was seen in the medial ganglionic eminence, a transient fetal structure between the caudate nucleus and the thalami. There was no BRAFV600Emutation identified by direct sequencing in the 20 subependymal giant cell astrocytomas that we studied. In conclusion, TTF-1 is a useful marker in distinguishing subependymal giant cell astrocytoma from its mimics. Expression of TTF-1 in the fetal medial ganglionic eminence indicates that subependymal giant cell astrocytoma may originate from the progenitor cells in this region.

Subependymal giant cell astrocytoma is a benign brain tumor mostly associated with tuberous sclerosis complex. However, it may be misinterpreted as other high-grade brain tumors due to the presence of large tumor cells with conspicuous pleomorphism and occasional atypical features, such as tumor necrosis and endothelial proliferation. In this study, we first investigated thyroid transcription factor-1 (TTF-1) expression in a large series of subependymal giant cell astrocytomas and other histologic and locational mimics to validate the diagnostic utility of this marker. We then examined TTF-1 expression in non-neoplastic brain tissue to determine the cell origin of subependymal giant cell astrocytoma. Twenty-four subependymal giant cell astrocytoma specimens were subjected to tissue microarray construction. For comparison, a selection of tumors, including histologic mimics (21 gemistocytic astrocytomas and 24 gangliogliomas), tumors predominantly occurring at the ventricular system (50 ependymomas, 19 neurocytomas, and 7 subependymomas), and 134 astrocytomas (3 pleomorphic xanthoastrocytomas, 45 diffuse astrocytomas, 46 anaplastic astrocytomas, and 40 glioblastomas) were used. Immunohistochemical stain for TTF-1 was positive in all 24 subependymal giant cell astrocytomas, whereas negative in all astrocytomas, gangliogliomas, ependymomas, and subependymomas. Neurocytomas were positive for TTF-1 in 4/19 (21%) of cases using clone 8G7G3/1 and in 9/19 (47%) of cases using clone SPT24. In the three fetal brains that we examined, TTF-1 expression was seen in the medial ganglionic eminence, a transient fetal structure between the caudate nucleus and the thalami. There was no BRAFV600Emutation identified by direct sequencing in the 20 subependymal giant cell astrocytomas that we studied. In conclusion, TTF-1 is a useful marker in distinguishing subependymal giant cell astrocytoma from its mimics. Expression of TTF-1 in the fetal medial ganglionic eminence indicates that subependymal giant cell astrocytoma may originate from the progenitor cells in this region.

•Patients with neoadjuvant chemotherapy-induced pathologic complete response had higher expressions of eight genes, KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1,and CA4, compared to non-pathologic complete response patients.•The 8-gene signature was associated with better relapse-free survival in patients receiving chemotherapy.•The expression of eight immune-related genes was involved in better drug responses and was positively correlated with immune cell infiltrations.

Peritoneal involvement is an important adverse prognostic factor in colorectal cancer (CRC) and determines a shift in the pathologic tumor node metastasis stage. Because peritoneal involvement is difficult to identify, use of special stains highlighting the peritoneal elastic lamina and mesothelial surface has been proposed. This study aims to determine whether use of elastic stain or CK7 immunohistochemistry on a single tissue section can refine the level of tumor invasion and determine whether restaging based on this assessment has prognostic significance in pT3N0 CRCs. Elastic stains were applied to 1 block per case from 244 consecutively resected pT3N0M0 CRCs. CK7 was evaluated in a 169-case subset. The elastic lamina was identified in only 101 cases (41). Of those, 60 cases (24.6) displayed elastic lamina invasion (ELI). This finding was associated with significantly worse (P<0.001) disease-free survival (DFS) (5-y DFS=60) and significantly worse (P=0.01) overall survival (OS) (5-y OS=66.7) compared with patients with no ELI (5-y DFS=87.8, OS=92.7) and those for whom no elastic lamina was identified (5-y DFS=82.5, OS=86.0). CK7 staining highlighted mesothelial cells in only 27 of 169 cases tested and helped demonstrate serosal invasion in only 5 cases (3). In summary, the use of a single elastic stain is a useful and inexpensive method to demonstrate peritoneal involvement by tumor and should be considered for routine use in all pT3N0 CRCs. As tumors with ELI have an adverse prognosis, we propose that they should be upstaged compared with pT3N0 tumors without ELI.

We evaluated the predictive value of O6-methylguanine-DNA methyltransferase (MGMT) protein expression and MGMT promoter methylation status in glioblastomas (GBM) treated with temozolomide (TMZ) in a Taiwan medical center. Protein expression by immunohistochemical analysis (IHC) and MGMT promoter methylation detected by methylation-specific polymerase chain reaction (MSP) were performed in a series of 107 newly diagnosed GBMs. We used endothelial cells as an internal reference for IHC staining because the staining intensities of the MGMT-expressing cells in different specimens varied considerably; a positive result was defined as the staining intensity of the majority of tumor cells similar to that of the adjacent endothelial cells. Immunostainings for microglialendothelial markers were included as part of the MGMT IHC evaluation, and in cases that were difficult to interpret, double-labeling helped to clarify the nature of reactive cells. The MGMT protein expression was reversely associated with MGMT promoter methylation status in 83.7 of cases (MSPIHC−and MSP−IHC; Pearson r=−0.644, P<0.001). Twenty-two of 24 (91.7) IHCtumors did not respond to TMZ treatment. Combining MSP and IHC results, all the 15 MSP−IHCGBMs were TMZ resistant. The MGMT status detected by either IHC or MSP was significantly correlated with the TMZ treatment response (both P<0.001) and survival of GBM patients (both P<0.05).

Approximately 10% of patients with glioblastoma survive more than 2 years after diagnosis. Distinguishing these patients from those who died within 2 years of diagnosis is clinically significant. We studied the MIB-1 labeling index (LI) and DNA topoisomerase II alpha LI of glioblastomas from 34 patients who lived for more than 2 years after diagnosis and of glioblastomas from 34 age- and sex-matched control patients who died within 2 years of diagnosis. The means of MIB-1 and topoisomerase II alpha LIs of the group with a better outcome were lower. With 35 as the cutoff point for the MIB-1 LI and 26 as the cutoff point for the topoisomerase II alpha LI, both MIB-1 and topoisomerase II alpha LIs were related significantly to survival. Our study showed that both MIB-1 and topoisomerase II alpha could help predict long-term survival of patients with glioblastomas. Multivariate analyses revealed that MIB-1 was a better prognostic marker than topoisomerase II alpha.

Although there are criteria for interpretation of the staining results for Her-2/neu in the DAKO HercepTest, the determination of staining intensity and percentage of complete membrane staining is subjective. We studied 46 cases of invasive breast carcinoma to evaluate interobserver reproducibility among 5 pathologists. Complete agreement was achieved in 22 (48%) of46 cases. Generalized kappa values indicated substantial agreement (0.80). Discrepancies between negative (0, 1+) and positive (2+, 3+) results occurred in 2 cases (kappa = 0.96). One was because of a tangential cut of the basal part of the tumor that mimicked complete membranous staining, and the other was a borderline case that revealedfocal (5%-15%) complete membranous staining. Distinguishing weakly (2+) from strongly (3+) positive results showed agreement in only 13 (59%) of 22 positive cases (kappa = 0.38). If more than 50% of tumor cells revealing strong complete membrane staining were regarded as strongly positive, agreement would be improved (kappa = 0.78). While there was a high percentage (70%-80%) of negative cases during routine evaluation, the good interobserver agreement and high negative predictive value made immunohistochemical analysis an effective screening test to exclude negative cases.

Although various histopathologic features have been associated with aggressive behavior or recurrence of meningiomas, there is little agreement about which features are the most important and in what combination. The objective of this study was to formulate diagnostic criteria for atypical meningioma. Eighty-three patients with meningiomas who underwent macroscopic total resection and had been followed until they developed recurrent disease or for at least 10 years were studied. Thirteen histopathologic parameters that related to recurrence of the tumor were evaluated in each patient. All possible combinations of histologic parameters that were related significantly to recurrence were used to formulate scoring models. The model that included the fewest parameters and that could distinguish tumor recurrence best within 10 years was chosen as the final model. The final model included three parameters: loss of architecture, mitoses ≥ 1.5/mm², and necrosis. Of the 52 tumors with a score &lt; 2 (0 or 1 of the 3 parameters), all except 1 tumor did not recur within 10 years, and they were all considered benign meningiomas. Of the 31 tumors with a score ≥ 2 (2 or 3 of the 3 parameters), 94% recurred within 10 years (76% recurred within 5 years), and they were considered atypical meningiomas. The estimated 5-year and 10-year recurrence rates for the benign meningiomas were 0.0% and 1.9%, respectively, for benign meningiomas and 71.0% and 93.5%, respectively, for atypical meningiomas (P &lt; 0.001). The estimated 5-year and 10-year mortality rates also were significantly different (0.0% and 0.0% vs. 22.1% and 26.7%, respectively; P &lt; 0.001). The MIB-1 labeling index (LI) for the entire group studied ranged from 0.4 to 33.5 (mean LI, 8.4). Fifty-two tumors with an LI of &lt; 10 did not recur within 10 years. Of the 31 tumors with an LI ≥ 10, 97% recurred (71% within 5 years). Histopathology and MIB-1 LI were able to predict clinical outcomes of patients with meningioma. The authors propose that atypical meningioma may be diagnosed when two of the following three criteria are present: loss of architecture, mitoses ≥ 1.5/mm², and necrosis. Cancer 2002;94:1538–47. © 2002 American Cancer Society. DOI 10.1002/cncr.10351

Optimal histologic criteria for the classification of and grading of ependymomas, including their anaplastic forms, remain elusive. This is especially true because of the poor correlation of these criteria with clinical outcome. The aim of this study was to identify the histopathologic parameters that could distinguish different prognostic groups of patients with ependymomas. Eighty-one patients with ependymal tumors, including those originally diagnosed ependymomas, anaplastic ependymomas and myxopapillary ependymomas, were enrolled in this study. Thirteen histologic parameters, including hypercellularity, nuclear pleomorphism, mitoses, endothelial proliferation, necrosis, clear cell, thrombi, dystrophic calcification, psammoma bodies, bone, cartilage, Rosenthal fibers and MIB-1 labeling index (LI), were evaluated in each patient and correlated with clinical outcome. We assigned one score for each histopathologic parameter evaluated and used a stepwise selection method with entry model based on the significance of the log-rank statistic to formulate a scoring model. Four parameters were chosen in this process, including mitoses ≥ 4/10 hpf (1.7/mm2), hypercellularity, endothelial proliferation and necrosis. The sum of these four parameters (scores) was the histopathologic score of the tumor. The progression-free survival (PFS) and overall survival (OS) of patients with histopathologic scores 0 and 1 were significantly better than those with histopathologic scores 2, 3 and 4 (p < 0.001 and p = 0.005, respectively). Because of the latter finding, we proposed that anaplastic ependymoma could be diagnosed by the presence of any two of the aforementioned four parameters. Multivariate analyses including clinical and histopathologic variables showed that histopathologic score ≥ 2 and subtotal resection were the factors related to increased risk of recurrence, while histopathologic score ≥ 2 was the only factor related to overall survival. Based on the above findings, we concluded that histopathology is an important prognostic indicator for patients with ependymomas.

Objective.The goal of this study was to assess whether the MIB-1 labeling index (LI) and conventional parameters could distinguish between a good and a poor prognosis in patients with squamous cell cervical carcinoma of the same FIGO stage.

The prognosis of pediatric patients with nonpilocytic astrocytoma, and in particular those with anaplastic astrocytoma, is somewhat unpredictable. This study used MIB-1 monoclonal antibody, a proliferative marker that can be used in formalin fixed paraffin embedded tissues, to study nonpilocytic pediatric astrocytoma. Astrocytoma, anaplastic astrocytoma, and glioblastoma specimens excised from a total of 101 pediatric patients during the period from January 1975 to September 1996 were retrieved from the authors' surgical pathology file. Histologic grading of the specimens was performed based on a modified Ringertz system. The proliferative potential of the tumors was estimated by using the MIB-1 labeling index (LI), which was evaluated with morphologic grades of tumors and survival of the patients. Of the 101 patients, 34 had astrocytoma, 33 had anaplastic astrocytoma, and 34 had glioblastoma. Their mean survival times were 165.2 ± 14.9 months (mean ± standard error; SE), 46.1 ± 9.9 months, and 21.8 ± 5.6 months, respectively. The mean MIB-1 LI of different tumor grades were as follows: astrocytoma, 3.9 ± 4.3 (mean ± standard deviation; range, 0.0-21.6); anaplastic astrocytoma, 24.3 ± 15.6 (range, 1.7-62.8); and glioblastoma, 35.9 ± 16.4 (range, 7.36-63.3). The mean survival of the entire group of patients with LIs ≤ 11 was 173.2 ± 12.2 months (mean ± SE), and the mean survival of those with LIs > 11 was 20.3 ± 4.1 months. The survival of anaplastic astrocytoma patients with LIs ≤ 11 was similar to that of astrocytoma patients, whereas the survival of anaplastic astrocytoma patients with LI > 11 was similar to that of patients with glioblastoma. The results of the current study show that histopathologic grading can predict the outcome for patients with astrocytomas and glioblastomas, whereas MIB-1 LI can separate better and worse prognostic groups in patients with anaplastic astrocytoma. Cancer 1998;82:2459-2466. © 1998 American Cancer Society.

Supplemental Digital Content is available in the text

No abstract.

Approximately 10% of patients with glioblastoma survive more than 2 years after diagnosis. Distinguishing these patients from those who died within 2 years of diagnosis is clinically significant. We studied the MIB-1 labeling index (LI) and DNA topoisomerase IIα LI of glioblastomas from 34 patients who lived for more than 2 years after diagnosis and of glioblastomas from 34 age- and sex-matched control patients who died within 2 years of diagnosis. The means of MIB-1 and topoisomerase IIα LIs of the group with a better outcome were lower. With 35 as the cutoff point for the MIB-1 LI and 26 as the cutoff point for the topoisomerase IIα LI, both MIB-1 and topoisomerase IIα LIs were related significantly to survival. Our study showed that both MIB-1 and topoisomerase IIα could help predict long-term survival of patients with glioblastomas. Multivariate analyses revealed that MIB-1 was a better prognostic marker than topoisomerase IIα.