Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report

Background Secretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC. Case presentation Three cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30–32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis. Conclusions High-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type.

Canine smooth muscle tumors: A clinicopathological study

Canine smooth muscle tumors (SMTs) commonly develop in the alimentary and female genital tracts and less frequently in soft tissue. The definition of histological criteria of malignancy is less detailed for SMTs in dogs than in humans. This study evaluated the clinicopathologic features of canine SMTs and compared the veterinary and human medical criteria of malignancy. A total of 105 canine SMTs were evaluated histologically and classified according to both veterinary and human criteria. The Ki67 labeling index was assessed in all SMTs. Estrogen receptor (ER) and progesterone receptor (PR) expression was evaluated for soft tissue SMTs. Follow-up data were available in 25 cases. SMTs were diagnosed in the female genital tract (42%), alimentary tract (22%), and soft tissue (20%). Soft tissue SMTs frequently arose in the perigenital area, pelvic cavity, and retroperitoneum. A subset of soft tissue SMTs expressed ER and/or PR, resembling the gynecologic type of soft tissue SMT in humans. SMTs were less frequently malignant when assessed with human criteria than with veterinary criteria, better reflecting their benign behavior, especially in the genital tract where human criteria tolerate a higher mitotic count for leiomyoma. Decreased differentiation was correlated with increased proliferation, necrosis, and reduced desmin expression. Mitotic count, Ki67 labeling index, and necrosis were correlated with metastases and tumor-related death. Further prognostic studies are warranted to confirm the better performance of the human criteria when assessing SMT malignancy, especially genital cases, to confirm their usefulness in ER/PR-expressing soft tissue SMTs, and to better define the most useful prognostic parameters for canine SMTs.

The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.

Surgery to Oligometastatic Breast Cancer after Excellent Response to Palbociclib and Letrozole Therapy: Pitfall of Ultrasound Therapeutic Evaluation

A 48-year-old woman with regional recurrences of breast cancer in the axillar and supraclavicular regions was referred to our hospital. Under the diagnosis of recurrent luminal breast cancer with a high Ki-67 labeling index of >30% and a disease-free interval of 13 years, the patient began to receive palbociclib, letrozole, and luteinizing hormone-releasing hormone agonist, resulting in marked response of the supraclavicular lesion and stable disease of the axillar lesion on ultrasound (US) evaluation. Positron emission tomography (PET)/computed tomography of the axillar and supraclavicular foci showed high and no avidities before and after treatment, respectively. The unmovable neck lesion became movable with the treatment. The patient, therefore, underwent surgical resection of the 2 metastatic foci to examine the discordant therapeutic efficacy against the 2 metastatic foci on 2 image modalities, that is, US and PET, and to possibly get a cure of the breast cancer oligometastasis. Pathological examination showed marked fibrosis and scant cancer cell residuals with microcalcifications in the neck tumor and massive sarcoid-like reaction with scant cancer cell residuals in the axillary nodes. The residual cancer cells showed estrogen and progesterone receptor positivities, human epidermal growth factor receptor type 2 negativity, and an extremely low Ki-67 labeling index of 2.5%. The patient recovered uneventfully and has continued palbociclib-containing endocrine therapy for 1 year without any recurrences. Breast oncologists should well understand the basic principles of internal echo formation on US and take the presence of sarcoid-like reaction in the cancer cell clusters into consideration on the therapeutic evaluation of metastatic breast cancer.

High Inter- and Intratumoral Variability of Ki67 Labeling Index in Newly Diagnosed Prostate Cancer with High Gleason Scores

<b><i>Background:</i></b> The majority of studies investigating the role of Ki67 labeling index (LI) in prostate carcinoma (PC) focused on localized PC treated radically, where Ki67 LI is regarded as a prognostic marker. The relevance of Ki67 in advanced PC remains largely unexplored. While Gleason score is still one of the best indicators of clinical outcomes in PC, differences in progression-free survival and overall survival in patients with high Gleason scores suggest that additional factors are involved in tumor progression. Understanding the underlying mechanisms could help to optimize treatment strategies for an individual patient. Here, we aimed to determine the inter- and intratumoral distribution of Ki67 LI in patients with PC with high Gleason scores and to correlate Ki67 LI with the status of ERG, PTEN, and Bcl-2. <b><i>Methods:</i></b> Immunohistochemistry for Ki67, ERG, PTEN, and Bcl-2 was performed on core needle biopsies from 112 patients with newly diagnosed PC Gleason score 8, 9, and 10. <b><i>Results:</i></b> Using a cutoff of ≥10%, 17/112 cases (15%) had a homogeneously low and 95/112 cases (85%) a high Ki67 LI. 41% of cases showed intratumoral heterogeneity containing areas with low and high proliferation. There was no association between Ki67 LI and ERG, PTEN, or Bcl-2 status. <b><i>Conclusions:</i></b> Our data demonstrate major inter- and intratumoral variability of Ki67 LI in high-grade PC with a surprisingly low Ki67 LI in a subset of cases. Further studies are necessary to explore the molecular basis and potential clinical implications of a paradoxically low proliferation rate in high-grade PC.

Clinicopathological and Genetic Analyses of Small Cell Neuroendocrine Carcinoma of the Prostate: Histological Features for Accurate Diagnosis and Toward Future Novel Therapies Short Running Title: Characteristics of Prostatic Small Cell Neuroendocrine Carcinoma

Differentiating small cell neuroendocrine carcinoma (SCNC) of the prostate from prostatic cancer with diffuse neuroendocrine (NE) differentiation based on morphological features alone can be challenging. Given that treatment strategies vary depending on histological type, accurate diagnosis is critical. This study firstly aimed to identify the accurate diagnostic factors for primary prostate NE tumors. Furthermore, the possibility of novel treatment strategies through genetic analysis is also an aim. Specifically, prostate biopsies conducted in our hospital between January 2017 and May 2020 were included. As a result seven cases of SCNC and four cases of prostatic cancer with diffuse NE differentiation were identified. No significant differences in serum neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), and prostate-specific antigen (PSA) levels were observed between SCNC and adenocarcinoma with diffuse NE differentiation. The Ki-67 labeling index was significantly higher and PSA immunoreactivity tended to be lower in SCNC. Genetic analysis did not detect any ALK mutations but confirmed several other mutations, including those of PIK3CA and TP53. In conclusion, given the heterogeneity in serum NE markers in SCNC, diagnosis based on these markers alone is difficult. A high Ki-67 labeling index and low PSA immunoreactivity may be useful for diagnosing, but p53 immunoreactivity is insufficient to distinguish these tumors. Although further studies are required to interpret the results of the genetic analysis involving ALK, PIK3CA, and TP53 mutations, the results of our genetic analysis suggest that PIK3CA mutations in SCNC of the prostate may provide a novel therapeutic strategy.

Relationship Between Ultrasound Features and Ki-67 Labeling Index of Soft Tissue Sarcoma

ObjectivesTo explore the relationship between ultrasound (US) features and Ki-67 labeling index (LI) of soft tissue sarcoma (STS).MethodsForty-six patients with 47 STS lesions, between September 2014 and April 2020, were enrolled in the study. Point-biserial correlation analysis and Spearman’s correlation analysis were utilized to examining the relationship between the US features and the Ki-67 LI of STS. The differences of US features between high and low Ki-67 proliferation groups were statistically analyzed by independent t test, Wilcoxon rank-sum test, and Fisher’s exact test. The optimal cut-off points of US features revealing significant differences were estimated by the maximum Youden index.ResultsA moderate correlation between the vascular density grade and the Ki-67 LI (ρ = 0.409, P = 0.004) was found in this study. In addition, other ultrasound features were irrelevant to the Ki-67 LI. The cut-off for differentiating low- and high-proliferation groups was grade II according to the best Youden index. The area under receiver operating characteristic (ROC) curve was 0.74 (p = 0.011) with a sensitivity of 60.6% and specificity of 78.6%.ConclusionsOnly the vascular density grade of STS had a weak positive correlation with Ki-67 LI, and might be capable of predicting the proliferation of STS. Other ultrasonographic features of STS such as shape and tumor margin have no correlation with Ki-67 LI.