Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers.

BACKGROUND: The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states. RESULTS: We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. CONCLUSIONS: Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.

Circulating tumour mutation detection in triple-negative breast cancer as an adjunct to tissue response assessment.

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

Clonal fitness inferred from time-series modelling of single-cell cancer genomes.

Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1-7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright-Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours.

Comparison between AJCC 8th prognostic stage and UICC anatomical stage in patients with primary breast cancer: a single institutional retrospective study.

BACKGROUND: The 8th edition American Joint Committee on Cancer (AJCC) proposed a prognostic stage (PS), which included not only anatomical factors, but also biological factors. We aimed to investigate the clinicopathological significance of the PS and to compare PS and anatomical stage (AS) that has been established by the Union for International Cancer Control (UICC). METHODS: Between 2002 and 2017, 800 patients were included in the study. Patients were classified using pathological UICC AS and pathological AJCC PS. The usefulness of PS in comparison with AS was validated using the Akaike information criterion (AIC) and Harrell concordance index (C-index). RESULTS: A total of 401 (50.1%) patients had pathological AS I, 324 (40.5%) had AS II, and 75 (9.4%) had AS III. Meanwhile, 535 (66.8%) had pathological PS I, 163 (20.4%) had PS II, and 102 (12.8%) had PS III. The number of AS II cases was 1.99-fold higher than that of PS II cases. For each stage, these survival curves were almost similar between AS and PS classification. Therefore, many patients to be classified into stage I and stage III were included in AS II group, while many patients to be classified into stage II were included in AS I group. To trichotomize the survival groups, PS appeared to be more specific than AS, and AIC and C-index confirmed the speculation. CONCLUSION: For the prognostication of primary breast cancer patients, AJCC PS appeared to be able to stratify the cases more appropriately than UICC AS.

Aquaporin 3 Expression in Endometrioid Carcinoma of the Uterine Body Correlated With Early Stage and Lower Grade.

Aquaporins (AQPs) are a family of transmembrane water channel proteins distributed in various human tissues. Recent studies revealed that AQPs play important roles in cancer biology. Few studies have documented the relationship between the prognosis, stage, and histological grade of uterine endometrioid carcinoma, with AQP expression. Hence, the present study aimed to investigate this relationship between uterine endometrioid carcinoma and AQP expression. We retrospectively reviewed records of the patients who underwent surgery for uterine body cancer between 1990 and 2010 at the National Defense Medical College Hospital, Saitama, Japan. In 241 cases of endometrioid carcinoma, we immunohistochemically examined the expression of AQP 1, 2, 3, 4, and 5, and their relationship with clinicopathological parameters and the patients' prognosis. We investigated the relationship between the clinicopathological parameters and AQP3 expression, and found that as the FIGO stage and histological grade progressed, the percentage of AQP3 expression tends to decrease. Furthermore, we analyzed progression-free survival/overall survival (PFS/OS) using the log-rank test, and found that the AQP3-positive group had a better prognosis than AQP3-negative group (PFS: P < 0.001, OS: P = 0.002, respectively). Using Cox's univariate proportional hazard model, we revealed that AQP3 had a low hazard ratio. However, according to Cox's multivariate proportional hazard model, AQP3 was not an independent prognostic factor. Among the endometrioid carcinoma patients, the AQP3-positive group was associated with early stage and lower grade compared to the AQP3-negative group. Therefore, AQP3 has the potential to serve as a predictor of prognosis, although further investigation is necessary to elucidate the biological mechanism of AQP3 in endometrioid carcinoma.

Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Fusion Imaging for Prediction of Metastasis to Sentinel and Nonsentinel Nodes in Patients with Clinically Node-Negative Breast Cancer.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) is an important diagnostic tool in breast cancer. The utility of maximum standardized uptake values (SUVmax) of primary tumors has been evaluated to predict sentinel node (SN) and non-SN metastasis in clinically node-negative (cN0) patients. PATIENTS AND METHODS: 18F-FDG PET/CT was performed on 414 cN0 patients. The following parameters were evaluated: SUVmax at 60 min (SUVmax1), SUVmax at 120 min (SUVmax2), percent change between SUVmax1 and SUVmax2 (ΔSUVmax%), SN metastasis foci maximum size (SN meta size), and ratio of metastatic SNs to total SNs or SN ratio (SNR). It was assessed whether these were risk factors for SN metastasis. The relationship between these parameters and the status of SN and/or non-SN metastasis was retrospectively explored to predict non-SN metastasis. RESULTS: All SUV parameters significantly correlated with pathological T factor (pT), nuclear grade, lymphatic invasion (Ly), and Ki-67 labeling index. On multivariate analysis, pT and Ly were independent predictive factors for SN metastasis. In SN meta-positive cases, SN meta size, SNR, and ΔSUVmax% were predictors for non-SN metastasis on univariate analyses, and the former two were independent predictors on multivariate analysis. The combination of SUVmax2 and ΔSUVmax% was an independent predictor of non-SN metastasis (P = 0.0312) and was associated with prediction of non-SN metastasis negative status with high probability (92.3%). CONCLUSIONS: In patients with cN0 breast cancer, SUV parameters of the primary tumor were correlated with pathological features. The combination of SUVmax2 and ΔSUVmax% may be useful for predicting non-SN metastasis.

Dual time point 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer.

BACKGROUND: To evaluate the clinicopathological and prognostic significance of the percentage change between maximum standardized uptake value (SUVmax) at 60 min (SUVmax1) and SUVmax at 120 min (SUVmax2) (ΔSUVmax%) using dual time point 18F-fluorodeoxyglucose emission tomography/computed tomography (18F-FDG PET/CT) in breast cancer. METHODS: Four hundred and sixty-four patients with primary breast cancer underwent 18F-FDG PET/CT for preoperative staging. ΔSUVmax% was defined as (SUVmax2 - SUVmax1) / SUVmax1 × 100. We explored the optimal cutoff value of SUVmax parameters (SUVmax1 and ΔSUVmax%) referring to the event of relapse by using receiver operator characteristic curves. The clinicopathological and prognostic significances of the SUVmax1 and ΔSUVmax% were analyzed by Cox's univariate and multivariate analyses. RESULTS: The optimal cutoff values of SUVmax1 and ΔSUVmax% were 3.4 and 12.5, respectively. Relapse-free survival (RFS) curves were significantly different between high and low SUVmax1 groups (P = 0.0003) and also between high and low ΔSUVmax% groups (P = 0.0151). In Cox multivariate analysis for RFS, SUVmax1 was an independent prognostic factor (P = 0.0267) but ΔSUVmax% was not (P = 0.152). There was a weak correlation between SUVmax1 and ΔSUVmax% (P < 0.0001, R2 = 0.166). On combining SUVmax1 and ΔSUVmax%, the subgroups of high SUVmax1 and high ΔSUVmax% showed significantly worse prognosis than the other groups in terms of RFS (P = 0.0002). CONCLUSION: Dual time point 18F-FDG PET/CT evaluation can be a useful method for predicting relapse in patients with breast cancer. The combination of SUVmax1 and ΔSUVmax% was able to identify subgroups with worse prognosis more accurately than SUVmax1 alone.

Metachronous bilateral triple-negative breast cancer associated with neurofibromatosis type 1: A case report.

The present study reports a case of metachronous bilateral breast cancer associated with neurofibromatosis type 1 (NF1). A 67-year-old female, who had undergone a radical mastectomy of the left breast 34 years ago due to breast cancer, presented with a tumor of the right breast. The clinical stage of the original breast cancer was T2N0M0 stage IIA and adjuvant chemotherapy had not been not administered. With regard to the right-sided breast tumor, on physical examination, multiple neurofibromas and café-au-lait spots were found to be scattered over the skin. A 2-cm tumor was palpable. The preoperative histopathological diagnosis of the right-sided breast tumor was invasive ductal carcinoma, T2N0M0 stage IIA, with negative results for hormone receptors and human epidermal growth factor receptor 2. The patient underwent a modified radical mastectomy and axillary node dissection, and received adjuvant chemotherapy. The bilateral tumors were similar in histology and immunophenotype, each being histological grade 3, triple-negative and with a basal-like subtype. Based on a literature review of 90 breast cancers in 84 patients with NF1 (84 patients, 90 breasts), younger age onset, advanced clinical stage and hormone receptor negativity were characteristic features. Bilateral cancer occurred in 8.3% of patients and was characterized by ER negativity, earlier stage and younger age compared with patients with unilateral cancer.

Expressions of ATF6, XBP1, and GRP78 in normal tissue, atypical adenomatous hyperplasia, and adenocarcinoma of the lung.

Little is known about the association between the atypical adenomatous hyperplasia (AAH)-adenocarcinoma in situ sequence of the lung and endoplasmic reticulum-stress responders such as ATF6, XBP1, and GRP78. Using stored tissues, we examined (i) the percentage of a splicing form (active form) of XBP1 messenger RNA in normal lung tissue (NLT) and adenocarcinoma (ACA; using reverse-transcription polymerase chain reaction); (ii) ATF6 and GRP78 protein expressions in NLT and ACA (using Western blotting analysis); (iii) ATF6, XBP1, and GRP78 protein expressions in NLT, AAH, and ACA, including some adenocarcinoma in situ (using immunohistochemistry); and (iv) the incidence of nuclear translocation of the 3 proteins in these lesions. The percentage of the splicing form of XBP1 messenger RNA showed a borderline difference between NLT and ACA (P = .068). In the Western blotting analysis, the nuclear fractions of ATF6 (including the active form) and GRP78 proteins were higher in ACA than in NLT. In the immunohistochemistry, the values obtained for the incidence of the nuclear translocation of ATF6, XBP1, and GRP78 proteins were as follows, respectively: 13.3%, 2.2%, and 0.5% in low-grade AAH; 37.9%, 2.3%, and 2.2% in high-grade AAH; and 47.2%, 10.6%, and 4.4% in ACA. A significant difference was detected between low-grade AAH and ACA for ATF6. In terms of nuclear translocation, high-grade AAH seemed intermediate between low-grade AAH and ACA. These results support endoplasmic reticulum-stress responses, such as nuclear translocation of these 3 proteins (including their active forms), being in parallel with the progression of the adenoma-carcinoma sequence in the lung.

[VEGF secretion from Epstein-Barr virus-infected cells as a cause of severe anasarca in a patient with angioimmunoblastic T-cell lymphoma].

A 69-year-old woman presented to National Defense Medical College hospital for suspected nephrotic syndrome due to weight gain of 30 kg in 3 weeks and bilateral lower leg edema. However, her urinalysis showed microproteinuria, which excluded nephrotic syndrome. Computed tomography revealed severe systemic edema, pleural effusion, ascites, and enlarged cervical and axillary lymph nodes. Histological examination of axillary lymph node specimen showed a typical architecture of angioimmunoblastic T-cell lymphoma. One course of CHOP chemotherapy regimen was administered which improved the lymph nodes and systemic edema. The patient achieved complete remission after 6 courses of CHOP. Because serum vascular endothelial growth factor (VEGF) level was elevated before the treatment and normalized after the treatment, increased vascular permeability mediated by VEGF was hypothesized to have caused the systemic edema. In addition, VEGF secretion from Epstein-Barr virus (EBV)-infected cells was likely associated with the patient's clinical condition because B lymphocytes stained with CD20 were positive for Epstein-Barr virus-encoded small RNAs (EBERs) and VEGF.

Ectopic Hamartomatous Thymoma: A Review Of The Literature With Report Of New Cases And Proposal Of A New Name: Biphenotypic Branchioma.

Ectopic hamartomatous thymoma (EHT) is a rare benign neoplasm of the lower neck suggesting branchial origin. Despite use of the term thymoma in the nomenclature, there is no evidence of thymic origin or differentiation. It affects middle-aged adults with a remarkable male predominance. To date less than 80 cases have been reported in the English literature. We present here two additional cases of EHT. The first is a benign case in a 31-year-old man, showing typical histological features. The second is a malignant case in a 70-year-old woman, showing intraductal carcinoma arising in intimate association with an EHT. These cases are presented in the context of a review of cases reported in the English literature. The exact origin has not been identified, but is considered to be of branchial apparatus, creating a quandary about the best terminology. Recently, the designation "branchial anlage mixed tumor" or "thymic anlage tumor" were proposed, but do not quite reflect the true nature of the neoplasm. To avoid taxonomic confusion, international consensus on terminology is desired. As this entity is a neoplasm that shows dual mesoderm and endoderm derivation/differentiation, we propose a new name "biphenotypic branchioma."

A Case of Hemorrhagic Adrenal Pseudocyst Mimicking Solid Tumor.

BACKGROUND Adrenal pseudocysts are often discovered incidentally on imaging, but the diagnosis and treatment can be challenging. A case of adrenal pseudocyst with hemorrhage is presented that mimicked a solid tumor on imaging, resulting in adrenalectomy. CASE REPORT A 78-year-old woman was found to have a right adrenal lesion on abdominal imaging. Enhanced computed tomography (CT) showed a heterogeneously enhanced mass, and magnetic resonance imaging (MRI) showed a high-intensity T1-weighted and T2-weighed image, with an irregular enhanced margin. The imaging findings were suggestive of a solid tumor of the adrenal gland. Although full endocrine serological studies were negative, the lesion increased in size at two-year follow-up. Right laparoscopic adrenalectomy was performed, and a benign hemorrhagic adrenal pseudocyst was diagnosed histologically. CONCLUSIONS Adrenal pseudocyst can be associated with acute intracystic hemorrhage, and imaging will show contrast enhancement, suggesting malignancy. In such cases, surgical excision is both diagnostic and curative.

Role of tubulointerstitial plasmin in the progression of IgA nephropathy.

BACKGROUND: Plasmin has recently been reported to be associated with renal fibrosis in experimental models, but its role in human renal diseases is unclear. METHODS: Fifty-seven patients with IgA nephropathy (IgAN) were evaluated retrospectively. Plasmin in their renal biopsy tissues was assessed by in situ zymography using a plasmin-sensitive synthetic peptide, and the relationships between patients' histologic or clinical parameters and their renal plasmin activity [assessed semiquantitatively by calculating the positively stained percentage of the total tubulointerstitial (TI) area] were evaluated. RESULTS: Plasmin activity was observed almost exclusively in the TI space (mainly in the interstitium and partly in the tubular epithelial cells) and was significantly stronger in patients with TI lesion (tubular atrophy/interstitial fibrosis and tubulointerstitial inflammation) than in those without TI lesion. It was significantly and positively correlated with the global glomerulosclerosis rate and significantly and negatively correlated with estimated glomerular filtration rate not only at the time of renal biopsy but also at the end of the follow-up period. Double stainings for plasmin activity and inflammatory cells, cytokeratin, or α-smooth muscle actin (α-SMA) in selected patients revealed TI infiltration of inflammatory cells, attenuated tubular epithelial expression of cytokeratin, and augmented interstitial expression of α-SMA close to upregulated plasmin activity in the TI space. CONCLUSIONS: These data suggest that TI plasmin is associated with TI inflammation leading to renal fibrosis, and can cause the decline in renal function seen in patients with IgAN. Reducing plasmin in situ may therefore be a promising therapeutic approach slowing renal fibrogenesis and improving renal function.

Observation of Angiolymphoid Hyperplasia with Eosinophilia (ALHE) at Three Arterial Sites and Its Association with Membranous Nephropathy.

We herein report a case involving the systemic presentation of angiolymphoid hyperplasia with eosinophilia (ALHE) in association with membranous nephropathy (MN). A 34-year-old Japanese man presented with leg edema and bilateral temporal nodules. He had a history of Buerger's disease and recurrent coronary stenosis. A renal biopsy performed to assess nephrotic syndrome revealed MN. Furthermore, a temporal nodule was excised, and ALHE was diagnosed. We reevaluated the coronary and posterior tibial artery specimens obtained in his twenties and presumed that these lesions were also vascular tumors arising from ALHE. The association of ALHE and MN is quite rare.

Tumor-to-tumor metastasis from lung cancer: a clinicopathological postmortem study.

This study examined 47 cases of lung cancer concomitant with other tumors and found eight cases (17 %) with nine foci of tumor-to-tumor metastasis, defined as metastasis of lung cancer into another tumor. Donor lung cancers were four adenocarcinomas, two squamous cell carcinomas, and two small cell carcinomas. Tumor-to-tumor metastasis was found in five of six renal cell carcinomas (83 %), one of eight thyroid papillary carcinomas (13 %), one of three adrenocortical adenomas (33 %), one of three pancreatic endocrine microadenomas (33 %), and another lung cancer (one of six cases of multiple lung cancers, 17 %). The higher recipient incidence in renal cell carcinoma was statistically significant compared with prostatic carcinoma (0/16, P < 0.001), colorectal carcinoma (0/7, P = 0.005), and gastric carcinoma (0/5, P = 0.015). Generalized metastases were found in 88 % of the tumor-to-tumor metastasis cases. The total clinical course of patients with tumor-to-tumor metastasis was shorter than that of the patients without tumor-to-tumor metastasis (mean, 5.4 versus 18.8 months; P = 0.046). Tumor-to-tumor metastasis sometimes mimicked undifferentiated recipient tumor cells. Immunostains for thyroid transcription factor 1 (TTF-1), Napsin A, cytokeratin 7 (CK7), and CK5/6 were useful to confirm tumor-to-tumor metastasis. However, TTF-1-, Napsin A-, and/or CK7-negative lung adenocarcinoma components metastasized to renal cell carcinoma in three cases, and recipient renal cell carcinomas were focally Napsin A+ (two cases) or CK7+ (two cases). Tumor-to-tumor metastasis can occur as a result of metastasis from lung cancer with more aggressive behavior. Tumor-to-tumor metastasis should be carefully distinguished from undifferentiated recipient tumor cells.

Intra-adrenal bile ductules associated with adreno-hepatic fusion: a possible origin for adrenal epithelial cysts.

AIMS: To elucidate the relationship between the rare phenomenon of adrenal cysts and adreno-hepatic fusion (AHF)-related intra-adrenal bile ductules. METHODS AND RESULTS: We examined 673 right and 662 left postmortem adrenal glands. AHF was defined as an adhesion between the liver and an adrenal with closely intermingled parenchymal cells or partial absence of the capsule dividing the two organs. AHF was found in seven (1.0%) right adrenals. AHF-related intra-adrenal bile ductules were observed in four (0.6%) adrenals, and were accompanied by aberrant hepatocytes (two adrenals), microcystic changes (two adrenals) and, in one case, a 15-mm-sized cyst. The cyst-lining cells, which focally resembled the cells of the neighbouring intra-adrenal bile ductules, were positive for cytokeratin 7 (CK7), CK19 and epithelial membrane antigen, and negative for CK20, vimentin, CD34 and calretinin. Identical findings were made in bile ductules located within fused adrenals and livers. CD10 staining was weaker or absent in the microcystic or cystic bile ductules found within adrenals. CONCLUSIONS: The 15-mm cyst we describe may have been an adrenal epithelial cyst derived from AHF-related intra-adrenal bile ductules, a possible pathogenesis for the rare phenomenon of right adrenal epithelial cysts.

Sebaceous-like clear cell changes in primary lung cancer.

We examined two cases of primary lung cancer with sebaceous-like clear cells (SLCCs), defined as clear carcinoma cells with microvacuolated cytoplasm and centrally located nuclei, which were selected from among 281 surgical/autopsy cases of lung cancer (2/281, 0.7%). Both cases were higher stage (stage IIA and IIIA), and SLCCs were intermingled with adenocarcinoma cells of usual type. They showed minute mucin staining, no evidence of glycogen, diffuse positivity for epithelial membrane antigen and carcinoembryonic antigen, focal positivity for thyroid transcription factor-1, and negativity for Napsin A and gross cystic disease fluid protein-15. Oil red O stain and ultrastructural examination in both cases failed to reveal lipid in SLCCs. SLCCs could represent non-specific changes of lung adenocarcinoma with a relatively advanced stage, and should be discriminated from true sebaceous differentiation.

Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion, resembling extraskeletal myxoid chondrosarcoma: Case report with a review of Literature.

Reported herein is an extremely rare case of primary pulmonary myxoid sarcoma (PPMS). A 31-year-old man presented with a 2.7 cm-sized pulmonary tumor surrounded by capsule-like fibrosis. The patient has been free of disease for 5.8 years after surgery. This tumor focally showed endobronchial features, and consisted of reticular cords of oval, short spindle, or polygonal cells with swollen vesicular nuclei accompanied by an abundant myxoid stroma, closely resembling extraskeletal myxoid chondrosarcoma. Tumor cells were diffusely positive for vimentin and focally positive for epithelial membrane antigen, but were negative for cytokeratin, TTF-1, Napsin A, S-100 protein, CD34, desmin, smooth-muscle actin, CD10, p63, calponin, h-caldesmon, c-kit, HMB-45, synaptophysin, or glial fibrillary acid protein. Our reverse transcription-polymerase chain reaction using the formalin-fixed, paraffin-embedded tumor tissues detected EWSR1-CREB1 fusion transcript, but could not demonstrate EWSR1-ATF1 fusion or EWSR1/TAF15/TFG-NR4A3 fusion. These findings indicate that the current tumor is an additional case of PPMS with EESR1-CREB1 fusion, recently reported by Thway et al. Some cases of PPMS can behave in an indolent manner.

Aberrant cytokeratin 7 expression of centrilobular hepatocytes: a clinicopathological study.

AIMS: This study has attempted to elucidate the clinicopathological features of aberrant cytokeratin 7 (CK7) expression by centrilobular hepatocytes. METHODS AND RESULTS: A total of 113 liver biopsy specimens from patients with common non-neoplastic liver diseases, including hepatitis B or C, non-alcoholic steatohepatitis, alcoholic liver disease and other diseases were examined. In 56 specimens (49.6%), CK7-positive centrilobular hepatocytes (CK7 + CHs) were identified and sometimes showed binuclear features. CK7 + CHs were associated with patients' older age (P = 0.004), higher serum levels of aspartate aminotransferase (P = 0.016) and γ-glutamyltransferase (P = 0.006), centrilobular fibrosis (P < 0.001), prominent thickening of hepatocytic plates (P < 0.001) and higher scores of total and periportal CK7-positive hepatocytes (both P < 0.001), but were not correlated with gender, steatosis, serum levels of total bilirubin or alanine aminotransferase. In 55 cases of hepatitis B and hepatitis C only, CK7 + CHs were related to a higher stage of fibrosis (P = 0.006). CONCLUSION: CK7 + CHs occur relatively frequently in non-neoplastic liver disease, associated with centrilobular scarring and the presence of CK7-positive periportal hepatocytes, and appear to be a non-specific phenomenon with respect aetiology of underlying disease. CK7 + CHs may represent age-dependent activation of hepatic progenitor cells or a regenerative phenomenon of hepatocytes themselves, both of which might contribute to liver regeneration.