NF1 mutation and TUBB3 amplification in gastric histiocytic sarcoma: a case report and literature review.

Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course and poor response to treatment. Primary gastric histiocytic sarcoma is rarer and just reported sporadically.Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course and poor response to treatment. Primary gastric histiocytic sarcoma is rarer and just reported sporadically. A case of a 71-year-old female admitted with a one-year history of upper abdominal pain exacerbated after meals. After CT scans revealed a bulged mass at the lesser curvature of the gastric body, the patient underwent endoscopic submucosal dissection. Microscopically, non-cohesive neoplastic cells diffusely infiltrated lamina propria and submucosa, and diffusely expressed LCA, CD4, CD163, CD68 (KP1), Cyclin D1, Lysozyme, and Vimentin. PD-L1 (22CS) expression evaluated as CPS 60. The final pathological diagnosis was gastric histiocytic sarcoma. Subsequently, next-generation sequencing identified a nonsense mutation in exon 21 of NF1 gene [c.2446C > T (p.R816*)] and the TUBB3 gene amplification (copy number: 4.55). The patient refused further treatment and died of the tumor half a year later. This case broadens the spectrum of differential diagnosis of gastric cancer and emphasizes the value of immunohistochemical and molecular tests in the accurate diagnosis of histiocytic sarcoma. Furthermore, we performed literature review of 11 cases of gastric histiocytic sarcoma so as to strengthen the understanding of the clinicopathologic features, treatment, and prognosis.

Synchronous pulmonary MALT lymphoma and squamous cell lung cancer: a case report.

Pulmonary B-cell lymphoma in the extranodal marginal zone of mucosa-associated lymphoid tissue (MALT), a rare tumor originating from bronchial mucosa-associated lymphoid tissue, is the major histologic type of primary pulmonary lymphoma. Combined lung squamous cell carcinoma with pulmonary MALT lymphoma is rare. A 63-year-old male patient presented to the hospital because of a dry cough, and chest CT showed soft tissue density nodules in the upper lobe of the right lung, the boundary was visible lobulation and spiculation, and the middle lobe of the right lung showed patchy shadow, moderate enhancement, associated with bronchial traction. After a multidisciplinary diagnosis and treatment (MDT) discussion, surgical resection was done for the patient, and postoperative pathological results showed pulmonary MALT lymphoma combined with lung squamous carcinoma. For complex pulmonary multiple lesions, judgment needs to be made after MDT discussion, and timely intervention is required for lesions suspicious of malignancy. There are no uniform recommendations for the management of mixed tumors of the lung, and an individualized treatment plan needs to be developed based on the patient's actual condition.

Two cases of mammary acinic cell carcinomas with microglandular structures mimicking microglandular adenosis.

Acinic cell carcinoma (AcCC) of breast is a rare subtype of triple-negative breast carcinoma demonstrating a wide morphologic spectrum. In this study, we perform a detailed morphologic and immunohistochemical description of two cases of the rare entity and review the published relative literature. Histologically, the two cases both showed predominantly microglandular and solid structures overlapping with the histological features of microglandular adenosis (MGA), and one case presented spindle cell metaplastic carcinoma with chondromyxoid matrix as a minor morphologic pattern. In two cases, most of the cancer cells were positive for lysozyme and antitrypsin strongly and extensively, but negative for estrogen receptor (ER), progesterone receptor (PR), androgen receptors (AR) and human epidermal growth factor receptor 2 (HER2). The true relationship between breast AcCC and MGA or carcinoma arising in MGA(CAMGA) may remain unclear; re-excision is advised when the MGA-like content extends to the surgical margins in the setting of breast AcCC. More cases and further molecular investigations are required to elucidate the true histogenesis and give the patients appropriate treatment.

Primary ovarian carcinoid arising in associated mature cystic teratoma.

BACKGROUND: Primary ovarian carcinoid is a very rare ovarian low-grade neuroendocrine tumor, accounting for about 0.1% of all ovarian neoplasms. CASE PRESENTATION: We reported a case of primary ovarian carcinoid arising from a mature cystic teratoma in a 50-year-old woman. Intraoperative frozen section of left ovarian mass was assessed and a malignant epithelial tumor was considered. Morphologically, the main tumor was composed of cells forming trabeculae, and mature cystic teratoma was observed adjacent to the main part. Immunohistochemistry revealed that the trabecular cells were diffuse positive for pan Cytokeratin, CD56 and synaptophysin with low Ki-67 index (about 1%). CONCLUSIONS: Careful morphological observation combined with appropriate accessory examination are essential for the diagnosis of primary ovarian carcinoid arising from mature cystic teratoma. In addition, the classification criteria of the primary ovarian neuroendocrine tumor are discussed.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

Muir-Torre Syndrome With a Frame-shift Mutation in the MSH2 Gene: A Rare Case Report and Literature Review.

Muir-Torre syndrome is a rare subtype of Lynch syndrome characterized by coincidence of skin neoplasm and visceral malignancies. Here, we report a case of this rare disease, whose diagnosis of the syndrome was first suspected by the pathologist. This was a 60-yr-old woman who presented with an axillary skin nodule, which was diagnosed as basal cell carcinoma. Further inquiry revealed that she was hospitalized for evaluation of a recurrent vaginal stump endometrial carcinoma. Histologic workup and immunohistochemistry for mismatch repair proteins of both the skin and vaginal tumor suggested the possibility of Muir-Torre syndrome. NexGen sequencing identified a frame-shift mutation in the MSH2 gene. The patient was found to have a metachronous colorectal carcinoma, uterine endometrial carcinoma, and skin cancer from 1998 to 2016. Five family members had also suffered from colorectal cancer or glioma. This case report illustrates the importance of the multidisciplinary care approach, mismatch repair protein and gene testing, and detailed medical history taking into consideration the diagnosis of Muir-Torre syndrome.

Galectin-3 expression is prognostic in diffuse type gastric adenocarcinoma, confers aggressive phenotype, and can be targeted by YAP1/BET inhibitors.

BACKGROUND: Overexpression of Galectin-3 (Gal-3), a ß-galactoside binding protein, has been noted in many tumour types but its functional significance and clinical utility in gastric adenocarcinoma (GAC) are not well known. METHODS: We studied 184 GAC patients characterised by histologic grade, sub-phenotypes (diffuse vs intestinal), and ethnicity (Asians vs North Americans). Immunohistochemistry was performed to assess the expression of Gal-3 in human GACs and we correlated it to the clinical outcomes. Cell proliferation, invasion, co-immunoprecipitation and kinase activity assays were done in genetically stable Gal-3 overexpressing GC cell lines and the parental counterparts to delineate the mechanisms of action and activity of inhibitors. RESULTS: Most patients were men, Asian, and had a poorly differentiated GAC. Gal-3 was over-expressed in poorly differentiated (P=0.002) tumours and also in diffuse sub-phenotype (P=0.02). Gal-3 overexpression was associated with shorter overall survival (OS; P=0.026) in all patients. Although, Gal-3 over-expression was not prognostic in the Asian cohort (P=0.337), it was highly prognostic in the North American cohort (P=0.001). In a multivariate analysis, Gal-3 (P=0.001) and N-stage (P=<0.001) were independently prognostic for shorter OS. Mechanistically, Gal-3 induced c-MYC expression through increasing RalA activity and an enhanced YAP1/RalA/RalBP complex to confer an aggressive phenotype. YAP1/BET bromodomain inhibitors reduced Gal-3-mediated aggressive phenotypes in GAC cells. CONCLUSIONS: Gal-3 is an independent prognostic marker of shorter OS and a novel therapeutic target particularly in diffuse type GAC in North American patients.

The dose-response effect of physical activity on cancer mortality: findings from 71 prospective cohort studies.

BACKGROUND: The WHO recommends moderate physical activity to combat the increasing risk of death from chronic diseases. We conducted a meta-analysis to assess the association between physical activity and cancer mortality and the WHO recommendations to reduce the latter. METHODS: MEDLINE and EMBASE were searched up until May 2014 for cohort studies examining physical activity and cancer mortality in the general population and cancer survivors. Combined HRs were estimated using fixed-effect or random-effect meta-analysis of binary analysis. Associated HRs with defined increments and recommended levels of recreational physical activity were estimated by two-stage random-effects dose-response meta-analysis. RESULTS: A total of 71 cohort studies met the inclusion criteria and were analysed. Binary analyses determined that individuals who participated in the most physical activity had an HR of 0.83 (95% CI 0.79 to 0.87) and 0.78 (95% CI 0.74 to 0.84) for cancer mortality in the general population and among cancer survivors, respectively. There was an inverse non-linear dose-response between the effects of physical activity and cancer mortality. In the general population, a minimum of 2.5 h/week of moderate-intensity activity led to a significant 13% reduction in cancer mortality. Cancer survivors who completed 15 metabolic equivalents of task (MET)-h/week of physical activity had a 27% lower risk of cancer mortality. A greater protective effect occurred in cancer survivors undertaking physical activity postdiagnosis versus prediagnosis, where 15 MET-h/week decreased the risk by 35% and 21%, respectively. CONCLUSIONS: Our meta-analysis supports that current physical activity recommendations from WHO reduce cancer mortality in both the general population and cancer survivors. We infer that physical activity after a cancer diagnosis may result in significant protection among cancer survivors.

Immunohistochemistry as a quick screening method for clinical detection of BRAF(V600E) mutation in melanoma patients.

With the increased uses of targeted therapeutics, diagnostic detection of target mutations becomes essential for the effective clinical applications of targeted therapeutics. Currently, there are two types of methods detecting target mutations in clinics: one is based on DNA sequence and the other uses the newly developed mutation-specific antibodies recognizing mutated proteins. Each method has its own advantages and disadvantages. Here, we explored the sensitivity and specificity of a new commercially available BRAF(V600E) mutation-specific mouse monoclonal antibody. Using routine manual immunohistochemistry (IHC), we tested tumor tissues from 38 melanoma patients. For those melanoma tissues with abundant endogenous melanin, we pretreated the tumor tissues with 3 % hydrogen peroxide to remove melanin for reliable signal detection. We also performed DNA sequencing and ARMS-PCR analyses for these 38 tumor samples. Comparing to the results from DNA-based detection methods, the IHC method with this BRAF(V600E) mutation-specific antibody displayed 100 % sensitivity and 92.9 % specificity. Hence, this IHC detection is sensitive for clinic uses as a simple, fast, inexpensive, and reliable method to screen cancer patients for the BRAF(V600E) mutation and could be easily adapted for use in most hospital pathology laboratories.

Allograft inflammatory factor-1 alleviates liver disease of BALB/c mice infected with Schistosoma japonicum.

Allograft inflammatory factor-1 (AIF-1) plays an important role in various inflammatory conditions. Our previous study demonstrated that AIF-1 was over-expressed in the liver of BALB/c mice infected with Schistosoma japonicum and played significant role in the pathogenesis of schistosomiasis. The aim of this study was to focus on the effect of AIF-1 treatment on liver fibrosis and necrosis of BALB/c mice infected with S. japonicum. Seventy-two BALB/c mice were infected with cercariae of S. japonicum and then divided into three groups: AIF-1-treated group, saline-treated group, and control group. The vital signs, liver function, egg load, and hepatic pathological changes of the mice were assessed, and the levels of AIF-1 and TNF-α in the liver and spleen were measured at 5, 8, and 14 weeks postinfection. The treatment of AIF-1 on the mice infected with S. japonicum suppressed the expression of TNF-α and increased the effectiveness of AIF-1 in the liver and spleen at 14 weeks postinfection. Histopathological analysis and Masson trichrome staining for the liver tissues showed that the liver fibrosis and necrosis were alleviated previously compared with other infected mice at 14 weeks postinfection. The treatment of AIF-1 on the mice infected with S. japonicum can alleviate hepatic fibrosis and necrosis which indicate that AIF-1 use may prevent and cure the liver fibrosis.

A neuroendocrine tumor arising in a tailgut cyst: Case report and literature review.

INTRODUCTION AND IMPORTANCE: Cystic lesions in the retrorectal space include developmental abnormality, inflammatory process, and tumor-relevant cysts. Among them, the tailgut cyst is the most common lesion which is featured by the complex epithelium lining the wall. It is generally accepted that tailgut cysts are embryonic residues and are mostly benign, but there are also reports about malignant transformation and even metastasis. CASE PRESENTATION: A 44-year-old female complained a sacrococcygeal discomfort more than one year. The imaging diagnosis was an infectious cyst. After surgery, a solid region was defined in a cyst. Morphologically, the region was composed of bland epithelia forming glandular or ribbon-like structure, with round nuclei and fine chromatin. Immunohistochemically, the cells were positive for CK7, CD56 and synaptophysin. The Ki-67-positive cells were about 1 %. The final diagnosis is a low-grade neuroendocrine tumor arising in a tailgut cyst. The patient was living without recurrence by the follow-up of 20 months after surgery. CLINICAL DISCUSSION: By reviewing the previously reported NET arising from tailgut cysts, we summarized 29 cases of neuroendocrine neoplasms that reported detailed information, and the majority are women. We found that the higher-grade tumor presented a higher tendency of distant metastasis or recurrence after surgery. Complete resection and full evaluation by pathologists are necessary to get a correct diagnosis and avoid disease progression. CONCLUSION: We reported the rare case of NET G1 arising from a tailgut cyst and reviewed relevant reports, in order to broaden differential diagnoses when an isolated mass is identified in the retrorectal space.

68Ga-FAPI-04 PET/CT in Non-Small Cell Lung Cancer: Accurate Evaluation of Lymph Node Metastasis and Correlation with Fibroblast Activation Protein Expression.

Fibroblast activation protein (FAP) is a promising diagnostic and therapeutic target in various solid tumors. This study aimed to assess the diagnostic efficiency of 68Ga-labeled FAP inhibitor (FAPI)-04 PET/CT for detecting lymph node metastasis in non-small cell lung cancer (NSCLC) and to investigate the correlation between tumor 68Ga-FAPI-04 uptake and FAP expression. Methods: We retrospectively enrolled 136 participants with suspected or biopsy-confirmed NSCLC who underwent 68Ga-FAPI-04 PET/CT for initial staging. The diagnostic performance of 68Ga-FAPI-04 for the detection of NSCLC was evaluated. The final histopathology or typical imaging features were used as the reference standard. The SUVmax and SUVmean, 68Ga-FAPI-avid tumor volume (FTV), and total lesion FAP expression (TLF) were measured and calculated. FAP immunostaining of tissue specimens was performed. The correlation between 68Ga-FAPI-04 uptake and FAP expression was assessed using the Spearman correlation coefficient. Results: Ninety-one participants (median age, 65 y [interquartile range, 58-70 y]; 69 men) with NSCLC were finally analyzed. In lesion-based analysis, the diagnostic sensitivity and positive predictive value of 68Ga-FAPI-04 PET/CT for detection of the primary tumor were 96.70% (88/91) and 100% (88/88), respectively. In station-based analysis, the diagnostic sensitivity, specificity, and accuracy for the detection of lymph node metastasis were 72.00% (18/25), 93.10% (108/116), and 89.36% (126/141), respectively. Tumor 68Ga-FAPI-04 uptake (SUVmax, SUVmean, FTV, and TLF) correlated positively with FAP expression (r = 0.470, 0.477, 0.582, and 0.608, respectively; all P ≤ 0.001). The volume parameters FTV and TLF correlated strongly with FAP expression in 31 surgical specimens (r = 0.700 and 0.770, respectively; both P < 0.001). Conclusion: 68Ga-FAPI-04 PET/CT had excellent diagnostic efficiency for detecting lymph node metastasis, and 68Ga-FAPI-04 uptake showed a close association with FAP expression in participants with NSCLC.

Indolent T-cell lymphoproliferative disorder of gastrointestinal tract with unusual clinical courses: report of 6 cases and literature review.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (iTLPD-GI) is a rare neoplasm usually having an indolent clinical course and easily misdiagnosed as inflammatory bowel disease or other T-cell lymphomas. A subset of the disorders that progressed to overt peripheral T-cell lymphoma have been reported, and the etiology and pathogenesis are poorly understood. The current study retrospectively examined the pathological, molecular, and clinical features of 6 cases of iTLPD-GI. Hematoxylin and eosin staining, immunohistochemistry, in situ hybridization, T-cell receptor gene rearrangement, and next-generation sequencing (NGS) were performed with the diseased tissues. All the 6 patients were immunocompetent Chinese men, who presented with recurrent abdominal pain and diarrhea for 4 to 13 years. Histologically, the intestinal tissue was expanded by lymphoid infiltration, composed of small-to-medium-sized lymphocytes with gland intact. The neoplastic cells were CD4 - /CD8 + with expression of TIA1 and variable granzyme B in five cases, and the other one was CD4 + /CD8 - . Two of the 5 patients progressed to more aggressive T-cell lymphoma and died of disease with complications. NGS identified TET2 and DDX3X mutations in patient 1, and BIRC6 and REV3L mutations in patient 2. Literature review indicated that iTLPD-GI with CD4 - /CD8 + immunophenotype was more commonly reported in Chinese cases. Our limited data indicated CD4-/CD8 + iTLPD-GI have similar potential to progress to more aggressive T-cell lymphoma as that of CD4 + /CD8 - , and gradually increased expression of granzyme B and Ki-67 may be early signs of the disease progression. Gain of novel gene mutations may be indicators of the pathogenesis.

Management of granulomatous lobular mastitis: an international multidisciplinary consensus (2021 edition).

Granulomatous lobular mastitis (GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions, etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology. The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidence-based consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

Tumor Immune Microenvironment Components and Checkpoint Molecules in Anaplastic Variant of Diffuse Large B-Cell Lymphoma.

BACKGROUND: Anaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear. METHODS: Thirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis. RESULTS: Patients with A-DLBCL presented higher expression of PD-L1 (40% vs 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% vs 4.0%, P=0.001). The numbers of PD-1+ TILs (tumor infiltrating lymphocytes) and CD8+T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3+ Th2 cells, FOXP3+ Tregs and CD33+ myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1+ TILs was lower and the number of CD33+ MDSCs was higher in patients with mutated TP53 compared to those with wild-type TP53. The number of FOXP3+ Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8+ T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1+, mPD-L1+(PD-L1+ nonmalignant stromal cells) or mPD-L1+ status had a significantly poorer overall survival (OS) than those with PD-L1- status. An increase in the number of CD3+ T cells, FOXP3+ Treg cells and T-bet+ Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL. CONCLUSION: Our study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.

[In-vitro amplification of oval cells with preservation of stem cell phenotype].

OBJECTIVE: To explore cell culture techniques for amplification of oval cells with preservation simultaneously of the stem cell characteristics. METHODS: Oval cell line OC3 was cultured in RPMI 1640 supplemented with 15% fetal bovine serum and 20 µg/L EGF. Cells were harvested every 5 passages and were examined with biomarkers including OV-6, c-kit, gamma-glutamyl transpeptidase, placental form of glutathione-S-transferase (GST-P), pyruvate kinase M2, pyruvate kinase L and albumin using techniques including RT-PCR, immunocytochemistry, and enzymo-cytochemistry. RESULTS: OC3 cell lines could be amplified abundantly in-vitro associating with expression of infant liver cell markers at various level, including OV-6, c-kit, gamma-glutamyl transpeptidase, GST-P, pyruvate kinase M2, but no expression of mature hepatocyte markers detected including pyruvate kinase L and albumin. CONCLUSIONS: Amplification of OC3 cells with preservation of the stem cell phenotype and high proliferation index can be achieved up to the 79(th) passages by culturing in RPMI 1640 supplemented with 15% fetal bovine serum and 20 µg/L EGF.

A rare face of follicular lymphoma: reverse variant of follicular lymphoma.

BACKGROUND: Reverse Variant of Follicular Lymphoma (RVFL) is one of the rare morphological variants of FL, characterized by dark staining small centrocytes in the center and pale staining large centroblasts at the periphery of the neoplastic follicles. Only rare cases of RVFL have been described to date. The histological appearance of this little known variant of FL may be misinterpreted if pathologists are unaware of its existence. The main purpose of this study is to draw pathologists' attention to such an uncommon growth pattern of FL so that this variant can be correctly recognized and the clinical significance further studied in the future. METHODS: Four cases of FL with unusual morphologic features were evaluated for the expression pattern of CD20, CD10, BCL6, BCL2, CD21, CD23, CD3, CD5, Cyclin D1, IgD and Ki67 by immunohistochemistry. Fluorescence in situ hybridization (FISH) with break-apart probes was performed to detect BCL2 gene rearrangement. RESULTS: All four cases showed distinctive morphologic pattern of RVFL; in addition, each also exemplified unique morphological features. Immunohistochemical stains confirmed the cells in both the central areas and the peripheral cuffs had the same immunophenotypic profiles, contrasting to the FL with marginal zone differentiation in which only the center of the nodules showed expression of CD10. FISH demonstrated BCL2 gene rearrangement in all cases. CONCLUSION: The growth pattern of this rare FL variant may mimic FL with marginal-zone differentiation and other entities including but not limited to marginal zone lymphoma (MZL), progressive transformation of germinal centers (PTGC) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Pathologists should be familiar with this unusual morphological variant to avoid diagnostic pitfalls.

SIPA1 enhances SMAD2/3 expression to maintain stem cell features in breast cancer cells.

SIPA1, a GTPase activating protein that negatively regulates Ras-related protein (Rap), is a potential modulator of tumor metastasis and recurrence. In this study, we first showed that SIPA1 facilitated the stemness features of breast cancer cells, such as of tumorsphere formation capability and the expression of stemness marker CD44. In addition, SIPA1 promoted the expression of four stemness-associated transcription factors through increasing the expression of SMAD2 and SMAD3 in vitro and in vivo. The stemness features were abolished by blocking the phosphorylation of SMAD3 with its specific inhibitor SIS3. Furthermore, SIPA1 decreased the breast cancer cell sensitivity to chemotherapy drugs. This effect was, however, competitively reversed by blocking the SMAD3 phosphorylation by SIS3 treatment in breast cancer cells. Taken together, SIPA1 promotes and sustains the stemness of breast cancer cells and their resistance to chemotherapy by increasing the expression of SMAD2 and SMAD3, and blocking SMAD3 phosphorylation could suppress the cancer cell stemness and increase the sensitivity to chemotherapy in breast cancer cells expressing a high level of SIPA1.