Interferon-γ (IFN-γ), a key effector molecule in anti-tumor immune response, has been well documented to correlate with the intratumoral infiltration of immune cells. Of interest, however, a high level of IFN-γ has been reported in salivary adenoid cystic carcinoma (SACC), which is actually a type of immunologically cold cancer with few infiltrated immune cells. Investigating the functional significance of IFN-γ in SACC would help to explain such a paradoxical phenomenon. In the present study, we revealed that, compared to oral squamous cell carcinoma cells (a type of immunologically hot cancer), SACC cells were less sensitive to the growth-inhibition effect of IFN-γ. Moreover, the migration and invasion abilities of SACC cells were obviously enhanced upon IFN-γ treatment. In addition, our results revealed that exposure to IFN-γ significantly up-regulated the level of programmed death ligand 1 (PD-L1) on SACC cell-derived small extracellular vesicles (sEVs), which subsequently induced the apoptosis of CD8⁺ T cells through antagonizing PD-1. Importantly, it was also found that SACC patients with higher levels of plasma IFN-γ also had higher levels of circulating sEVs that carried PD-L1 on their surface. Our study unveils a mechanism that IFN-γ induces immunosuppression in SACC via sEV PD-L1, which would account for the scarce immune cell infiltration and insensitivity to immunotherapy.
B7-H1 Antigen/metabolism* ; CD8-Positive T-Lymphocytes/pathology* ; Carcinoma, Adenoid Cystic/pathology* ; Carcinoma, Squamous Cell/pathology* ; Cell Line, Tumor ; Humans ; Immunosuppression Therapy ; Interferon-gamma/pharmacology* ; Mouth Neoplasms/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Salivary Gland Neoplasms/pathology*

OBJECTIVEThis study aimed to investigate the expression of midkine (MK) and microvessel density (MVD) in patients with salivary adenoid cystic carcinoma (SACC) and its clinical significance, as well as detect the correlation between the expression of MK and MVD in SACC.

METHODSImmunohistochemistry analysis (SP method) for MK and MVD were performed on 60 cases of SACC and 26 cases of normal salivary gland tissue. The expression of MK and MVD, as well as the correlation between the expression of MK and MVD in SACC were detected.

RESULTSIn SACC, the MK expression rate was 70.0% (42/60), and MK was not expressed in normal tissue. Statistical significance was found between SACC and normal tissue (P<0.05). The MVD values in SACC and normal salivary gland tissues were 38.73 +/- 8.96 and 11.15 +/- 3.33, respectively. These values were statistically significant (P<0.05). The expression levels of MK and MVD were unrelated to age, gender, and type in SACC (P>0.05), but correlated with tumor size, lymph node metastasis, and tumor-node-metastasis in SACC (P<0.05). The expression of MK and MVD was positively correlated with SACC (r=0.560, P<0.05).

CONCLUSIONSACC is correlated with the expression of MK protein and the increase in MVD, which may be some of the early diagnostic markers in SACC.

Carcinoma, Adenoid Cystic ; enzymology ; pathology ; Cytokines ; genetics ; metabolism ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Microvessels ; Nerve Growth Factors ; Salivary Gland Neoplasms ; enzymology ; pathology ; Salivary Glands ; enzymology

PURPOSE: To investigate the difference of expression of autophagy and reactive oxygen species (ROS) related proteins in adenoid cystic carcinoma (ACC) of lacrimal gland in comparison with ACC of salivary gland. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissue samples from patients pathologically diagnosed as lacrimal gland ACC (n=11) and salivary gland ACC (n=64) were used. Immunochemistry was used to measure expression of autophagy related proteins [beclin-1, light chain (LC) 3A, LC3B, p62, and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] and ROS related proteins [catalase, thioredoxinreductase, glutathione S-transferasepi (GSTpi), thioredoxin interacting protein, and manganese superoxide dismutase (MnSOD)]. The prognostic factors related to disease-free and overall survival (OS) in lacrimal gland ACC by log-rank tests, were determined. RESULTS: GSTpi in stromal cells was more highly expressed in lacrimal gland ACC (p=0.006), however, MnSOD in epithelial cells was expressed more in salivary gland ACC (p=0.046). LC3B positivity and BNIP3 positivity in epithelial component were associated with shorter disease-free survival (both p=0.002), and LC3A positivity in stromal component was the factor related to shorter OS (p=0.005). CONCLUSION: This is the first study to demonstrate the expression of autophagy and ROS related proteins in lacrimal gland ACC in comparison with the salivary gland ACC, which would provide a basis for further study of autophagy and ROS mechanism as novel therapeutic targets in lacrimal gland ACC.
Adult ; Aged ; *Autophagy ; Beclin-1 ; Biomarkers, Tumor/metabolism ; Carcinoma, Adenoid Cystic/*metabolism/pathology ; Carrier Proteins ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Lacrimal Apparatus/metabolism/pathology ; Lacrimal Apparatus Diseases/*metabolism/pathology ; Male ; Membrane Proteins ; Middle Aged ; Proto-Oncogene Proteins ; Reactive Oxygen Species/*metabolism ; Salivary Gland Neoplasms/metabolism/*pathology ; Salivary Glands/pathology

OBJECTIVETo explore the clinical features, management approach and treatment outcomes for adenoid cystic carcinoma (ACC) of the breast.

METHODSThe clinicopathological data of 25 patients with breasts ACC treated in our hospital from years 1990 to 2012 were retrospectively reviewed and their prognosis was analyzed.

RESULTSThe median age of these 25 patients was 53 years (ranged from 31 to 81 years). With the exception of one male case, all patients were female including 17 cases of postmenopausal women. The most frequent presenting symptom is breast lumps, most (48.0%) were in the upper outer quadrant and areola area of the breast. Core needle biopsy was performed in five patients. The specimen finding were adenoids in three and invasive carcinoma in two cases. Axillary lymph node dissection was performed in 23 patients. Only two patients had histologically positive lymph nodes (3 of 14 and 2 of 20). Expression of ER and PR in 14 cases was detected by immunohistochemistry, showing one PR-positive and three ER-positive cases. The median follow-up of the 25 cases was 118 months (ranged from 12 to 244 months). Two patients died of lung metastases at 3 and 10 years after the surgery, respectively.

CONCLUSIONSDue to the complexity of the histology of ACC, adequate sampling of specimens is essential for accurate diagnosis. ACC of the breast is a rare disease with a relatively good prognosis. The low incidence of axillary lymph node metastasis suggests that axillary node dissection is not recommended as a routine procedure. Breast ACC are often with negative ER and PR expression, and the value of adjuvant therapy needs to be further investigated.

Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Axilla ; Breast Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Breast Neoplasms, Male ; drug therapy ; metabolism ; pathology ; secondary ; surgery ; Carcinoma, Adenoid Cystic ; drug therapy ; metabolism ; pathology ; surgery ; Chemotherapy, Adjuvant ; Cyclophosphamide ; therapeutic use ; Female ; Fluorouracil ; therapeutic use ; Follow-Up Studies ; Humans ; Lung Neoplasms ; secondary ; Lymph Node Excision ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Male ; Mastectomy ; methods ; Methotrexate ; therapeutic use ; Middle Aged ; Postmenopause ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Retrospective Studies

OBJECTIVETo study the clinicopathologic features and possible molecular mechanisms of adenoid cystic carcinoma with high-grade transformation.

METHODSFour cases of adenoid cystic carcinoma with high-grade transformation were enrolled into the study. Immunohistochemical study for smooth muscle actin, p63, p53 and Ki-67 was carried out. C-myc gene status was analyzed by fluorescence in-situ hybridization.

RESULTSThere were altogether 3 males and 1 female. The mean age of the patients was 55.5 years. Two patients died 17 months and 29 months after operation, respectively. One patient had distant metastasis 23 months after operation and was still alive at 26-month follow up. The remaining patient remained tumor free at 3-month follow up. High-grade transformation in adenoid cystic carcinoma presented either as poorly differentiated adenocarcinoma or undifferentiated carcinoma. Histologic examination showed sheets of pleomorphic tumor cells occupying more than one low-power field. The high-grade carcinoma cells showed increased nuclear-cytoplasmic ratio, prominent eosinophilic nucleoli and active mitosis (ranging from 8 to 25 per high-power field). Comedo necrosis was observed in 2 cases and multiple foci of calcifications in 3 cases. Immunohistochemical study demonstrated loss of myoepithelial differentiation, overexpression of p53 and high proliferative index by Ki-67. No c-myc translocation or copy-number changes were observed.

CONCLUSIONSHigh-grade transformation in adenoid cystic carcinoma is rare. The histopathologic features are rather distinctive and the biologic behavior is aggressive. C-myc gene mutation does not seem to play a key role in the pathogenesis.

Actins ; metabolism ; Adenocarcinoma ; genetics ; metabolism ; pathology ; Adult ; Aged ; Carcinoma ; genetics ; metabolism ; pathology ; Carcinoma, Adenoid Cystic ; genetics ; metabolism ; pathology ; Cell Transformation, Neoplastic ; Eye Neoplasms ; genetics ; metabolism ; pathology ; Female ; Follow-Up Studies ; Genes, myc ; Humans ; Ki-67 Antigen ; metabolism ; Lacrimal Apparatus ; Lacrimal Apparatus Diseases ; genetics ; metabolism ; pathology ; Lung Neoplasms ; genetics ; metabolism ; pathology ; Male ; Maxillary Sinus Neoplasms ; genetics ; metabolism ; pathology ; Membrane Proteins ; metabolism ; Middle Aged ; Mutation ; Parotid Neoplasms ; genetics ; metabolism ; pathology ; Survival Rate ; Tumor Suppressor Protein p53 ; metabolism

Adult ; Breast Neoplasms ; metabolism ; pathology ; secondary ; Carcinoid Tumor ; metabolism ; pathology ; surgery ; Carcinoma, Adenoid Cystic ; pathology ; Carcinoma, Lobular ; metabolism ; pathology ; secondary ; Cervical Intraepithelial Neoplasia ; metabolism ; pathology ; surgery ; Chromogranin A ; metabolism ; Diagnosis, Differential ; Female ; Humans ; Hysterectomy ; Keratins ; metabolism ; Neoplasms, Multiple Primary ; metabolism ; pathology ; surgery ; Ovarian Neoplasms ; metabolism ; pathology ; Sex Cord-Gonadal Stromal Tumors ; metabolism ; pathology ; Synaptophysin ; metabolism ; Uterine Cervical Neoplasms ; metabolism ; pathology ; surgery

Adenocarcinoma ; pathology ; Adenocarcinoma, Clear Cell ; genetics ; metabolism ; Carcinoma ; pathology ; Carcinoma, Acinar Cell ; pathology ; Carcinoma, Adenoid Cystic ; genetics ; metabolism ; Carcinoma, Mucoepidermoid ; genetics ; pathology ; Humans ; Myoepithelioma ; pathology ; Neoplasm Grading ; Oncogene Fusion ; Oncogene Proteins, Fusion ; metabolism ; Salivary Gland Neoplasms ; genetics ; pathology ; Salivary Glands ; pathology ; Translocation, Genetic

OBJECTIVETo investigate the clinicopathologic and immunohistochemical features as well as the differential diagnoses of the solid variant of mammary adenoid cystic carcinoma with basaloid features.

METHODSClinical and pathological data were collected in four cases of the solid variant of mammary adenoid cystic carcinoma with basaloid features, and microscopic pathological examination and immunohistochemistry EnVision method were performed. The relevant literature was also reviewed.

RESULTSThe four patients were female, with age ranged from 46 - 65 years old (average 56 years) and the maximum tumor diameter ranged from 1.5 to 2.5 cm. Microscopically, the tumors exhibited a predominantly solid architecture with a myxoid or hyalinized stroma. The tumor cells showed moderate to marked nuclear atypia, and a basaloid appearance with scanty cytoplasm and inconspicuous nucleoli, and ≥ 5 mitotic figures per 10 high power fields. Glandular space embedded within tumor islands could be noticed. These spaces were genuine glandular structures and the cells lining these true glandular lumens had more abundant and eosinophilic cytoplasm. Pseudoglandular spaces of cribriform pattern or variable shape were also occasionally seen, and these cysts contained homogenous eosinophilic material. Focal necrosis was found. All cases were negative for ER, PR and HER2. Immunohistochemical staining for CK5/6, CK7 and CK14 was positive in the genuine glandular structures. All cases were positive for CD10, but also positive with varying intensity from weak to strong for vimentin and CD117. Staining for Ki-67 in three patients showed 10% - 50% positive.

CONCLUSIONSThe solid variant of mammary adenoid cystic carcinoma with basaloid features is a histologically distinctive and also a rare subset of the mammary adenoid cystic carcinoma. Awareness of its pathological features can help with the diagnosis as well as differential diagnosis. More cases are still needed for accurately assessing the prognosis of this particular tumor.

Aged ; Breast Neoplasms ; metabolism ; pathology ; surgery ; Carcinoma, Adenoid Cystic ; metabolism ; pathology ; surgery ; Carcinoma, Basal Cell ; metabolism ; pathology ; surgery ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Carcinoma, Small Cell ; metabolism ; pathology ; Diagnosis, Differential ; Female ; Humans ; Immunohistochemistry ; Keratin-14 ; metabolism ; Keratin-5 ; metabolism ; Keratin-7 ; metabolism ; Mastectomy ; methods ; Middle Aged ; Proto-Oncogene Proteins c-kit ; metabolism ; Vimentin ; metabolism

OBJECTIVETo investigate the expression of ErbB-3 binding protein-1 (EBP-1), matrix metalloproteinase 9 (MMP-9) and E-cadherin (E-cad) in adenoid cystic carcinoma and their correlation.

METHODSImmunohistochemistry(PV6000 method) was used to detect EBP-1, MMP-9 and E-cad expression in 66 cases of adenoid cystic carcinoma tissues and matched para-cancerous normal tissues. In this study all cases were successfully followed up.

RESULTSThe positive expression rate of EBP-1 in adenoid cystic carcinoma tissues was 85%. EBP-1 expression was significantly correlated to pathological pattern and clinical stage (P < 0.05), but not to gender and age. In addition, there was a negative correlation between EBP-1 and E-cad expression, and positive correlation between EBP-1 and MMP-9.

CONCLUSIONSEBP-1 and its correlation with MMP-9 and E-cad may be used as useful indicators for clinical assessment of tumor biological behavior and prognosis in patients with adenoid cystic carcinoma.

Adaptor Proteins, Signal Transducing ; metabolism ; Biomarkers, Tumor ; metabolism ; Cadherins ; metabolism ; Carcinoma, Adenoid Cystic ; metabolism ; pathology ; secondary ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; secondary ; Lymphatic Metastasis ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; RNA-Binding Proteins ; metabolism ; Salivary Gland Neoplasms ; metabolism ; pathology

OBJECTIVETo assess the epidermal growth factor receptor (EGFR) status in salivary adenoid cystic carcinoma and explore its role in cancer invasion.

METHODSFifty-four patients with pathologically confirmed salivary adenoid cystic carcinoma (SACC) were divided into invasion group and non-invasion group. The EGFR expression was determined by immunohistochemstry (SP staining). The relations between the EGFR expression and the SACC clinical pathological characteristics were analyzed.

RESULTSEGFR were mainly expressed in the cell membrane and cytoplasm in the tissue of SACC. The positive rate of EGFR expression in the tumor tissue was 75.9% (41/54), and EGFR was over-expressed in the cytoplasm. The positive rate of EGFR expression in invasion group was higher than that in the non-invasion group (10.0%, P < 0.05). EGFR expression were related with the SACC T stages, histological types, distant metastasis, lymph node metastasis, and nerve invasion (P < 0.05).

CONCLUSIONSA higher expression of EGFR gene in the cytoplasm may have important effect on the progression of invasive carcinoma. Further investigations are required to develop new strategy in the treatment of salivary adenoid cystic carcinoma.

Carcinoma, Adenoid Cystic ; metabolism ; pathology ; Cell Membrane ; metabolism ; Cytoplasm ; metabolism ; Female ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasm Staging ; Receptor, Epidermal Growth Factor ; metabolism ; Salivary Gland Neoplasms ; metabolism ; pathology