Exploring histological predictive biomarkers for immune checkpoint inhibitor therapy response in non-small cell lung cancer.

Treatment challenges persist in advanced lung cancer despite the development of therapies beyond the traditional platinum-based chemotherapy. The early 2000s marked a shift to tyrosine kinase inhibitors targeting epidermal growth factor receptor, ushering in personalized genetic-based treatment. A further significant advance was the development of immune checkpoint inhibitors (ICIs), especially for non-small cell lung cancer. These target programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4, which enhanced the immune response against tumor cells. However, not all patients respond, and immune-related toxicities arise. This review emphasizes identifying biomarkers for ICI response prediction. While PD-L1 is a widely used, validated biomarker, its predictive accuracy is imperfect. Investigating tumor-infiltrating lymphocytes, tertiary lymphoid structure, and emerging biomarkers such as high endothelial venule, Human leukocyte antigen class I, T-cell immunoreceptors with Ig and ITIM domains, and lymphocyte activation gene-3 counts is promising. Understanding and exploring additional predictive biomarkers for ICI response are crucial for enhancing patient stratification and overall care in lung cancer treatment.

Well-Differentiated Papillary Mesothelial Tumor of the Scrotum with Suspicious Invasion.

Well-differentiated papillary mesothelial tumor (WDPMT) is a distinct form of mesothelioma with low malignant potential and is mostly found in the peritoneal cavity. It consists of mesothelial cells with papillary structure and bland cytology. We report a rare case of WDPMT with suspicious invasive foci in the tunica vaginalis. WDPMT with invasive foci is known to have a tendency for recurrence. Therefore, careful attention should be given to properly diagnosing and treating this rare entity.

Primary squamous cell carcinoma of the ovary accompanied by transition of a mucinous borderline ovarian tumor.

This report describes a woman with a rare primary squamous cell carcinoma of the ovary accompanied by transition of a mucinous borderline ovarian tumor. A woman in her late 40s was referred for abdominal discomfort, which worsened during defecation. Pelvic magnetic resonance imaging showed a multiloculated cystic lesion in the left adnexa measuring approximately 7.5 × 9.5 × 7.0 cm. An intraoperatively obtained frozen biopsy sample of the mass in the left ovary was positive for malignancy, resulting in a surgical staging operation. The tumor was composed of squamous cell carcinoma and mucinous borderline tumor. There was no evidence of capsular invasion or invasion of other internal organs, including pelvic and para-aortic lymph nodes (0/41). Immunohistochemistry showed that the tumor was diffusely positive for cytokeratin 7, cytokeratin 20, Ki-67, and P40 but negative for P16. After a debulking operation, the patient has been monitored regularly without adjuvant therapy owing to final surgical staging of the tumor as stage IA.

Systemic Lymphadenopathic Mastocytosis with Eosinophilia.

Systemic mastocytosis is a neoplastic proliferation of mast cells that most frequently involves cutaneous sites. Mastocytosis involves various extracutaneous sites, but the lymph node is rare. We present an interesting image of systemic mastocytosis in the lymph node with marked eosinophilia. It is a rare subtype of systemic mastocytosis requiring high suspicion levels for the correct diagnosis.

Massive Retinal Gliosis Mistaken as a Malignant Intraocular Tumor in Phthisis Bulbi.

Massive retinal gliosis (MRG) is a rare condition of non-neoplastic glial proliferation, which forms massive lesions that fill the eye. MRG is commonly associated with phthisis bulbi (a non-functional eye), congenital anomalies, or malformations. Herein, we report a case of massive retinal gliosis associated with a traumatic phthisis bulbi, which was initially mistaken as a malignant intraocular tumor and confirmed only after an eye enucleation. A 70-year-old woman presented with a protruding ocular mass in her left eye which had slowly grown for a year. She had phthisis bulbi in her left eye due to trauma during her childhood. An orbital CT revealed an intraocular mass lesion with calcifications, raising the possibility of retinoblastoma or other malignant intraocular tumors. Enucleation of the left eye globe was performed. Histopathologic examination revealed exuberant proliferation of the glial cells, metaplastic bone formation, hyalinized vessels, and hyperplasia of the retinal pigment epithelium, confirming the diagnosis of MRG. Although rare, the possibility of MRG should be considered as a differential diagnosis when encountering an intraocular mass lesion, as it can be misdiagnosed as a malignant tumor.

Aberrant synaptophysin expression in classic Hodgkin lymphoma.

BACKGROUND: Synaptophysin is an immunohistochemical marker for neuroendocrine differentiation and is widely used in pathologic diagnosis. Its expression in malignant lymphoma has not yet been described. However, we experienced an index case of classic Hodgkin lymphoma with synaptophysin expression. This experience prompted us to investigate synaptophysin expression in classic Hodgkin lymphoma. METHOD: Immunohistochemical staining of synaptophysin was performed in 59 diagnosed cases of classic Hodgkin lymphoma, 10 anaplastic large cell lymphomas, 16 diffuse large B-cell lymphomas, and 5 extranodal marginal zone lymphoma of the mucosa-associated tissue. Synaptophysin-positive cases were stained for both chromogranin and CD56a. RESULT: Of 59 classic Hodgkin lymphoma cases, 11 (19%) were positive for synaptophysin. None of the anaplastic large cell lymphomas expressed synaptophysin. Synaptophysin showed weak but specific expression in the cytoplasm of the Hodgkin lymphoma tumor cells. Other background inflammatory cells (such as macrophages, B-, and T-lymphocytes) were all negative for synaptophysin expression. Chromogranin and CD56a were not expressed in the synaptophysin-positive classic Hodgkin lymphomas. CONCLUSIONS: Synaptophysin is an integral glycoprotein present in presynaptic vesicles of neurons and neuroendocrine cells. It is a diagnostic marker for neuroendocrine tumors. Aberrant synaptophysin expression has been reported in non-neuroendocrine tumors but not in lymphoma or leukemia. To the best of our knowledge, synaptophysin positivity has only been reported in a single case of precursor T-lymphoblastic leukemia/lymphoma to date. Our study showed that aberrant synaptophysin expression in classic Hodgkin lymphoma is an unexpectedly frequent finding. The mechanism underlying, and prognostic significance of, such aberrant expression is unclear. Thus, in a small biopsy, aberrant synaptophysin expression could be a diagnostic pitfall and should be carefully avoided.

Deep Learning-Based Classification of Uterine Cervical and Endometrial Cancer Subtypes from Whole-Slide Histopathology Images.

Uterine cervical and endometrial cancers have different subtypes with different clinical outcomes. Therefore, cancer subtyping is essential for proper treatment decisions. Furthermore, an endometrial and endocervical origin for an adenocarcinoma should also be distinguished. Although the discrimination can be helped with various immunohistochemical markers, there is no definitive marker. Therefore, we tested the feasibility of deep learning (DL)-based classification for the subtypes of cervical and endometrial cancers and the site of origin of adenocarcinomas from whole slide images (WSIs) of tissue slides. WSIs were split into 360 × 360-pixel image patches at 20× magnification for classification. Then, the average of patch classification results was used for the final classification. The area under the receiver operating characteristic curves (AUROCs) for the cervical and endometrial cancer classifiers were 0.977 and 0.944, respectively. The classifier for the origin of an adenocarcinoma yielded an AUROC of 0.939. These results clearly demonstrated the feasibility of DL-based classifiers for the discrimination of cancers from the cervix and uterus. We expect that the performance of the classifiers will be much enhanced with an accumulation of WSI data. Then, the information from the classifiers can be integrated with other data for more precise discrimination of cervical and endometrial cancers.

Combined high NEDD9 expression and E-cadherin loss correlate with poor clinical outcome in gastric cancer.

BACKGROUND AND AIM: Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a member of the Cas family. Previous studies have revealed that NEDD9 coordinates the focal adhesion kinase and Src signaling cascades that are involved in integrin-dependent adhesion and migration, invasion, cell apoptosis and life cycle, and survival, which may play a role in epithelial-mesenchymal transformation. The aim of this study was to analyze the expression of NEDD9 and E-cadherin in gastric cancer (GC) and evaluate their clinical significance. METHODS: NEDD9 and E-cadherin expression was analyzed with immunohistochemistry using tissue microarray technique in 435 GC patients who underwent gastrectomy. The NEDD9 expression level was defined by the combination score, which was determined by multiplying the staining intensity score and the proportion score (≥5; NEDD9-high, <5; NEDD9-low). E-cadherin loss was defined as a total loss of staining. The clinicopathologic parameters, overall survival, and disease-free survival rates were analyzed according to the NEDD9 and E-cadherin expression status. RESULTS: The combined NEDD9 and E-cadherin expression status correlated with lymphatic invasion (P = 0.001), vascular invasion (P = 0.020), and T stage (P = 0.001). Combined high NEDD9 expression and loss of E-cadherin expression status had a worse overall survival rate (P < 0.001) and served as a poor prognostic factor (Hazard ratio 2.49, 95% CI 1.25-5, P = 0.01). CONCLUSIONS: Immunohistochemical staining for NEDD9 and E-cadherin may function as a candidate prognostic marker for gastric cancer in everyday practice, especially when applied in combination.

Primary angiosarcoma of the breast: a case report.

BACKGROUND: Primary angiosarcoma of the breast is extremely rare, accounting for less than 0.05% of all primary malignancies of the breast. Here, we report here a case of primary angiosarcoma with full description of radiology and histology, including electron microscopic findings. CASE PRESENTATION: A 39-year-old woman complained of a diffuse hard mass in her right breast. She did not have any history of radiation exposure. Ultrasonography revealed a 7 cm sized mass with an irregular anechoic cystic portion replacing the entire right breast. Modified radical mastectomy was performed. The diagnosis of intermediate grade angiosarcoma was made by microscopic examination, immunohistochemical staining, and electron microscopic examination. The patient underwent four cycles of adriamycin-ifosfamide chemotherapy and received radiation therapy. Multiple bone metastases occurred 9 months after surgery and palliative treatment was given. Follow up was lost at post-operative 22 months. CONCLUSIONS: We report a rare case of intermediate grade primary angiosarcoma with detailed radiological and histological findings. Despite postoperative chemoradiation therapy, multiple metastases suggest that intermediate grade may have a more aggressive behavior.

Application of adipocyte-related antibodies in undifferentiated sarcomas to identify dedifferentiated liposarcomas based on histological and clinical analysis.

BACKGROUND: Due to morphologic similarities between undifferentiated sarcoma (US) and dedifferentiated liposarcoma (DDLPS), some portions of US could be identified as DDLPS. In this study, we applied adipocyte-related antibodies in order to discriminate possible cases of DDLPS from US. MATERIALS AND METHODS: A total of 46 cases, previously diagnosed as US, were examined. Immunohistochemistry for MDM2, CDK4, calreticulin, FABP4, and stathmin were performed. Histological findings were reviewed and clinical data was analyzed retrospectively. RESULTS: MDM2, CDK4, calreticulin, FABP4, and stathmin were positive in 17 (37.0%), 14 (30.4%), 3 (6.5%), 1 (2.2%), and 12 (26.1%) of the total 46 cases, respectively. MDM2/CDK4 positive cases showed more frequent positivity for calreticulin/FABP4/stathmin. Survival analysis, based on staining pattern, revealed a significantly better survival in the group where either MDM2 and CDK4 were positive and at least one of calreticulin, FABP4, or stathmin staining were positive. CONCLUSIONS: We conclude that when either MDM2-positive or CDK4-positive cases show any other positive results for calreticulin, FABP4, or stathmin, they have a significantly better survival and the possibility of DDLPS should be considered. Additional use of calreticulin, FABP4, or stathmin immunohistochemistry helps us to narrow the pool for further studies such as molecular analysis for a definite diagnosis.

Florid cystic endosalpingiosis associated with a retroperitoneal leiomyoma mimicking malignancy: a case report.

Florid cystic endosalpingiosis (FCE) is a rare type of endosalpingiosis that presents as a mass-like lesion. Here we report an unusual case of FCE associated with a retroperitoneal leiomyoma. A 46-year old female presented with a palpable abdominal mass. A pelvic CT revealed a 23.5×16.3×9.4 cm sized multilocular cystic and solid mass in the retroperitoneum. Surgical excision of the mass was performed. Microscopically, the cystic spaces were lined by a single layer of ciliated tubal epithelium. The solid areas consisted of thick bundles of spindle cells. There were no cytologic atypia, mitosis or necrosis. The spindle cells were positive for actin and desmin, and were negative for c-kit, CD34, S100 and HMB-45, confirming the diagnosis of FCE associated with retroperitoneal leiomyoma.

Prediction of KRAS Mutation in Rectal Cancer Using MRI.

AIM: The purpose of the study was to investigate imaging predictors of Kirsten-ras (KRAS) mutations using magnetic resonance imaging (MRI) in patients with rectal cancer. PATIENTS AND METHODS: A total of 275 patients with rectal cancer were enrolled. They underwent pretreatment rectal MRI, and then KRAS mutation evaluation following surgery. Two reviewers assessed diverse MRI findings associated with rectal cancer. RESULTS: KRAS mutations were detected in 107 (38.9%). KRAS mutations were associated with N stage, gross tumor pattern, axial length of the tumor, and the ratio of the axial to the longitudinal dimensions of the tumor (p=0.0064, p<0.0001, p=0.0003 and p=0.0090). The frequency of KRAS mutations was higher in N2 stage (53.70%), and polypoid tumors (59.09%). Tumors with KRAS mutations exhibited a longer axial length, as well as a larger ratio of the axial to the longitudinal dimensions. CONCLUSION: KRAS mutations were associated with N stage, a polypoid pattern, axial tumor length, and the ratio of the axial to the longitudinal dimensions of the tumor.

Single-port laparoscopic debulking surgery of variant benign metastatic leiomyomatosis with simultaneous lymphatic spreading and intraperitoneal seeding.

Benign metastatic leiomyomatosis (BML) is a rare disease characterized by smooth muscle cell proliferation in extrauterine sites including the lung, abdomen, pelvis, and retroperitoneum. Depending on location, BML is classified as intravenous leiomyomatosis and diffuse peritoneal leiomyomatosis. Pathogenesis of BML can be iatrogenic after previous myomectomy or hysterectomy, hormonal, or coelomic metaplasia. Treatment options are observation, hormonal suppression, and/or surgical debulking via laparotomy or laparoscopy. Laparoscopic surgery is gaining in popularity in the gynecologic field compared to laparotomic surgery and single-port laparoscopy has the benefits of cosmesis and early tissue extraction by transumbilical morcellation. We report a 39-year-old woman with BML who underwent single-port laparoscopy debulking surgery.

Intramural florid cystic endosalpingiosis of the uterus: a case report and review of the literature.

OBJECTIVE: We report a case of intramural florid cystic endosalpingiosis in the lower uterine segment of the uterus. CASE REPORT: A 43-year-old female presented with vaginal bleeding. Abdominal computed tomography suggested a leiomyoma with cystic degeneration. A total hysterectomy revealed a 4.0 cm × 3.8 cm cystic mass in the lower uterine segment. The cystic space microscopically was lined with a single layer or stratified layer of ciliated columnar cells that resembled tubal epithelium without cytologic atypia. The glandular spaces were surrounded by normal myometrium with no evidence of periglandular endometrial stroma, which was consistent with the diagnosis of florid cystic endosalpingiosis. CONCLUSION: Florid cystic endosalpingiosis involving the uterus is a rare and clinically unexpected finding; however, it should be considered in the differential diagnosis of a uterine mass.

A possible complementary tool for diagnosing tuberculosis: a feasibility test of immunohistochemical markers.

Differentiation of tuberculous granuloma (TG) from non-tuberculous granuloma (NG) is histopathologically difficult. We evaluated the usefulness of selected immunohistochemical markers to differentiate tuberculous granuloma (TG) and non-tuberculous granuloma (NG). We selected six biomarkers (FoxP3, TNF-beta, E-selectin [ESEL], indoleamine 2,3-dioxygenase [IDO], lactoferrin [LACT], and tartrate-resistant acid phosphatase [TRAP]) and immunohistochemically analyzed their expression in the presence of two types of granulomatous tissue samples, TG (n = 36) and NG (n = 31), using a microarray format. Three of those six biomarkers (LACT, IDO, and TNF-beta) were moderately accurate in discriminating TG from NG, individually and in combination, according to ROC analysis (AUC = 0.7-0.89, sensitivity = 55.6-77.8%, specificity = 71.0-100%). Our data indicate that selected immunohistochemical markers (LACT, IDO, and TNF-beta) can be used in ancillary tests to differentiate TG from NG in tissue samples. Further large-scale studies are required to validate our results.

Expression of histone deacetylases in diffuse large B-cell lymphoma and its clinical significance.

BACKGROUND: Histone deacetylase inhibitors are a new class of drugs used in treatment of malignant tumors. Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma, and it accounts for more than 40% of all B-cell lymphomas. In this study, we aimed to determine the expression patterns of histone deacetylases (HDACs) in DLBCL, to examine whether HDAC expression patterns differ among cases, and to assess whether these findings have clinical significance. MATERIALS AND METHODS: We selected 91 cases of DLBCL diagnosed at St. Vincent Hospital, The Catholic University of Korea, from 2001-2012. We performed a pathology slide review and collected clinical data including age, sex, tumor site, survival time, and mortality. Immunohistochemical analysis was performed using primary antibodies for HDACs, including HDAC1 and 2 of class I, HDAC4 and 5 of class IIa, and HDAC6 of class IIb. Expression site was determined to be nuclear, cytoplasmic, or both. Staining intensities were graded as low and high. We assessed correlations between HDAC expression levels and clinical data and survival analysis. RESULTS: Of the 91 cases examined, 46 (50.5%) were men and 45 (49.5%) were women. Most of the patients were elderly, and 74 (81.3%) cases were older than 46 y. Forty-six (50.5%) cases showed lymph node involvement, and 45 (49.5%) cases showed lymphoma at extranodal sites. In nodal lymphoma, staining was strongly positive for HDAC2, whereas staining was weak or negative for HDAC4; however, there was no significant correlation with survival. But nodal lymphoma cases with high nuclear expression of HDAC2 and nodal lymphoma cases with high nuclear expression of HDAC2 and low nuclear expression of HDAC4 showed significantly shorter survival times compared with other cases. CONCLUSIONS: High nuclear expression of HDAC2 may play an important role in survival of DLBCL patients, especially in those with nodal lymphoma, which is associated with a shorter survival time. Our results may have important implications for treatment of DLBCL by epigenetic regulation.