Two Cases of Biphasic Synovial Sarcoma With Expression of PAX8 and ER: A Diagnostic Pitfall.

Synovial sarcoma (SS) is a high-grade malignant neoplasm frequently arising in the deep soft tissue of the lower and upper extremities of young adults. Primary SS in the pelvis is extremely rare with scattered case reports. It often causes a diagnostic challenge in small biopsy and/or with aberrant expression of immunohistochemical markers. Here, we report 2 unusual cases of SS in the pelvis. Microscopically both cases present with biphasic morphology including spindle and epithelioid cells. In addition, the tumor cells in both cases expressed PAX8 and estrogen receptor. PAX8 is a transcription factor usually expressed in tumors of thyroid gland, kidney, and Müllerian system origin. The expression of PAX8 especially with co-expression of estrogen receptor can be misleading and result in a diagnosis of Müllerian tumors in female patients with pelvic masses. The diagnosis of SS for both cases was confirmed either with the fluorescence in situ hybridization or reverse transcription polymerase chain reaction showing a SS18 (SYT) (18q11) gene rearrangement. It is imperative to include SS in the differential diagnosis for malignant neoplasms exhibiting monotonous spindle cells (monophasic SS) and biphasic mixed monotonous spindle and epithelioid tumor cells in female patients with a pelvic mass. Molecular study for SS18 translocation is essential for the diagnosis in such cases.

High-Grade B-Cell Lymphoma With Malignant Effusions as the Initial Presentation.

OBJECTIVES: Malignant effusion is usually caused by metastatic carcinoma. Malignant lymphoma is often not included as a top differential diagnosis of malignant effusion. Here, we describe 3 cases of young female patients with no significant past medical history who presented with fluid overload and were diagnosed with high-grade B-cell lymphoma (HGBL). METHODS: We conducted histopathologic examination and immunophenotypic and cytogenetic analyses on three cases using immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), and karyotyping. We also included patients' clinical and radiological findings in our case reports. RESULTS: Histologic examination of the effusion samples showed numerous intermediate to large lymphoma cells with irregular nuclear contours and fine chromatin. The lymphoma cells were positive for CD10, CD20, BCL2, BCL6, and PAX5 and negative for CD34, cyclin D1, HHV-8, and TdT. In situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs was negative. The proliferation index by Ki-67 stain was more than 80%. Flow cytometry showed CD10-positive B cells with monotypic immunoglobulin light chain expression. Fluorescence in situ hybridization analysis demonstrated MYC, BCL2, or BCL6 rearrangements. These 3 patients were diagnosed as having HGBL with double-/triple-hit rearrangements. Despite receiving aggressive chemotherapy, all 3 patients had a dismal clinical course, with 2 patients dying less than 2 years after initial diagnosis. CONCLUSIONS: High-grade B-cell lymphoma should be considered in the differential diagnoses of malignant effusions. Flow cytometric and FISH analyses of the body fluid specimens are essential to reach an accurate and timely diagnosis.

Morphoproteomics Identifies SIRT1, EZH2 and CXCR4 Pathways in Diffuse Large B-Cell Lymphoma: Therapeutic Implications.

OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of non-Hodgkin's lymphoma. METHODS: We applied morphoproteomics to a tissue microarray of DLBCL cases to uncover commonalities in its biology with therapeutic implications. Morphoproteomic analysis of 9 individual cases of classic DLBCL included immunohistochemical probes to detect silent mating type information regulation 2 homolog 1 (SIRT1), enhancer of Zeste homolog 2 (EZH2) and C-X-C chemokine receptor 4 (CXCR4) and their cellular compartmentalization by bright field microscopy. RESULTS: We detected the expression of SIRT1 in the majority (>50%) of the tumoral nuclei of 8 of 9 cases of DLBCL and of EZH2 expression in the majority (>50%) of the tumoral nuclei in 9 of the 9 cases; and the expression of the tumoral stem cell marker, CXCR4 in the cytoplasmic and/or plasmalemmal compartment at >50% of the tumor cells in all 9 cases of DLBCL. The morphoproteomic findings of SIRT1 and EZH2 expression in DLBCL, for the most part, parallel the morphoproteomic findings in B-cell acute lymphoblastic leukemia. This concordance has pharmacogenomic and therapeutic implications. Similarly, the fact that EZH2 can enhance the expression of tumoral stem cell marker, CXCR4 implies that there is a block in differentiation in DLBCL. CONCLUSION: By targeting the Sirt1, EZH2 and CXCR4 pathways using relatively non-toxic adjuvant therapeutic agents such as metformin, melatonin, curcumin, sulforaphane, vitamin D3 and plerixafor, we should be able to target the biology of DLBCL.

Cytomorphology, ultrastructural, and cytogenetic findings in follicular dendritic cell sarcoma: a case report.

BACKGROUND: Follicular dendritic cell (FDC) sarcoma is a rare low-to-intermediate grade malignant dendritic cell neoplasm that often has an indolent clinical course. FDC sarcomas are often misdiagnosed on aspiration cytology. CASE: A 26-year-old woman presented with a solid, slowly growing, painless mass in her right neck for 3 months. Computed tomography revealed a 3.6-cm, well-defined homogenous solid mass located posterior to the mandible and submandibular glands. Fine needle aspiration cytology revealed many large, spindle to ovoid epithelioid cells in singles, small clusters, and syncytial sheets with moderate to abundant cytoplasm, indistinct cell borders, irregular nuclear membrane, fine to vesicular chromatin, and conspicuous nucleoli. The background contained many small mature lymphocytes intimately mixed with large epithelioid tumor cells. Tumor cells were strongly positive for CD21, CD35, CD23, and fascin. Diagnosis of FDC sarcoma was rendered; follow-up surgical resection and ultrastructural study confirmed the diagnosis. The cytogenetic study showed a normal female karyotype 46,XX. CONCLUSION: Although the cytomorphology of FDC sarcoma is characteristic, a preoperative diagnosis of FDC sarcoma based on fine needle aspiration cytology is very challenging, if not impossible. Immunohistochemistry is always necessary for rendering and/or confirming the diagnosis, and ultrastructural studies are helpful.

The role of routine immunohistochemistry for Helicobacter pylori in gastric biopsy.

Helicobacter pylori infection is associated with gastritis, gastric ulcer, gastric adenocarcinoma, and mucosal associated lymphoid tissue lymphoma. Documenting the presence of H pylori in a gastric biopsy is essential for appropriate patient care. Several special stains and immunohistochemistry (IHC) stain for H pylori are available, and many laboratories are routinely using one of them. We introduced routine IHC for H pylori about a year ago, and this study aims to investigate the value of this protocol. A total of 224 patients qualified for the study criteria during this period. The diagnoses were chronic active gastritis (68), chronic gastritis (76), no pathologic abnormality (50), reactive gastropathy (24), and polyps (6). Fifty-four cases were positive for H pylori on IHC, including 50 chronic active gastritis and 4 chronic gastritis. The IHC positive rate was 73.5% (50/68) in chronic active gastritis, 5.3% (4/76) in chronic gastritis, and 0% (0/80) in other diagnoses. The sensitivity/specificity of finding H pylori by blindly reviewing hematoxylin and eosin slides was 100%/100%, 100%/100%, 95%/100%, and 100%/100% from the 4 authors. Our results showed that many gastric biopsies (35.7%, 80/224) had no pathologic abnormality or reactive gastropathy and did not need a routine IHC for H pylori. Hematoxylin and eosin slide review had a very good sensitivity and specificity with all levels of observers. In summary, IHC for H pylori should not be routinely used, especially during these economically challenging times. Immunohistochemistry should be reserved for unexplained gastritis and previously treated patients with likely low organism density.

HIV-associated plasmablastic lymphoma in the era of HAART: a single-center experience of 21 patients.

OBJECTIVES: Patients with HIV infection have an increased risk of developing plasmablastic lymphoma (PBL). In this study, we reviewed the clinicopathologic features of PBL in HIV+ patients in the era of HAART from a single health center. DESIGN: Retrospective study. METHODS: The morphologic, immunophenotypic, and clinical features were reviewed in these HIV+ patients with PBL and univariate analysis was employed to determine the survival prognosis. RESULTS: During the interval of 1 January 2008 to 30 December 2018, we identified 95 HIV+ patients with aggressive non-Hodgkin B-cell lymphomas. Among these patients, there were 21 (22%) patients with PBL (19 men and two women; median age: 45 years). Seven patients had PBL at their initial HIV diagnosis and 14 developed PBL after a median interval of 7.7 months of HIV diagnosis. Lymph nodes (n = 10), oral cavity/sinonasal mass (n = 6), and rectal masses (n = 5) were the common involved sites, and five of 15 (33%) had bone marrow involvement. Lymphoma cells were immunoreactive for MUM-1/IRF4 (100%), CD138 (90%), CD45 (63%), CD79a (47%), and CD30 (25%). Proliferation rate assessed by Ki67 was at least 90% in 18 of 20 cases. Eighteen patients received chemotherapy including etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (n = 13) and cyclophosphamide, doxorubicin, vincristine, and prednisone (n = 2). With a median follow-up time of 19 months, nine out of 17 patients died. Bone marrow involvement was associated with a poorer overall survival (median: 4.7 months, P = 0.015). CONCLUSION: PBL is the second most common type of aggressive lymphoma and often presents in lymph nodes of patients with poorly controlled HIV infection. Bone marrow involvement is associated with a poorer outcome.

Tumor-Infiltrating Lymphocyte Volume Is a Better Predictor of Disease-Free Survival Than Stromal Tumor-Infiltrating Lymphocytes in Invasive Breast Carcinoma.

OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) have recently emerged as a prognostic factor in breast cancer. In our previous study, we proposed that tumor stroma should also be considered in the calculation of TILs and we introduced tumor infiltration lymphocyte volume (TILV) in triple-negative breast cancer. METHODS: We assessed the disease-free survival predictive value of TILV in all subtypes of invasive breast carcinoma and compared the predictive value of TILV with TILs. Differences between disease-free survival curves were determined by using the log-rank test, and Kaplan-Meier survival plots were generated for both groups. RESULTS: TILV was significantly correlated with disease-free survival in both invasive ductal carcinoma (P = .03) and all subtypes of invasive breast carcinoma (P = .043), whereas TILs failed to show a statistical significance. CONCLUSIONS: Tumor-stroma ratio needs to be considered in estimation of tumor immunity, and TILV adds more predictive power to TILs.

Tumor-infiltrating lymphocyte volume is a better predictor of neoadjuvant therapy response and overall survival in triple-negative invasive breast cancer.

Triple-negative breast cancer (TNBC) has an aggressive behavior, limited therapeutic options, and high mortality rate. Neoadjuvant chemotherapy is a standard treatment for TNBC, and patients with pathological complete response (pCR) have a favorable outcome. We conducted a comprehensive evaluation of cancer clinicopathological parameters and correlated these parameters with the pCR rate and the overall survival. Fifty-eight patients with TNBC of no special type who underwent breast biopsy, neoadjuvant therapy, and mastectomy in our institution during 2005-2016 were included in this study. Among the 58 TNBC patients, 26 (45%) achieved pCR, and 32 (55%) had residual disease. The study parameters included age, histologic grade, clinical stage, mitotic count, Ki-67 proliferation index, stromal ratio, stromal type, tumor necrosis, stromal tumor-infiltrating lymphocytes (TILs), tumor intraepithelial lymphocytes, and tumor-infiltrating lymphocytes volume (TILV). Whereas most factors did not affect pCR, stromal TILs and TILV showed significant correlation with pCR (P = .01 and P = .0008, respectively). In the residual disease group, all factors showed no significant differences before and after neoadjuvant chemotherapy, except for tumor sizes. Lastly, pCR, TILs, and TILV were all significantly correlated with the overall survival, with P = .028, .029, and .015, respectively. In summary, we proposed a new concept of TILV to precisely evaluate the tumor immunity, and our data showed that TILV had a better predictive value than TILs for the pCR and the overall survival in TNBC.

Loop Electrosurgical Excision Procedure vs. Cold Knife Cone in Treatment of Cervical Intraepithelial Neoplasia: Review of 447 Cases.

Loop electrosurgical excision procedure (LEEP) and cold knife cone (CKC) are often used for the treatment of high-grade cervical intraepithelial lesions. LEEP is an in-office procedure with less discomfort and fewer complications than CKC. However, concerns related to LEEP include the interpretability of the resection margins, positive margins, and the tissue fragmentation. Negative for dysplasia in LEEP or CKC specimens are not uncommon, which may be associated with lesion regression or interpretation errors. 447 cases with 259 LEEP and 188 CKC were included in this study. Patients with CKC were significantly older than patients with LEEP (38 vs. 31, p=0.0001). LEEP was associated with more tissue fragmentation (45.2% vs. 8.5%, p=0.0001) and un-interpretable surgical margins than CKC (10.4% vs. 2.7%, p=0.001). LEEP and CKC had similar positive surgical margin rate. 380 cases had both in-house biopsy and LEEP/CKC (219 LEEP and 161 CKC) specimens. Twenty four cases were negative for dysplasia on the LEEP/CKC (6.3%, 24/380), and the negative rates were similar between LEEP and CKC groups (6.8% vs. 5.6%, p=0.67). Reviewing the previous biopsy or cytology of the 24 negative cases confirmed high-grade squamous intraepithelial lesion (HSIL/CIN2+) in 22 cases, and the remaining 2 cases were misinterpretations of low-grade squamous intraepithelial lesion (LSIL/CIN1) in the biopsy or cytology. The negative rate was higher in cervical cytology only group comparing to cervical biopsy confirmed CIN2+ group (10.8% vs. 5.4%), but it was not statistically significant (p=0.15). The residual/recurrent rate for cervical dysplasia was only 2.9% (11/373).

SIRT1 overexpression in cervical squamous intraepithelial lesions and invasive squamous cell carcinoma.

Invasive squamous cell carcinoma (SCC) of the cervix involves the progression of premalignant cervical intraepithelial neoplasia (CIN) and is associated with persistent human papillomavirus infection. Most CINs will regress, and the challenge is to identify the lesions likely to progress to invasive cancer. We evaluated Sirtuin 1 (SIRT1) expression in nonneoplastic cervix, CINs, and SCCs as a potential biomarker to predict disease progression. A total of 101 cases were selected including 29 CIN 1s, 32 CIN 2s, 16 CIN 3s, 2 microinvasive SCCs, and 22 invasive SCCs. Cervical nonneoplastic squamous epithelium showed weak positivity of SIRT1 in the basal layer. SIRT1 cytoplasmic overexpression was found in 13.8% of CIN 1s (4/29), 40.6% of CIN 2s (13/32), and 50% of CIN 3s (8/16), and it was statistically significant between CIN 1 and CIN 2/3 lesions (P=.01). All 24 cases of invasive and microinvasive SCC showed SIRT1 overexpression, with 25% (6/24) showing cytoplasmic staining only, 4.2% (1/24) showing nuclear staining only, and 70.8% (17/24) showing both nuclear and cytoplasmic staining. From CIN 1 to SCC, SIRT1 expression showed steady and statistically significant increase (CIN 1 versus CIN 2-3, P=.01; CIN 2-3 versus SCC, P=.0001). Thus, SIRT1 may serve as a potential biomarker for predicting the progression of CIN to invasive SCC.

Clinical significance of acquired cytogenetic clones in patients with treated follicular lymphoma.

BACKGROUND: Follicular lymphoma (FL) is the second most common B-cell non-Hodgkin lymphoma worldwide. In most patients, the disease is diagnosed at advanced stages and cannot be cured using conventional therapeutic approaches. To assess the role of cytogenetic abnormalities in therapy-related myeloid neoplasms (tMNs), we studied the clinicopathologic and cytogenetic features of treated FL patients who subsequently developed a new acquired cytogenetic clone (ACC). PATIENTS AND METHODS: Twenty-five treated FL patients developed new cytogenetic abnormalities from 2009 to 2012. Patients were divided into 3 groups based on the presence and absence of tMNs: group 1, ACC without tMNs after a median follow-up of 15 months; group 2, ACC with possible tMN after silent ACC detection; group 3, tMNs present at the first ACC detection. RESULTS: The most frequent cytogenetic aberrations involved chromosome 7. Compared with group 1, group 3 had significantly greater size of ACC, higher frequency of chromosome 7 aberrations, more likely showed dysplasia, and lower platelet count (P = .03). CONCLUSION: Our results indicate that the presence of ACC alone is insufficient for diagnosis of tMNs. The proportion of cells with specific aberrations at first ACC, bone marrow dysplasia, and low platelet counts might predict outcome of ACC.

Clinically silent clonal cytogenetic abnormalities arising in patients treated for lymphoid neoplasms.

Newly emerged clonal cytogenetic abnormalities (CCA) in patients with prior cytotoxic therapy are highly concerning for therapy-related myeloid neoplasms (t-MN). In some patients, however, CCA appeared to be clinically "silent". In this study, we describe 25 patients who developed CCA after they received cytotoxic therapies for lymphoid neoplasms but never developed t-MN. These clinically "silent" CCA were always present as single abnormalities, often detected in a small subset of cells, and tended to disappear over time. We conclude that the occurrence of CCA is not always associated with t-MN. Clinical correlation is essential to guide a proper management of these patients.

SIRT1 is a useful biomarker for high-grade dysplasia and carcinoma in Barrett's esophagus.

The diagnosis of epithelial dysplasia and subsequent grading of the dysplasia in Barrett's esophagus (BE) are clinically significant for the patient's follow-up and management. However, histologic diagnosis for these lesions often proves challenging for general practicing pathologists and even GI pathologists. Certain biomarkers, such as p53 and racemase, have shown some value in diagnosing these lesions. We previously showed that SIRT1, the mammalian homologue of silent mating type information regulator 2 in budding yeasts, was over-expressed in colonic adenomas. The goal of this study was to investigate the value of SIRT1 in BE-related dysplasia. Twenty BE cases without epithelial dysplasia, 11 with low-grade dysplasia, 4 with high-grade dysplasia, and 8 invasive carcinomas were included in this study. Twenty-nine of 31 cases with no epithelial dysplasia or low-grade dysplasia showed weak nuclear staining at the base of the crypts, but the surface epithelium was negative in all cases. Ten of twelve cases with high-grade dysplasia or carcinomas had 2-3+ diffuse nuclear staining including the surface epithelium. Using 2+ surface nuclear staining as the cutoff, BE with high-grade dysplasia and carcinoma had significantly higher SIRT1 expression than BE with no dysplasia or low-grade dysplasia (p=0.0001). Therefore, SIRT1 appears to be a very promising biomarker in the diagnosis of BE with high-grade dysplasia and carcinoma. This is the first report using SIRT1 as an adjunctive marker on evaluation of BE-related dysplasia, but large-scale and prospective studies are needed to confirm and validate our findings.