Xiaohong I. Wang

Human Papillomavirus in Metastatic Lymph Nodes from Unknown Primary Head and Neck Squamous Cell Carcinoma

Objective. Determine human papillomavirus (HPV) incidence in unknown primary squamous cell carcinomas (SCCa) of the head and neck and assess if HPV status influenced survival. Study Design. Historical cohort study. Setting. Tertiary care center. Subjects. Patients with unknown primary SCCa despite a complete workup who underwent neck dissection or excisional biopsy and postoperative comprehensive ± chemoradiotherapy between 2002 and 2009. Methods. HPV fluorescence in situ hybridization (FISH) and p16INK4a immunohistochemistry (p16 IHC) were performed. Results were compared with survival, age, race, gender, tobacco use, alcohol use, and nodal stage. Results. Twenty-five patients met the inclusion criteria, of whom 88% were >10 pack year tobacco users. Twenty-eight percent were HPV positive defined by both p16+ and FISH+. Five-year overall survival was 66.7% in HPV-positive and 48.5% in HPV-negative patients (P = .35). Similarly, 5-year disease-free survival rates were 66.7% in HPV-positive and 48.5% in HPV-negative patients (P = .54). All 3 HPV-positive nonsmokers were survivors, but this was not significant because of the small sample size (P > .05). No other characteristics were associated with survival (P > .05). Conclusion. Twenty-eight percent of metastatic lymph nodes from occult primary tumors were HPV positive. There was no survival difference associated with HPV status. Most of the HPV-positive patients in this study were tobacco users who had similar survival to HPV-negative patients, so caution should be used in interpreting HPV status in these patients.

Changing trends in human papillomavirus-associated head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) continues to be a significant disease with varying rates of incidence and mortality worldwide. Numerous studies have demonstrated that human papillomavirus (HPV) is etiologically linked with a subset of HNSCC, independent of tobacco and alcohol use. This subset of tumor shows increased sensitivity to radiation therapy and association with better outcomes. The study aims to determine the HPV burden and trend among patients with HNSCC in the southern region of the United States over the past 10 years. Of 142 cases from 2000 to 2004, 18 (13%) were positive for high-risk HPV. Nine of these were oropharyngeal tumors, including 4 cases from the tonsil. These constitute 38% (9/24) of all oropharyngeal tumors and 57% (4/7) of tonsillar tumors. Of 35 cases from 2009 to 2010, 14 (40%) were positive for high-risk HPV. Thirteen of these were oropharyngeal tumors, including 9 cases from the tonsil. These constitute 59% (13/23) of oropharyngeal tumors and 64% (9/14) of tonsillar tumors. When data from the 2 periods are combined, the results show that African American patients are less likely to have HPV-associated disease compared with white patients (9% vs 22%). Human papillomavirus-positive and oropharyngeal HNSCC are more likely to be nonkeratinizing (P < .0001). In conclusion, the HPV detection rate in oropharyngeal squamous cell carcinoma increased from 38% to 59% between the 2000-to-2004 and 2009-to-2010 periods.

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.

Therapy-related myeloid neoplasms with isolated del(20q): comparison with cases of de novo myelodysplastic syndrome with del(20q).

The isolated deletion of chromosome 20q [del(20q)] has been observed in both de novo and therapy-related cases of myelodysplastic syndrome (MDS). The clinicopathologic features of de novo MDS with isolated del(20q) are well characterized. However, relatively little is known about therapy-related myeloid neoplasms (t-MNs) with isolated del(20q). In this study, we identified five cases of t-MN and 26 cases of de novo MDS with isolated del(20q) over a 10-year period. All cases had a long latency interval from the treatment of the primary malignancy to the onset of t-MN, and all were associated with frequent bone marrow dysplasia. The del(20q) was the sole abnormality detected at the time of diagnosis of t-MN in three cases, six years prior to diagnosis in one case, and at the time of relapse of acute myeloid leukemia (AML) in one case. Three patients with therapy-related MDS (t-MDS) had a relatively indolent clinical course, whereas two patients presented with AML or developed AML shortly after t-MDS. The patients with de novo MDS with isolated del(20q) presented frequently with anemia and thrombocytopenia which were associated with bone marrow dysplasia. The median overall survival was 64 months. In all cases, del(20q) was present at the time of diagnosis.

Myeloid Neoplasms Associated with t(3;12)(q26.2;P13) Are Clinically Aggressive and Frequently Harbor FLT3 Mutations: A Report of 8 Cases and Review of Literature

The t(3;12)(q26.2;p13) involving EVI1/ETV 6 is a rare recurrent translocation that has been identified in myeloid neoplasms. The clinicopathologic features of these are not well characterized. We identified 5 cases of Acute Myeloid Leukemia (AML) and 3 cases of Myelodysplastic Syndrome (MDS) associated with t(3;12)(q26.2;p13). There were 5 men and 3 women, with a median age of 60 years. The AML cases included 2 de novo, 2 arising from prior MDS and 1 relapsed AML. The median bone marrow blast count was 50% (range, 35-91%). Dysplasia involving one or more lineages dysplasia was noted in all cases. Of the 3 MDS cases, two were classified as refractory anemia with excess blasts and one therapy related. Two that had follow up data rapidly evolved to AML within 6 months. Conventional cytogenetic analysis showed t(3;12) (q26.2;p13) in all neoplasms and additional abnormalities in 5 patients, Including chromosome 7 abnormalities in 3 patients. FISH confirmed ETV6 rearrangement in all 3 cases assessed and EVI1 rearrangement in both cases assessed. FLT3 ITD was identified in 3 of 5 cases assessed. The median overall survival was 12 months (range, 7-58 months). We conclude that t(3;12) can occur as either a primary or secondary event in myeloid neoplasms. The t(3;12) is associated with multilineage dysplasia, chromosome 7 aberrations and an aggressive clinical course.

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.

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.

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.

Double-hit of FLT3 gene in a fatal case of acute myemonocytic leukaemia

Mutations of the fms-like tyrosine kinase 3 ( FLT3) gene located at chromosome 13q12, alone or in combination with other oncogene mutations, occur in approximately 40% of cases of acute myeloid leukaemia (AML).1–3 Two major types of FLT3 mutations have been identified: (1) internal tandem duplication within the juxtamembrane domain; and (2) mutations affecting codons 835 or 836 of the second tyrosine kinase domain.1 Internal tandem duplications of FLT3 are known to be associated with a poorer prognosis. The t(12;13)(p13;q12) has been reported in a few cases of AML, involving ectopic expression of the homeobox gene CDX2 at chromosome 13q12.4 ,5 The t(12;13)(p13;q12), resulting in a FLT3/EVT6 fusion gene, has not been reported in AML. We report a case of AML that initially was associated with an internal tandem duplication of FLT3 and subsequently developed t(12;13)(p13;q12) and a FLT3/EVT6 fusion gene associated with FLT3 overexpression. The onset of t(12;13)(p13;q12) was followed by a rapidly progressive disease course and death. A patient presented with a history of asbestosis, worsening dyspnoea, fever and marked leukocytosis, leading to the patients referral at a leukaemia clinic in his late 60s. A complete blood count showed haemoglobin of 9.3 g/dl, platelet count of 22 000/mm3 and a white blood cell count of 101 700/mm3 with a differential count of 14.0% neutrophils, 16.0% lymphocytes, 1.0% monocytes and 64% blasts in the blood smear. Bone marrow (BM) aspiration and biopsy were performed. The aspirate smear showed 52% blasts and the biopsy specimen was hypercellular. Flow cytometry immunophenotypic analysis revealed a myeloid immunophenotype; blasts were positive for CD13, CD33, CD49d, CD64 (dim), CD117, CD123, CD184, HLA-DR, myeloperoxidase and TdT (subset), and were negative for CD14, CD19 CD34 and CD56. Conventional cytogenetic analysis revealed a diploid karyotype in all the 20 cells analysed. Molecular testing showed an …