Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia: Should We Screen for Lynch Syndrome in Precancerous Lesions?

Screening for Lynch syndrome (LS) is routinely performed in patients with endometrial carcinoma. Currently, no screening recommendations exist for LS in precancerous lesions. The study goal was to determine the incidence of abnormal protein expression in endometrioid intraepithelial neoplasia/atypical hyperplasia (EIN/AH). We analyzed mismatch repair (MMR) protein expression by immunohistochemistry in EIN/AH concurrent with MMR-deficient endometrial carcinomas, and in endometrial biopsy/curettage specimens with EIN/AH from an unselected group of patients. Of 63 patients with MMR-deficient endometrial carcinoma, 34 demonstrated loss of MLH1/PMS2 expression; 1 showed loss of PMS2 alone; 12 showed loss of MSH2/MSH6, and 15 had loss of MSH6 alone. Genetic testing identified deleterious mutations in 14 cases (LS). 15 tumors demonstrated MLH1 promoter hypermethylation. Abnormal MMR expression in EIN/AH and adjacent carcinoma was concordant in 100% of LS cases and 71% of MLH1 promoter hypermethylation cases. Of 118 patients from the unselected group with EIN/AH, 4 (3%) cases demonstrated absent expression of one or more MMR proteins. Of these, 2 patients were later confirmed to have deleterious mutations in subsequent specimens with endometrial carcinoma. The prevalence of abnormal MMR expression in EIN/AH adjacent to carcinoma and in the unselected group of patients with EIN/AH is similar to the reported prevalence of LS in endometrial carcinoma. Identifying patients at high risk for LS through abnormal MMR expression in EIN/AH provides the benefit of early surveillance, treatment and timely diagnosis for the patient and affected family members.

Teenage cervical screening in a high risk American population.

BACKGROUND: The new 2009 ACOG guideline for cervical cytology screening changed the starting age to 21 years regardless of the age of onset of sexual intercourse. However, many recent studies have shown a dramatic increase in the incidence of cervical epithelial abnormalities among adolescents within the past two decades. MATERIALS AND METHODS: For this study, the reports of 156,342 cervical cytology were available of which 12,226 (7.8%) were from teenagers. A total of 192 teenagers with high grade intraepithelial lesion (HSIL) cervical cytology were identified. The ages ranged from 13 to 19 years with a mean of 17.7 years and a median of 18 years. Among them, 31.3% were pregnant, 12.0% were postpartum, and 13.5% were on oral contraceptive. Ninety-eight had prior cervical cytology. RESULTS: The teenagers had statistically significant higher detection rates of overall abnormal cervical cytology (23.6% vs. 6.6%, P = 0), with 15.4% vs. 3.2% (P = 0) of low grade intraepithelial lesion (LSIL) and 1.8% vs. 1.0% (P = 2.56 × 10(-13) ) of HSIL compared to women ≥20 years. The teenage group had the highest abnormal cytology among all age groups. The LSIL/HSIL ratio was 8.5:1 for teenagers and 3.1:1 for women ≥20 years. A total of 131 teenagers had cervical biopsies within 12 months of the HSIL cytology, with diagnoses of 39 CIN 3, 1 VAIN 3, 15 CIN 2, 62 CIN 1, and 14 had a negative histology (CIN 0). Only in 19 of these 39 women, the CIN 2/3 lesion proved to be persistent. CONCLUSION: We conclude that cytology screening of high risk teenagers is effective in detecting CIN 2/3 lesions. Moreover, treatment and careful follow-up can be realized.

Challenges in the Pap diagnosis of endocervical adenocarcinoma in situ.

INTRODUCTION: Recognition of adenocarcinoma in situ (AIS) in cervical cytology is challenging. MATERIALS AND METHODS: We calculated the sensitivity and accuracy of Papanicolaou (Pap) tests obtained within 1 year of a histologic diagnosis of AIS from 2007 to 2016. We also correlated it with the coexistence of squamous lesions, calculated the interobserver agreement, and compared these measures with those of endocervical adenocarcinoma (ECCA). We correlated AIS detection with high-risk human papillomavirus (hrHPV) status. RESULTS: Of 72 patients with histologic AIS and 48 patients with ECCA, 92% and 87.5%, respectively, had abnormal Pap test results. A glandular abnormality was detected in 44.4% of the AIS and 77.1% of the ECCA cases. Complete cytohistologic concordance was reached in 8.3% of AIS and 22.9% of ECCA cases. In addition, 27.8% of AIS and 6.3% of ECCA cases were diagnosed on Pap as a high-risk squamous abnormality. Concurrent squamous lesions were present in 79.2% of patients with AIS and 29.2% of patients with ECCA. The Paps from the AIS and ECCA cases were diagnosed as pure squamous abnormalities in 47.2% and 10.4% of cases, respectively. In the AIS cases, interobserver agreement was substantial for detection of any high-risk cytologic abnormality (kappa = 0.67) and fair for detection of any glandular abnormality (kappa = 0.34). Among the 26 patients with AIS tested for hrHPV, 92% had positive results and 8% had negative results. CONCLUSIONS: The cytologic sensitivity for the detection of AIS remains low. It is directly related to the coexistence of squamous lesions. Cytology and hrHPV as stand-alone screening tests fail in the early detection of a small proportion of glandular lesions, although combined testing will improve their detection rates.

The diagnostic utility of Merkel cell polyomavirus immunohistochemistry in a fine needle aspirate of metastatic Merkel cell carcinoma of unknown primary to the pancreas.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with a high tendency for metastases. We report a case of MCC initially presenting as axillary and pancreatic metastases. A 33-year-old HIV-positive Hispanic male presented with a history of a rapidly growing axillary mass. A needle core biopsy demonstrated an epithelioid neoplasm composed of small to medium-sized cells with high nuclear-cytoplasmic ratio, nuclear molding, and frequent mitotic figures. A subsequent PET scan revealed a 1.5 cm FDG avid mass in the pancreas. Endoscopic ultrasound-guided FNA of the pancreatic mass showed neoplastic cells with similar morphology to those of the axillary mass. The tumor cells were positive with pancytokeratin AE1/AE3, CK20, CD56, synatophysin, chromogranin, and Merkel cell polyomavirus (MCPyV). This case of MCC most likely originated from a resolved primary skin lesion drained by the involved axillary lymph node with subsequent metastases to the pancreas and distant lymph nodes.

Follicular dendritic cell sarcoma of the tonsil: a case report and literature review.

We describe a case of follicular dendritic cell sarcoma (FDCS) of the tonsil in a 59-year-old woman. She was successfully treated with excision of the mass and postoperative radiation therapy. According to our review of the literature, only 25 cases of extranodal FDCS in the head and neck have been previously reported, including only 10 cases that involved a tonsil. We briefly review these earlier reports, and we discuss the diagnosis and management of FDCS.

NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer.

UNLABELLED: Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H: quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and ß-lapachone (ß-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. ß-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by ß-lap using long-term survival assays. The combination of nontoxic ß-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD(+), and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating ß-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to ß-lap-induced radiosensitization. Mol Cancer Ther; 15(7); 1757-67. ©2016 AACR.

A Transistor-like pH Nanoprobe for Tumour Detection and Image-guided Surgery.

Because of profound genetic and histological differences in cancerous tissue, it is challenging to detect a broad range of malignant tumours at high resolution. Here, we report the design and performance of a fluorescent nanoprobe with transistor-like responses (transition pH = 6.9) for the detection of the deregulated pH that drives many of the invasive properties of cancer. The nanoprobe amplifies fluorescence signal in the tumour over that in the surrounding normal tissues, resulting in a discretized, binary output signal with spatial resolution smaller than 1 mm. The nanoprobe allowed us to image a broad range of tumours in mouse models using a variety of clinical cameras, and to perform real-time tumour-acidosis-guided detection and surgery of occult nodules (< 1 mm3) in mice bearing head-and-neck or breast tumours, significantly lengthening mice survivability. We also show that the pH nanoprobe can be used as a reporter in a fast, quantitative assay to screen for tumour-acidosis inhibitors. The binary delineation of pH achieved by the nanoprobe promises to improve the accuracy of cancer detection, surveillance and therapy.

In vivo optical imaging of folate receptor-ß in head and neck squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Folate receptor (FR) expression, although known to be elevated in many types of cancer and inflammatory cells, has not been well characterized in head and neck squamous cell carcinoma (HNSCC). We hypothesized that tumor infiltrating inflammatory cells expressing FR-ß could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low. STUDY DESIGN: Retrospective review of clinical pathologic specimens and in vivo animal study. METHODS: A tissue microarray with tumor and tumor-free tissue from 22 patients with HNSCC was stained with antibodies to FR-α and FR-ß. We characterized FR-ß(+) cells by examining CD45, CD68, CD206, and transforming growth factor (TGF)-ß expression. To investigate fluorescent imaging, mice with orthotopic tumor xenografts were imaged in vivo after intravenous injections of folate conjugated fluorescein isothiocyanate (folate-FITC) and were histologically evaluated ex vivo. RESULTS: All tumor samples demonstrated significant FR-ß staining and negligible FR-α staining. FR-ß(+) cells found in tumors coexpressed CD68 and had increased expression of CD206 and TGF-ß characteristic of tumor-associated macrophages. In the xenograft models, tumors showed strong in vivo fluorescence after folate-FITC injection in contrast to surrounding normal tissues. Histologic examination of the xenograft tissue similarly showed folate-FITC uptake in areas of inflammatory cellular infiltrate. CONCLUSIONS: Although HNSCC tumor cells do not express FR, HNSCC tumors contain a significant population of FR-ß-expressing macrophages. Folate conjugated fluorescent dye is able to specifically target and label tumor xenografts to permit macroscopic fluorescence imaging due to FR-ß expression on the infiltrating inflammatory cells.

The value of duplicate slides on atypical squamous cells, cannot exclude high-grade intraepithelial lesion.

Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) category was added to the 2001 Bethesda System. ASC-H accounts for a small percentage (0.2-0.6%) of abnormal Pap smears and includes heterogenous group of lesions. There are more high-grade cervical lesions (30-50%) in ASC-H than ASC-US (10-15%). An accurate Pap diagnosis is crucial for appropriate patient follow-up and treatment. A total of 43 consecutive ASC-H cases were collected from October 2007 to March 2008, and all duplicate and the original slides were reviewed blindly at the end of the study. On review of the duplicate Pap slides, 18 cases had diagnostic SIL cells (15 HSIL, 2 LSIL with ASC-H, and 1 LSIL). The duplicate slides could have potentially changed 18 (41.9%) ASC-H diagnoses to a more definitive SIL diagnosis. On review of the original Pap slides, 8 of these 18 cases also had HSIL cells. Twenty-one follow-up cervical biopsies (21/43, 48.8%) showed 12 CIN 2/3, 4 CIN 1, 1 VAIN 1, 2 cervical polyps, 1 negative for dysplasia, and 1 insufficient for diagnosis. The CIN 2/3 rate was 57.1% (12/21) based on the original ASC-H Pap diagnosis. The CIN 2/3 rates were 80% (8/10) with SIL cells on duplicate slides and 36.4% (4/11) without SIL cases on duplicate slides. Our study suggested that duplicate slides were very useful for further classification of ASC-H, but other ancillary tests might be necessary for some cases. We propose a systematic approach using combined duplicate slides and reflex HPV testing to further classify ASC-H.

Cervical thoracic duct cyst: Importance of preoperative suspicion for appropriate management of left-sided neck mass.

Cervical thoracic duct cysts occur infrequently but are an important consideration when evaluating cystic supraclavicular masses. Only 22 cases have been reported to date. We review the clinical presentation, evaluation, and treatment of 2 cases of large thoracic duct cysts treated with surgical resection. A high suspicion of thoracic duct cyst based on location, radiographic findings, and fine-needle aspiration results is sufficient evidence for recommendation of surgical excision. However, enlarged cysts, as noted in our cases, can obliterate or attenuate the thoracic duct, making it difficult to identify intraoperatively. A high suspicion of thoracic duct cyst is important for identifying and ligating the duct to prevent complications such as chyle leak or chylothorax.

Skull base osteomyelitis and bisphosphonate use in multiple myeloma: report of two cases and literature review.

OBJECTIVES: Although osteoradionecrosis of the mandible is a well known entity, skull base osteomyelitis involving the temporal bone unrelated to otitis externa in patients with multiple myeloma using bisphosphonates has not been reported. We described a new entity of skull base erosion resulting from osteonecrosis, presenting with malignant features in patients using bisphosphonates for multiple myeloma. METHODS: Two patients with multiple myeloma and prior zolendronic acid use were referred to our cancer center for management of maxillary and temporal bone masses with skull base erosion. Both patients were in remission and not immunocompromised. Clinical symptoms included pain, cranial nerve deficits, and vertigo. An oroantral fistula developed in the maxillary patient. In both cases, repeat CT and MRI revealed an eroding mass consistent with malignancy. After repeated biopsies, however, no malignancy was seen, and pathology revealed chronic inflammation with bacterial colonization. RESULTS: Imaging with technetium and gallium revealed osteomyelitis of the skull base in the temporal bone patient and actinomyces in the maxillary patient. Prolonged intravenous antibiotics resulted insignificant improvement in symptoms and imaging after eight weeks of treatment. CONCLUSION: Bisphosphonate-associated osteomyelitis and necrosis of the mandible has been described in recent literature as a diagnostic and management dilemma. However, skull base osteomyelitis from the temporal bone has not been reported, and few cases from the maxilla have been reported. Early recognition and differentiation from similarly presenting malignant disease may prevent intracranial complications resulting from delayed treatment.