Creation of a Quality Payment Program Measure for Mismatch Repair or Microsatellite Instability Biomarker Testing Status in Colorectal, Endometrial, Gastroesophageal, or Small Bowel Carcinoma.

CONTEXT.­: Quality measures that are supported by evidence-based clinical practice guidelines are preferred for assessing the quality of pathologists' practices. Careful testing of a measure ensures that scores obtained by that measure reflect the quality of a pathologist's practice. OBJECTIVE.­: To specify a new quality measure and to demonstrate through testing that it is suitable for measuring pathologists' appropriate incorporation of information regarding microsatellite instability (MSI) and/or mismatch repair (MMR) status in pathology reports for colorectal, endometrial, gastroesophageal, and small bowel carcinoma. DESIGN.­: The College of American Pathologists collaborated with the American Gastroenterological Association to specify and test the new measure. Face validity testing was used to investigate the validity of the measure. Feasibility testing was conducted to understand if data elements required by the measure specification were readily accessible. Signal-to-noise analysis was used to characterize the measure's reliability. RESULTS.­: Guideline recommendations for MSI and/or MMR testing supported specifications for the measure. Face validity testing indicated that the measure could distinguish the quality of care provided. Data elements required by the measure specification were found to be accessible, which supported the measure's feasibility. Reliability testing showed that differences in measure score were attributable to real differences in performance rather than random variation in scoring. CONCLUSIONS.­: The Mismatch Repair or Microsatellite Instability Biomarker Testing Status in Colorectal Carcinoma, Endometrial, Gastroesophageal, or Small Bowel Carcinoma measure was appropriately specified, and testing demonstrated that it is well suited for characterizing the quality of pathologists' communication of MMR and/or MSI status.

Alignment of Fellowship Training with Practice Patterns for Molecular Pathologists: A Report of the Association for Molecular Pathology Training and Education Committee.

In the two decades since Accreditation Council for Graduate Medical Education-accredited Molecular Genetic Pathology fellowships began, the field of clinical molecular pathology has evolved considerably. The American Board of Pathology gathered data from board-certified molecular genetic pathologists assessing the alignment of skills and knowledge gained during fellowship with current needs on the job. The Association of Molecular Pathology conducted a parallel survey of program directors, and included questions on how various topics were taught during fellowship, as well as ranking their importance. Both surveys showed that most training aligned well with the practice needs of former trainees. Genomic profiling of tumors by next-generation sequencing, bioinformatics, laboratory management, and regulatory issues were topics thought to require increased emphasis in training. Topics related to clinical genetics and microbiology were deemed less important by those in practice, perhaps reflecting the increasing subspecialization of molecular pathologists. Program directors still viewed these topics as important to provide foundational knowledge. Parentage, identity, and human leukocyte antigen testing were less important to both survey audiences. These data may be helpful in guiding future adjustments to the Molecular Genetic Pathology curriculum and Accreditation Council for Graduate Medical Education program requirements.

Vulvar seborrheic keratosis: is there a relationship to human papillomavirus?

OBJECTIVE: We sought to determine the prevalence of human papillomavirus (HPV) subtypes in vulvar seborrheic keratoses (SK) by polymerase chain reaction (PCR) in women with a theoretically low risk of recent HPV transmission. We also attempted to identify which histopathologic features best correlated with HPV and specific subtypes. METHODS: Twenty-eight cases of vulvar SK in women older than 50 years old were retrospectively pulled from our files from a 7-year period. Cases were histologically examined for the presence of 7 features: parakeratosis, horn cysts, pigmentation, "clonal" cells, papillomatosis, "whorls," and reticulation of rete. For controls, PCR was performed on all cases for HPV detection and typing. Ten cutaneous SK and 7 vulvar condyloma acuminata were also evaluated for HPV by PCR. RESULTS: Twenty-one vulvar SK had sufficient genetic material for HPV PCR analysis. Only 3 (14.29%) were positive for HPV, 2 were type 6, and 1 was an unknown type. All cutaneous SK were negative and all condyloma acuminatum were positive for HPV. There was no histologic feature that separated HPV-positive from HPV-negative vulvar SK, although there was a tendency for parakeratosis to be associated with HPV positivity. CONCLUSIONS: The rate of HPV positivity in vulvar SK in women older than 50 years is much lower than expected and not statistically significantly associated with specific histologic features. One explanation may be that vulvar SK have diminishing levels of HPV genetic material in the relatively older ages of the patients in our study. Alternatively, vulvar SK may have no relationship to HPV, and strict histologic criteria may separate vulvar SK from condyloma acuminatum. In this instance, the few cases of HPV-positive vulvar SK may reflect incidental persistence of HPV in vulvar epidermis. Furthermore, these possibilities may vary among different populations, for example, based on patient age.

Influenza a outbreak in an ambulatory stem cell transplant center.

BACKGROUND: In the era of cost-consciousness regarding healthcare , provision of medical services in an outpatient setting has become increasingly attractive. We report an influenza outbreak in an ambulatory stem cell transplant center in 2013 that highlights unique identification and infection control challenges in this setting. METHODS: Nasopharyngeal swabs were performed on patients with suspected influenza-like illnesses (ILI), defined by subjective fever or measured temperature of ≥37.7°C (≥100°F) with cough or sore throat during July 25, 2013 through August 7, 2013. In addition, testing was triggered by an elevated C-reactive protein (CRP). Specimens were analyzed by using eSensor Respiratory Viral Panel. Clinical and epidemiologic information was collected in real time, and frequencies were calculated on demographics, baseline clinical parameters, treatment methods, comorbidities, and symptoms of affected persons. RESULTS: Thirty-one patients had influenza A (H3N2) infection during July 25, 2013 through August 7, 2013. Only 7 patients (23%) met the Centers for Disease Control and Prevention and Council of State and Territorial Epidemiologists ILI case definition. Twenty-five patients (81%) had received ≥1 transplant, with 13 (42%) having occurred within 1 year before the outbreak. Twenty-five patients (81%) had received B-cell active chemotherapy <60 days before influenza diagnosis, 6 (19%) were neutropenic, and 25 (81%) lymphopenic. Among clinical and laboratory markers analyzed, abnormal CRP was the most sensitive screening tool for influenza. Twelve (39%) patients were hospitalized (median stay, 10 days; range, 2-20). No deaths occurred. CONCLUSIONS: Immunocompromised hosts with influenza have atypical presentations. Existing surveillance case definitions might be insufficient to reliably identify influenza outbreaks in such patients.

Phase II trial of dose-dense chemotherapy followed by dose-intense erlotinib for patients with newly diagnosed metastatic non-small cell lung cancer.

This phase II study investigated dose-intense erlotinib maintenance after dose-dense chemotherapy for patients with metastatic non-small cell lung cancer and examined two cell cycle biomarkers. Patients with newly diagnosed metastatic non-small cell lung cancer received docetaxel 75 mg/m² and cisplatin 75 mg/m² on day 1 and pegfilgrastim on day 2 every 14 days for four cycles. Patients then received erlotinib with initial doses based on smoking status. Doses were increased in 75 mg increments every two weeks depending on toxicities until each patient's maximal tolerable dose (MTD) was achieved. Cyclin D1 and D3 biomarkers were measured by immunohistochemistry. The objectives of the study were to evaluate time to progression (TTP) and overall survival (OS) for the entire population and biomarker subgroups. Forty-five patients were enrolled. Intra-patient erlotinib MTD ranged from 0 to 525 mg. Median MTD achieved in smokers was higher than in non-smokers (300 vs. 150 mg; P=0.019). TTP for the entire cohort was not significantly improved compared to historical controls. Patients with high cyclin D1 expressing tumors demonstrated improved TTP on erlotinib (8.2 vs. 4.7 months; hazard ratio, 4.1; 95% CI, 1.6-0.6; P=0.003) and improved OS (20.5 vs. 8.0 months; hazard ratio 2.8; 95% CI, 1.2-6.3; P=0.016). Intratumoral cyclin D3 expression did not impact clinical outcomes. Current smokers but not former smokers exhibit a higher erlotinib MTD. High cyclin D1 expression was associated with favorable TTP and OS.

Human papillomavirus detection: testing methodologies and their clinical utility in cervical cancer screening.

Human papillomavirus (HPV) is a well-studied etiologic agent for cervical cancer dysplasia and neoplasia. HPV E6 and E7 viral proteins drive oncogenesis by blocking the activity of pRB and p53, respectively. Consensus screening guidelines focus on appropriate use of both cervical cytology and HPV testing to reduce the morbidity and mortality associated with cervical cancer. HPV testing is indicated for women aged 21 to 64 years with atypical squamous cells of undetermined significance (ASC-US) on cytology. In women aged 30 to 64, testing is also indicated for routine screening in conjunction with cervical cytology. Various methods are available for HPV detection and several Food and Drug Administration-approved assays are on the market using either signal or target amplification methodologies. Most of the approved tests target DNA, but tests for mRNA detection are also available. Recently, assays for type specific detection of HPV types 16 and 18 have been Food and Drug Administration approved, and the use of genotyping has been incorporated into management algorithms. HPV testing can be performed on liquid-based cytology samples and options for automation are available making the introduction of HPV testing into many pathology laboratories possible.

Vanishing bile duct syndrome in human immunodeficiency virus infected adults: a report of two cases.

Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.

Aggressive angiomyxoma.

Aggressive angiomyxoma is a rare mesenchymal tumor that most commonly arises in the vulvovaginal region, perineum, and pelvis of women. The term aggressive emphasizes the often infiltrative nature of the tumor and its frequent association with local recurrence. Patients often present with nonspecific symptoms which are frequently misdiagnosed with more common entities, such as a Bartholin cyst, lipoma, or hernia. Histologic examination reveals a hypocellular and highly vascular tumor with a myxoid stroma containing cytologically bland stellate or spindled cells. The tumor cells are characteristically positive for estrogen and progesterone receptors, suggesting a hormonal role in the development of the tumor. Chromosomal translocation of the 12q13-15 band involving the HMGA2 gene has been described. Surgical excision is the treatment of choice, although treatment with gonadotropin-releasing hormone agonists is an emerging therapy. Metastases are exceedingly rare, and overall, the prognosis is good.

Microlithiasis, endoscopic ultrasound, and children: not just little gallstones in little adults.

PURPOSE: Biliary microlithiasis is an uncommon but recognized cause of upper abdominal pain, cholecystitis, cholangitis, and pancreatitis in adults. Gallstones smaller than 3 mm may not be seen on transabdominal ultrasound and may only be seen on endoscopic ultrasound. This condition is poorly described in children. The aim of this study is to review the results of laparoscopic cholecystectomy to treat biliary microlithiasis in a pediatric case series. METHODS: We performed a retrospective case review of children with biliary microlithiasis who were treated with laparoscopic cholecystectomy. RESULTS: Three children were diagnosed with biliary microlithiasis. Two patients had recurrent right upper quadrant pain and nausea. A third patient had midepigastric pain and idiopathic pancreatitis. All 3 had a normal gallbladder on transabdominal ultrasound. Additional imaging with hepatobiliary scan, computed tomography, and magnetic resonance cholangiopancreatography revealed no biliary source for symptoms. Endoscopic ultrasound was performed on all 3 children, demonstrating microlithiasis of the gallbladder. Each child had a laparoscopic cholecystectomy with intraoperative cholangiogram. No abnormalities were seen on intraoperative cholangiogram. All 3 children had alleviation of pain and improvement of symptoms in postoperative follow-up. CONCLUSION: Children with biliary microlithiasis and associated clinical symptoms can be successfully treated with laparoscopic cholecystectomy. Endoscopic ultrasound should be considered in the evaluation of the child with clinical biliary symptoms and a negative transabdominal ultrasound result.

Human papillomavirus detection in head and neck squamous cell carcinomas.

Squamous cell carcinomas of the head and neck (HNSCC) are a frequent diagnosis in anatomic pathology practice. Tobacco use and heavy alcohol consumption are known risk factors for HNSCC but in other cases human papillomavirus (HPV) is linked to carcinogenesis. HPV proteins E6 and E7 promote oncogenesis by blocking the action of p53 and pRB, respectively. An absence of p53 mutations in addition to expression of p16 are part of the distinct molecular profile identified in the subset of HNSCCs because of HPV. Various methods are available for HPV detection but polymerase chain reaction and in situ hybridization techniques are commonly used. Both methods are amenable for testing formalin-fixed paraffin-embedded tissue that is a sample type readily available to the pathologist. HPV is detectable in approximately a quarter of all HNSCCs, and is particularly prevalent in the oropharynx in which the positivity rates approach 40%. A vast majority of HPV-related HNSCCs are owing to HPV type 16 with types 18, 31, and 33 accounting for almost all of the remaining cases. HPV-related HNSCCs are associated with better prognosis for both recurrence and survival. This group of tumors has also been shown to respond well to radiation treatment. As the clinical relevance of HPV in HNSCCs continues to emerge, anatomic pathologists are likely to receive increasing requests for testing. Herein, the authors review the biological and clinical aspects of HPV-associated HNSCC and review techniques for HPV detection.

Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib.

In imatinib-treated chronic myeloid leukemia (CML), secondary drug resistance is often caused by mutations in the BCR-ABL kinase domain (KD). As alternative therapies are available for imatinib resistance, early identification of mutations may prevent disease progression. Because most patients are routinely monitored by BCR-ABL quantitative polymerase chain reaction (PCR), it is important to define the optimal increase in BCR-ABL that should trigger mutation testing. Expert panels have provisionally recommended a 10-fold BCR-ABL increase as the trigger for mutation screening, acknowledging the lack of consensus. To address this question, we monitored 150 CML patients by quantitative PCR and DNA sequencing. Thirty-five different mutations were identified in 53 patients, and, during 22.5 months (median) of follow-up after sequencing, mutations were significantly predictive of shorter progression-free survival. An unbiased receiver operating characteristic analysis identified a 2.6-fold increase in BCR-ABL RNA as the optimal cutoff for predicting a concomitant KD mutation, with a sensitivity of 77% (94% if including subsequent samples). The 2.6-fold threshold approximated the analytic precision limit of our PCR assay. In contrast, transcript rise cutoffs of 5-fold or greater had poor diagnostic sensitivity and no significant association with mutations. We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable.

Testicular relapse of non-Hodgkin Lymphoma noted on FDG-PET.

Testicular relapse of leukemia and lymphoma is a well-recognized phenomenon, with testicular relapse of lymphoma being more common in the adult population and leukemia relapse being more common in the pediatric population. With the advent of F-18 fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in the evaluation of lymphoma it is possible to evaluate testicular uptake of FDG and to detect primary testicular lymphoma or testicular relapse on the FDG-PET examination. Testicular relapse of non-Hodgkin lymphoma (NHL) detected on FDG-PET has been reported previously. We report an additional case in which there was testicular activity at presentation, a response to therapy (orchiectomy not performed) and then testicular relapse followed by orchiectomy. We review the literature with regard to testicular recurrence and testicular uptake of FDG-PET. There have been studies that have examined normal standardized uptake value maximum (SUVmax) values in the testicle, with normal values ranging from 2.81 (30-39 years) to 2.18 (80-89 years), depending upon age. However, it should be noted that there could be considerable variability in SUVmax values depending upon the units used (e.g. normalized to lean body mass vs. body weight) and depending upon examination variables such as dietary conditions, muscle uptake or extravasation of FDG. Elevated activity or lateralizing activity should be viewed with suspicion, with etiologies including primary testicular tumor, primary or secondary testicular lymphoma and metastatic disease with other etiologies less likely.

An intron-derived insertion/truncation mutation in the BCR-ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy.

Although targeted inhibition of BCR-ABL with imatinib is an effective therapy for patients with chronic myeloid leukemia (CML), a minority of patients acquire mutations in the BCR-ABL kinase domain, resulting in imatinib resistance. The spectrum of kinase domain mutations discovered to date is quite heterogeneous, consisting almost exclusively of single nucleotide substitutions affecting key amino acids that regulate drug binding or BCR-ABL function. Here, we describe an alternative kinase domain insertion/truncation mutation in three CML patients undergoing kinase inhibitor therapy. In each of these patients, direct DNA sequencing of BCR-ABL RT-PCR products revealed that the same 35 nucleotides from ABL intron 8 had been inserted at the normal exon 8 to 9 splice junction. This 35-bp intronic sequence was flanked by excellent consensus splice donor and acceptor sequences, suggesting alternative splicing as the likely mutational mechanism. The insertion created a premature translational stop codon after 10 intron-encoded amino acids (amino acid 484). This resulted in truncation of 653 C-terminal amino acids, which included part of the kinase domain and the entire "last exon" region. These findings demonstrate that kinase domain insertions are an alternative (and not entirely uncommon) mutational mechanism in CML patients undergoing kinase inhibitor therapy.

HER2 testing: a review of detection methodologies and their clinical performance.

The ERBB2 proto-oncogene, commonly referred to as the human epidermal growth factor receptor-2 (HER2) gene, encodes a 185 kd receptor tyrosine kinase. Overexpression of the protein leads to constitutive activity of the HER2 receptor and breast tumor development through enhanced cell proliferation, survival, motility and adhesion. Overabundance of the HER2 receptor, typically caused by amplification of the HER2 gene, is present in approximately 10-30% of invasive breast cancers, and is associated with an aggressive disease course and decreased disease-free and overall survival in node-positive patients. Tratuzumab, a humanized murine monoclonal antibody, offers a targeted treatment modality for tumors that over express the HER2 protein. Tratuzumab, shown to be effective and initially approved for treatment of metastatic breast cancer, has recently been shown to be very effective in the adjuvant setting. Thus, to offer prognostic information and to direct appropriate treatment it is important to provide accurate laboratory assessment of the status of HER2. This article provides an overview of the methods currently used to assess HER2.

Fluorescence in situ hybridization for detecting transitional cell carcinoma: implications for clinical practice.

OBJECTIVE: To determine the diagnostic sensitivity of genetic studies using fluorescence in situ hybridization (FISH) for detecting both new and recurrent cases of transitional cell carcinoma (TCC) in a routine clinical practice setting, as bladder cancer has a significant risk of recurrence and progression to invasive disease and thus sensitive surveillance testing is very important. PATIENTS AND METHODS: FISH was performed using the UroVysion kit (Vysis Inc., Downers Grove, IL, USA) Consecutive patients were assessed using FISH, both to evaluate those with a history of TCC or with suspicious symptoms, and the FISH results were compared with concurrent biopsy and cytological assessments. RESULTS: In all, 521 consecutive FISH tests from 300 patients were evaluated; 47% had a history of bladder cancer and 53% had suspicious symptoms. Of the 521 FISH tests, 24% were positive; concurrent cytology was available for 84% of the FISH tests, with a concordance rate of 78% (6% were positive for both and 72% were negative by both tests). For the discordant cases, FISH was positive and cytology negative in 21% of cases, and cytology was positive with a negative FISH for 1%. In all, 99 FISH tests had concurrent biopsy data. Of the 44 cases histologically positive for TCC, 32 were FISH-positive, resulting in an overall sensitivity (95% confidence interval) of 73 (60-88)%. FISH detected 95% of cases with high-grade carcinoma, while only seven of these 17 were positive by concurrent cytological assessment. FISH detected 56% and cytology detected 32% of low-grade lesions. FISH detected all nine new cases with positive histology. Overall, the specificity of FISH was 65 (53-78)%. Of 112 patients with previous TCC, 28 had a recurrence; 22 of these had positive FISH results. CONCLUSION: FISH analysis has a high sensitivity for detecting new cases of TCC, as well as recurrences. From the present data FISH is considerably more sensitive and only slightly less specific than cytology in diagnosing TCC. Therefore, we recommend FISH as a useful initial diagnostic tool in patients suspected of both new and recurrent TCC.