Rodney A. Schmidt

Thyroid Transcription Factor-1 Is Expressed in Extrapulmonary Small Cell Carcinomas but Not in Other Extrapulmonary Neuroendocrine Tumors

Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription factor that is expressed in the developing thyroid, respiratory epithelium, and diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or thyroid neoplasms, and it is expressed in a significant subset of pulmonary non–small cell carcinomas, small cell carcinomas, and carcinoids but not in nonpulmonary, non–small cell carcinomas. Neuroendocrine tumors from sites other than the lung have not been evaluated for TTF-1 expression. We examined TTF-1 expression using immunohistochemistry on formalin-fixed, paraffin-embedded sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21 paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous neuroendocrine) carcinomas; and 1 renal carcinoma. No gastrointestinal carcinoid tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma expressed TTF-1. All of the medullary thyroid carcinomas strongly expressed TTF-1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive, including four of four prostate, two of four bladder, and one of seven cervical small cell carcinomas. We conclude that TTF-1 expression is not specific for small cell carcinomas of pulmonary origin and should not be used to distinguish primary from metastatic small cell carcinomas in extrapulmonary sites. However, TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and cutaneous metastasis of small cell carcinomas. Among well-differentiated neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid tumors of the lung and medullary carcinomas of the thyroid and may be of differential diagnostic value when dealing with a metastatic well-differentiated neuroendocrine tumor.

Poorly differentiated synovial sarcoma : Immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors

Synovial sarcoma is a relatively common sarcoma in adults, which in its classic bimorphic form infrequently poses a diagnostic problem. Monomorphic spindled variants, as well as the less common poorly differentiated variants, may be confused with other soft-tissue sarcomas; the poorly differentiated variant (PDSS), in particular, may be histologically indistinguishable from other small, blue, round cell tumors, including primitive neuroectodermal tumors (PNETs). Detection of the synovial sarcoma-associated t(X;18) by either cytogenetic or molecular genetic approaches may be necessary to confirm the diagnosis of synovial sarcoma in difficult cases. We evaluated 10 cases of PDSS from eight patients using a panel of antibodies (including those to intermediate filament proteins, nerve-sheath associated markers, and neuronal and neuroectodermal associated markers) in order to better establish the immunophenotype of this tumor and to help distinguish it from the tumors with which it may be confused, particularly PNETs and high-grade malignant peripheral nerve sheath tumors (MPNSTs). Our results showed PDSS to have significant immunophenotypic overlap with both PNETs and MPNSTs. In most instances these three entities may be differentiated by a panel of antibodies that should include those to both low and high molecular weight cytokeratins, epithelial membrane antigen, type IV collagen, CD99, CD56, and S-100 protein. Our results also suggest that synovial sarcoma may be a tumor showing combined neuroectodermal and nerve sheath differentiation--perhaps because of translocation-associated expression of specific proteins--rather than a carcinosarcoma of soft tissues or a tumor of specialized arthrogenous mesenchyme.

Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

PURPOSE The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization. RESULTS Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.

High resolution CT in respiratory bronchiolitis-associated interstitial lung disease

High-resolution CT findings have been described for several diffuse lung diseases. Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is an inflammatory lung disorder associated with cigarette smoking. This condition has only recently been described and distinguished from desquamative interstitial pneumonitis, which it closely resembles. We describe high-resolution CT findings in five cases of biopsy-proven RB-ILD. The findings are variable and range from no detectable abnormality to atelectasis, ground-glass opacities, emphysema, and linear and reticular interstitial abnormalities.

Relationship Between Non-small Cell Lung Cancer FDG Uptake at PET, Tumor Histology, and Ki-67 Proliferation Index

Introduction: We compared primary non-small cell lung cancer (NSCLC) 18F-fluorodeoxyglucose (FDG) uptake at positron emission tomography (PET) to tumor histologic features and Ki-67 proliferation index. This large, prospectively-recruited patient cohort has previously been analyzed based on differences in FDG uptake across stage groups; the current analysis adds further dimensions to this characterization. Materials and Methods: One hundred seventy-eight patients with potentially-resectable NSCLC were scanned with FDG PET before therapy. A partial volume correction algorithm was used to correct FDG uptake values for their dependence on tumor size. Primary tumor resection specimens, core biopsies, and biopsies of metastatic lymph nodes were used to assess each tumor’s NSCLC histologic subtype, degree of differentiation, and Ki-67 proliferation index. Results: Bronchioalveolar carcinomas were found to have lower FDG uptake at PET and lower Ki-67 scores than any other histologic subtype. Non-bronchioalveolar adenocarcinomas had lower FDG uptake and Ki-67 scores than squamous cell carcinomas or large cell undifferentiated carcinomas. Better differentiated NSCLCs had lower FDG uptake and Ki-67 scores than more poorly differentiated NSCLCs. There was a significant positive correlation between FDG uptake and Ki-67 scores. Partial volume correction increased the strength of this correlation, while also diminishing the strong positive correlation between FDG uptake and tumor size. Conclusions: There are significant differences in NSCLC FDG uptake across histologic subtypes and differentiation groups. These differences parallel nearly identical differences in Ki-67 scores, implying that differences in NSCLC tumor cell proliferation may give rise to commensurate differences in tumor glucose metabolism.

Head and neck osteosarcoma at the University of Washington

Head and neck osteosarcoma is a comparatively rare and aggressive malignancy. Our goal was to examine the experience of head and neck osteosarcoma patients seen over a 15‐year period at the University of Washington Medical Center and compare this with the published experience of other centers in terms of demographics, histology, treatment, and survival rate.

Antibody-Mediated Depletion of Tumor Necrosis Factor-α Impairs Pulmonary Host Defenses to Legionella pneumophila

Tumor necrosis factor-alpha (TNF-alpha) has been shown to stimulate the resistance of alveolar macrophages and neutrophils to Legionella pneumophila in vitro. To determine whether endogenous TNF-alpha is necessary for host defense against legionellosis in vivo, anti-TNF-alpha IgG or control IgG was administered to rats exposed to aerosolized L. pneumophila. Treatment with anti-TNF-alpha neutralized >90% of the intrapulmonary TNF-alpha response to infection, resulting in persistent pneumonitis and failure to clear L. pneumophila from the lungs. Depletion of TNF-alpha limited the recruitment of mononuclear cells to the lungs and resulted in a progressive increase in the proportion of alveolar macrophages that were infected; neutrophil recruitment and phagocytosis were not impaired. Both systemic and intrapulmonary IFN-gamma levels were significantly higher in rats depleted of TNF-alpha. These observations indicate that TNF-alpha is required for the prompt resolution of pneumonic legionellosis and point to a direct role for TNF-alpha in the activation of phagocytes.

Achieving 95% Cross-Methodological Concordance in HER2 Testing Causes and Implications of Discordant Cases

We were interested in determining our concordance between fluorescence in situ hybridization (FISH) and a previously validated immunohistochemical HER2 assay to identify possible reasons for discordance and to determine if all reasons for discordance were addressed by the American Society of Clinical Oncology/College of American Pathologists guidelines. We reviewed 697 cases (2004-2007) in which HER2 immunohistochemical and FISH testing were concurrently done. Overall concordance between nonequivocal immunohistochemical and FISH results was 96%. Of the 19 discordant cases, 13 (68%) were interpreted as positive immunohistochemically but negative by FISH. The primary reason for this discordance was immunohistochemical interpretation. Weak stain intensity, granular staining, and interpretation in areas of crush artifact were identified as the most common issues. Of the 6 cases interpreted as immunohistochemically negative and FISH-positive, 2 were from patients known to be receiving trastuzumab at the time of biopsy, 1 was very close to the FISH equivocal category, and 4 cases had fewer than 1.5 CEP17 signals per cell (1 patient in this group was also receiving trastuzumab). Focusing on issues with HER2 immunohistochemical interpretation can improve concordance rates for immunohistochemically positive cases, but biologic reasons may explain some discordant immunohistochemically negative cases.

The p75 neurotrophin receptor, relative to other Schwann cell and melanoma markers, is abundantly expressed in spindled melanomas

Seventeen cases of spindled melanomas and eleven cases of epithelioid melanomas were immunolabeled with various melanoma and Schwann cell markers. Standard melanoma markers included S100, HMB45, HMB50, tyrosinase, and Melan A. Schwann cell markers included the p75 neurotrophin receptor (p75NTR), glial fibrillary acidic protein (GFAP), and the L1 adhesion protein. The degree of immunocytochemical labeling was scored by levels of both intensity and pervasiveness. The results confirmed a distinct difference in labeling between epithelioid and spindled melanomas. The p75NTR was strongly expressed in spindled melanomas and weakly expressed in the epithelioid melanomas. The usual melanoma markers, including HMB45, HMB50, MelanA, and tyrosinase had the reverse pattern, being strongly expressed in virtually all epithelioid melanomas, but rarely expressed in the spindled variants. S100 was unique among the markers in being expressed by both epithelioid and spindled melanomas. Glial fibrillary acidic protein and L1 adhesion protein were expressed moderately, with preferential labeling of the spindled melanomas. The greatest immunophenotypic difference between spindled and epithelioid melanomas was the high abundance of p75NTR expression in spindled melanomas. The functional significance of the high level of p75 neurotrophin receptor expression may contribute to the high predisposition of perineural extension in the desmoplastic subset of spindled melanomas.

Use of the argon beam electrocoagulator for performing pulmonary wedge resections.

The argon beam electrocoagulator (ABC) is a new form of electrocautery that is thought to be more effective than standard electrocautery. It has been used primarily in procedures associated with major blood loss such as liver transplantation and laparotomy for trauma. It has not been used in thoracic operations. We evaluated the safety and efficacy of the argon beam electrocoagulator for performing pulmonary wedge resections in an animal model by comparing it with standard electrocautery and suture closure. Variables used to compare the three methods of resection included perioperative blood loss, duration of chest tube air leak, and depth of necrosis and severity of inflammatory reaction in the lung at ten days and 3 weeks after resection. The argon beam electrocoagulator was as effective as standard electrocautery and suture closure in controlling air leaks, and caused less acute tissue injury than standard electrocautery. The argon beam electrocoagulator provides a safe and effective method for performing small pulmonary wedge resections, and should be evaluated in the clinical setting for this purpose.