Allan L. Abramson

Laryngeal Papillomavirus Infection during Clinical Remission

Biopsy samples from 20 patients with a history of laryngeal papillomas were analyzed by Southern blot hybridization for the presence of human papillomavirus DNA. All papillomas examined contained papillomavirus DNA sequences. Four samples from uninvolved sites in two patients with active disease and eight samples from patients in remission also contained viral DNA. No human papillomavirus DNA was detected in a third patient seen during remission. These results explain the clinical pattern of frequent recurrences even after long-term remission in laryngeal papillomatosis.

Laryngeal papillomatosis: Clinical, histopathologic and molecular studies

The clinical course and pathology of 57 patients with laryngeal papillomatosis were reviewed. Tissues from 26 patients were analyzed for human papillomavirus (HPV) DNA by Southern blot hybridization. Histopathologic evaluation of the papillomas showed no correlation with age of onset or clinical pattern of remission and recurrence. The pathology was characterized by abnormal squamous maturation with parakeratosis, retardation of superficial cell maturation, papillomatosis, and basal hyperplasia. HPV DNA was present in all lesions, with 92% containing either HPV‐6 or 11. Latent HPV DNA was detected in clinically uninvolved tissues of 11 of 14 (78.5%) patients studied. There was no correlation between HPV type, histopathology and/or clinical pattern. Despite homogeneity of pathology, the clinical expression of laryngeal HPV infection varied widely. A mechanism for the pathogenesis of laryngeal papillomatosis, based on the concept of maturational arrest, is proposed.

Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to human papillomavirus‐6 and ‐11

Bonagura VR, Hatam LJ, Rosenthal DW, DeVoti JA, Lam F, Steinberg BM, Abramson AL. Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to human papillomavirus‐6 and ‐11. APMIS 2010; 118: 455–470.

Efficacy of DHE photodynamic therapy for respiratory papillomatosis: immediate and long-term results.

Objectives/Hypothesis: Recurrent respiratory papillomatosis is a potentially life‐threatening disease that affects both children and adults and can result in complete respiratory obstruction. Conventional therapies cannot prevent multiple recurrences. The authors have been evaluating photodynamic therapy (PDT) to treat this disease since 1988. This study compared the efficacy of PDT with dihematoporphyrinether (DHE) with traditional therapy. Study Design: This was a randomized prospective trial of DHE‐PDT. Patients were randomly assigned to receive one of two doses of DHE—3.25 mg/kg or 4.25 mg/kg body weight. They were compared with a concurrent control group. Disease extent was evaluated by direct laryngoscopy before treatment and over a 1‐year period following treatment. Results were also compared with two historical cohorts of patients treated with lower doses of DHE. Methods: Eighty‐one patients, ages 4 to 74 years, with moderate to severe recurrent disease were enrolled. Forty‐eight received PDT and 33 in the control group were treated with conventional therapy. Both PDT groups received 50 J laser light to activate the drug. Patients received an intravenous infusion of DHE as outpatients 48 to 72 hours before treatment. During direct laryngoscopy, light (630 nm) was delivered by an argon‐pumped dye laser. Tissue biopsies were analyzed for presence of human papillomavirus (HPV). Results: There was notable improvement with either drug dose over the first year. Those receiving 4.25 mg/kg DHE experienced a significantly larger decrease in papilloma growth rate. Three‐year follow‐up of a subset of patients confirmed that improvement was maintained. There was no impact of DHE‐PDT on persistence of HPV DNA. Conclusion: This therapy holds promise for the treatment of laryngeal papillomas.

Human papillomavirus type 6a DNA in the lung carcinoma of a patient with recurrent laryngeal papillomatosis is characterized by a partial duplication

Transcriptionally active human papillomavirus type 6a (HPV-6a) DNA was detected in a lung carcinoma of a patient with recurrent laryngeal papillomatosis. The carcinoma contained episomal HPV-6a genomes that had a duplication of the upstream regulatory region, the late region and a portion of the early region. HPV-6a genomes found in benign laryngeal papillomas from the same patient did not contain this duplication. A role for the mutant molecules in the pathogenesis of the malignancy is suggested.

Endolaryngeal jet ventilation: A 10‐year review

Jet ventilation for microsurgery of the larynx has been in common use at our institution since 1978. There were 942 cases performed, with ages ranging from 7 days to 90 years. A specially modified laryngoscope with multiple ports into which a 14‐ or 16‐gauge ventilation needle can be advanced just distal to the vocal cords simplifies this form of anesthesia and ventilation.

Frontal sinusitis and its intracranial complications

Although there has been a significant decrease in the incidence of frontal sinus disease since the advent of antibiotics, frontal sinus infection still occurs and may follow a clinical course not unlike that seen during the preantibiotic era. Secondarily to cranial and intracranial invasion the following complications may occur: osteomyelitis, cavernous sinus thrombosis, meningitis, extradural, subdural and cerebral abscess. The proximity of the frontal sinus to both the dura and the marrow of the frontal bone, as well as a rich communicating venous system, lends support to the facility of intracranial extension. Classically, frontal sinusitis presents with headache or pain usually following an upper respiratory infection. Purulent nasal discharge may be noted on physical examination. Roentgenographic studies will show opacification or an air-fluid level within the sinus. We present 4 cases of intracranial complications of frontal sinusitis seen in male adolescents. It is our contention that this disease bears a notable preponderance in males; a postulation that appears to be substantiated in the literature. Frequently even the classic signs and symptoms of frontal sinusitis may be undetected, which indicates that certainly the more subtle presentation of this disease may escape diagnosis during the course of examination. The use of CT scanning has proved an invaluable tool in the diagnosis of both frontal sinusitis and intracranial involvement. The importance of its incorporation into the diagnostic workup of the patient with frontal sinus disease cannot be overemphasized. We advocate aggressive medical and surgical management for all adolescents presenting with frontal sinusitis in an attempt to avoid possible intracranial complications.

Activating killer cell immunoglobulin-like receptors 3DS1 and 2DS1 protect against developing the severe form of recurrent respiratory papillomatosis

The polymorphic killer cell immunoglobulin-like receptors (KIR) control natural killer (NK) cell response against viral infection and tumor transformation. Here we investigated if select KIR genes are associated with recurrent respiratory papillomatosis (RRP), a rare disease of the larynx and upper airway caused by human papillomaviruses (HPV)-6/11. DNA from 66 RRP patients and 195 healthy controls were characterized for KIR and HLA gene polymorphism. Patients lacking activating KIR genes 3DS1 and 2DS1 were more common in severe RRP compared with mild-moderate RRP (78.8% vs 48.5%, p = 0.019). Further, patients carrying any of the known susceptible HLA-DRB1/DQB1 alleles were more frequently negative for KIR3DS1 (p = 0.006), KIR2DS1 (p = 0.003) or KIR2DS5 (p = 0.004) compared with controls carrying any of these HLA allotypes. Nearly 80% of the patients with severe disease were missing the protective HLA-DQB1*0602 allele as well as both KIR3DS1 and KIR2DS1 genes. Phenotyping of papilloma-infiltrating mononuclear-cells revealed an elevated numbers of NK cells and CD57(+)CD4(+) T cells in KIR3DS1(-)KIR2DS1(-) patients compared with patients carrying either one or both of these KIRs. Our data suggest that NK cells expressing activating receptors KIR3DS1 and KIR2DS1 may be necessary to trigger an effective early immune response against HPV-infected targets to establish resistance to RRP development.

Anterior-Posterior and Medial Compression of the Supraglottis: Signs of Nonorganic Dysphonia or Normal Postures?

Two vocal tract postures commonly identified as hallmarks of nonorganic dysphonia are anterior-posterior and medial compression of the supraglottis. However, insufficient data exist to support their diagnostic utility. The purpose of this study was to compare these two postures in patients with nonorganic dysphonia and normal controls using interval data derived from quantitative measures of videostroboscopic images obtained with an oral endoscope. Retrospectively, 40 patients with nonorganic dysphonia and 40 normal controls were selected. Relative anterior-posterior compression (LO(AP)) was calculated as the laryngeal outlet (LO) (the view of the true vocal folds during phonation) normalized to the anterior-posterior dimension in pixels. Relative ventricular fold medial compression (LO(w)) was calculated as the laryngeal outlet normalized to the medial dimension in pixels. Results were as follows: (1) LO(AP) was significantly greater for the dysphonic group, (2) the range of LO(AP) values between the two groups overlapped considerably, (3) no significant difference was found between groups for LO(w), (4) the correlation between LO(AP) and LO(w) within each subject yielded r values of 0.71 and 0.67 for the nonorganic dysphonia and normal control groups, respectively. It is concluded that medial compression of the ventricular folds can be a normal laryngeal posture, and that although anterior-posterior compression is present in greater degree in dysphonics, it is sufficiently common in normals to question its utility as a diagnostic sign of phonatory dysfunction.

Immune Dysregulation and Tumor-Associated Gene Changes in Recurrent Respiratory Papillomatosis : A Paired Microarray Analysis

Recurrent respiratory papillomas (RRP) are benign airway tumors, caused primarily by human papillomaviruses (HPV) types 6 and 11.The disease is characterized by multiple recurrences after surgical removal, with limited effective therapy. To identify novel targets for future therapy, we established transcriptional profiles for actively growing papillomas compared with autologous, clinically normal, laryngeal epithelia (adjacent tissue). Total ribonucleic acid (RNA) from 12 papillomas and 12 adjacent tissues were analyzed by microarray, and the matched sets of tissues compared by paired t test, to identify differentially expressed genes in papilloma tissues while minimizing variations intrinsic to individual patients. Quantitative polymerase chain reaction (PCR) was used to confirm the relative expression levels for a subset of genes. Within the 109 differentially expressed transcripts whose expression varied at least three-fold were two large groups of genes with related functions. The first group consisted of 18 genes related to host defense, including both innate and adaptive immunity. The second group contained 37 genes that likely contribute to growth of papillomas as benign tumors, since the altered pattern of expression also had been reported previously in many cancers. Our results support our previous studies that document a systemic TH2-like adaptive immune response in RRP, and suggest that there is a role for altered innate immunity in RRP as well. We propose that HPV 6 and 11 infection establishes a tumorigenic microenvironment characterized by alteration of both innate inflammatory signals and adaptive immune responses that prevent effective TH1-like response, in conjunction with altered expression of numerous genes that regulate cellular growth and differentiation.