The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease.

BACKGROUND: The impact of combination therapy on disease-related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well-defined. AIM: To examine the effect of combination therapy on disease outcomes in CD and UC. METHODS: Using a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti-TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD-related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders. RESULTS: We included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63-1.22) or UC (OR: 1.45, 95% CI: 0.63-3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37-0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14-0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45-1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti-TNF biologics. CONCLUSION: The benefit of combination immunomodulator-biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.

Colorectal cancer in women: hormone replacement therapy and chemoprevention.

Colorectal cancer (CRC) accounts for 9.4% of new cancer diagnoses among women world-wide. CRC is the third leading cause of incident cancer among women in the United States and has immense impact on morbidity and mortality. We summarize data on CRC pathogenesis and risk in women. We also review the findings from the Women's Health Initiative (WHI) on CRC risk reduction associated with hormone replacement therapy (HRT) use. We then review observational studies since the WHI which evaluated HRT as a chemopreventive agent for CRC among women. The potential mechanisms behind the association between HRT use and CRC are also reviewed. We then discuss the requirements for implementation of chemopreventive agents, and why HRT should not be used for this indication given current knowledge. Further data on the risk-benefit profile of short-term HRT use are needed and will determine whether there is any future role for HRT use in the chemoprevention of CRC.

Imaging characteristics of primary laryngeal lymphoma.

BACKGROUND AND PURPOSE: The larynx is a rare site for primary NHL. Fewer than 100 cases have been reported in the literature, with the largest imaging review involving only 4 patients. We describe the findings of laryngeal lymphoma on CT, PET, and MR imaging and identify features that may distinguish laryngeal lymphoma from the far more common laryngeal squamous cell carcinoma. MATERIALS AND METHODS: Multi-institutional retrospective chart review revealed 20 patients with histopathologically proved laryngeal lymphoma. Pretreatment CT, PET, and MR images were reviewed by a head and neck radiologist, focusing on extent of tumor, cervical lymph node involvement, and enhancement patterns. RESULTS: Patients ranged from 30 to 90 years of age with a mean of 63 years at the time of initial diagnosis and a 2:1 female predominance. The average tumor size was 37 +/- 19 mm. In all patients, laryngeal lymphoma involved the supraglottis but also extended into the glottis (65%) and hypopharynx (60%). The subglottis was less frequently involved (35%). Laryngeal cartilage invasion and cervical lymphadenopathy were each seen in 20% of patients. Lymphoma was consistently FDG-avid (100%) and usually enhanced uniformly with iodinated contrast (73%). Necrosis and calcification were not seen in any cases. CONCLUSIONS: Although laryngeal lymphoma is rare, particular imaging features suggest this diagnosis. A large uniformly enhancing supraglottic tumor without central necrosis and without cervical lymphadenopathy is a characteristic finding of lymphoma. Similar to squamous cell carcinoma, lymphoma may extend into the subglottis, pharynx, and laryngeal cartilages.

Mucoepidermoid carcinoma of upper aerodigestive tract: clinicopathologic study of 78 cases with immunohistochemical analysis of Dicer expression.

MicroRNAs (miR) are small noncoding RNAs that are predicted to regulate up to 30% of protein-encoding genes. miR maturation requires functional microRNA machinery, including the Dicer protein. We review our experience with mucoepidermoid carcinoma (MEC) and characterize the prognostic value of Dicer expression. Expression of Dicer was assessed in 78 MEC by immunohistochemistry. Dicer expression was scored semiquantitatively and relative to the internal controls: large excretory/striated ducts or basal/parabasal layers of normal squamous epithelium (mucosa). Dicer scores were then correlated with clinical and pathologic parameters. Dicer over- and/or under-expression were more commonly seen in high-grade MEC (83%) than in low/intermediate grade MEC (35%; p=0.002) and in stage III/IV MEC (80%) than in stage I/II MEC (41%; p=0.04). Abnormal Dicer expression correlates with high-grade and advanced stage, acting as a univariate predictor of poor disease-specific survival (DSS) in MEC. Age and stage were independent predictors of poor DSS on multivariate analysis. Abnormal immunoexpression of Dicer in aggressive MEC suggests a role for miR and miR machinery in tumor progression.

Eagle syndrome produced by a granular cell tumor.

Eagle syndrome includes elicitation of pain on swallowing, turning the head, or extending the tongue. The syndrome is thought to be caused by irritation of the glossopharyngeal nerve, most commonly caused by its impingement against an elongated styloid process. We present a rare case of a granular cell tumor presenting as Eagle syndrome. Granular cell tumors orignate from Schwann cells and are most common in the subcutaneous tissue of the head, neck, and oral cavity, especially the tongue. A granular cell tumor is typically benign and solitary, rarely malignant. The differential diagnosis, diagnostic algorithm, and treatment are presented.

Cytokeratin immunophenotyping of an unusual cervical vertebral chordoma with extensive chondroid foci and perilaryngeal recurrence: a case report with review of the literature.

Chordomas are midline, slowly growing, and locally destructive tumors derived from vestigial remnants of the notochord. We present an unusual case of a cervical vertebral chordoma with extensive chondroid change that aggressively recurred in the anterior larynx and surrounding neck structures, and subsequently in the mediastinum, resulting in the death of the patient. Recent literature has investigated and debated the significance of chondroid elements in chordomas as a differential diagnostic and a prognostic indicator. In particular, the use of immunohistochemical stains for cytokeratin and mesenchymal markers in these areas as a means of distinguishing true from pseudocartilage has received much attention. In this study, we used a spectrum of cytokeratin subtypes (CK 7, 20, 5/6, AE1/3) to further characterize these chondroid areas, and observed that they were positive for the majority of the cytokeratin subtypes, suggesting pseudo, rather than true, cartilaginous change. Clinicopathologic features of this lesion and the recent literature are reviewed.

Frequent allelic imbalance and loss of protein expression of the DNA repair gene hOGG1 in head and neck squamous cell carcinoma.

Reactive oxygen species produced by aerobic cellular metabolism or through exposure to environmental carcinogens can cause oxidative DNA damage by generating DNA base lesions and strand breakage. Prime among these base lesions is the conversion of guanine to 8-oxoguanine. Among 20 or so oxidative DNA base lesions, 8-oxoguanine is the most abundant and is critical in terms of mutagenesis because it is capable of mispairing with adenine, which, if not sufficiently repaired, may lead to G:C to T:A transversion upon DNA replication. The gene encoding human 8-oxoguanine DNA glycosylase 1 (hOGG1), capable of excision repair of 8-oxoguanine, has been recently cloned, characterized, and mapped to the short arm of chromosome 3 (3p25-26), a region showing frequent loss of heterozygosity (LOH) in head and neck squamous cell carcinoma (HNSCC). In the present study, we developed a tissue microdissection approach designed for use with formalin-fixed, paraffin-embedded specimens which is capable of detecting and characterizing the hOGG1 allelic loss using two highly informative, intragenic single nucleotide polymorphisms. Among 45 cases of HNSCC, 18 cases were informative. We analyzed these 18 cases and found that 11 showed evidence of hOGG1 allelic loss. By immunohistochemical staining on a total of 71 HNSCC cases using a commercially available anti-hOGG1 antibody, we showed that hOGG1 gene expression was markedly suppressed in up to 38% of the cases. The frequent allelic imbalance and suppression of the hOGG1 gene thus imply that repair for oxidative DNA damages may be relevant in future studies on head and neck squamous carcinogenesis.

Expression of androgen receptor, epidermal growth factor receptor, and transforming growth factor alpha in salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare, highly aggressive neoplasm that primarily affects the major salivary glands. It is a distinct clinicopathological entity characterized by its morphologic resemblance to ductal carcinoma of the breast, a high incidence of regional lymph node metastasis, and distant dissemination. Frequent expression of androgen receptor (AR) but not estrogen receptor or progesterone receptor in SDCs suggests that SDC bears a close immunophenotypic homology with prostatic carcinoma. An AR-mediated autocrine growth pathway consisting of epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGF-alpha), has been implicated in the carcinogenesis of prostatic carcinoma. Androgens, in the presence of AR, mediate their mitogenic effects on prostatic cancer cells by up-regulating the transcriptional and translational activities of EGFR and TGF-alpha. Through an autocrine mode of action, TGF-alpha produced in the tumor cells binds to its receptor, EGFR, which is also expressed by these cells, resulting in a proliferative response. OBJECTIVE: To investigate whether a TGF-alpha/EGFR autocrine pathway is present in SDCs. DESIGN: Retrospective analysis of the expression of AR, EGFR, and TGF-alpha in 12 SDCs. SETTING: An academic medical center. RESULTS: Salivary duct carcinoma expresses AR, TGF-alpha, and EGFR in 11 (92%), 8 (67%), and 11 (92%) of 12 cases, respectively. CONCLUSION: An AR-mediated TGF-alpha/EGFR autocrine pathway may be implicated in the tumorigenesis of SDC.

Expression of androgen receptor and prostatic specific markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature.

Salivary duct carcinoma (SDC) is an uncommon, pathologically distinct entity characterized by its morphologic resemblance to ductal carcinoma of the breast and highly aggressive behavior. Approximately two thirds of patients die within 4 years of initial diagnosis despite aggressive, combined surgical resection and radiotherapy. Review of the literature indicates that androgen receptor (AR), a marker frequently detected in prostatic carcinoma, is expressed in over 90% of SDCs, whereas two common breast carcinoma markers, estrogen and progesterone receptors (ER and PR), are expressed in only 1.3% and 6% of the tumors, respectively, by immunohistochemistry. This hormonal profile suggests that SDC, in contrast to its histiologic similarity to ductal carcinoma of the breast, is immunophenotypically more related to prostatic carcinoma. To substantiate this hypothesis, we performed immunohistochemical staining of 13 cases of SDC for the presence of AR and two prostatic markers, prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). Our results showed multifocal, scattered, moderate immunostaining for PAP and diffuse, moderate immunostaining for PSA in seven (58.3%) and two (16.7%) cases, respectively. These results create a potential diagnostic challenge to surgical pathologists who are dealing with a metastatic adenocarcinoma of AR+/PSA+/-/PAP+/- phenotype, particularly in male patients of unknown primary. Metastatic salivary duct carcinoma should be given serious thought if clinical investigation fails to reveal a prostatic primary. The immunophenotypic homology that exists between SDC and prostatic carcinoma also suggests that antiandrogen therapy as used in the treatment of prostatic carcinoma might be beneficial in patients with metastatic SDC when all other conventional modalities fail.

Histopathology of tissue samples removed using the microdebrider technique: implications for endoscopic sinus surgery.

Microdebriders are being used with increasing frequency in endoscopic sinus surgery to provide precise removal of soft tissue and bone with simultaneous suction and irrigation. To date, no one has analyzed whether histopathology of tissue processed through a microdebrider is maintained. Fifteen tissue samples (squamous cell cancer, esthesioneuroblastoma, lymphoma, sarcoma, inverted papilloma, benign thyroid, and nasal mucosa) were processed though a microdebrider in various modes and speeds. Pathology slides were developed, coded, and presented as unknowns to the pathologist for diagnosis. Specimens taken from routine biopsy techniques were then compared to those passed through the microdebrider. The study found no significant loss of morphologic features in the tissue passed through the microdebrider. The microdebrider may be used for both routine and oncologic procedures without altering the histopathology necessary for diagnosis.

Dendritic cell sarcoma of the thyroid.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) arises from nonlymphatic antigen-presenting cells found in lymph node B-cell follicles. This extremely rare tumor, which usually arises in lymph nodes, does occur in extranodal head and neck sites such as the tonsil and soft palate. METHODS: A retrospective review of the patient followed at the University of Pittsburgh Medical Center from 1993 to the present was performed. CONCLUSIONS: This is the first reported case of an FDCS of the thyroid. A review of the literature provides useful information to aid in detection, treatment, and outcome of this unusual soft tissue malignancy.

Placenta growth factor: potential role in pregnancy.

PROBLEM: In spite of the known requirement for adequate vascularity during placentation, little is known regarding the regulation of angiogenic growth factor production by trophoblast. Placenta growth factor (PIGF) is a recently discovered angiogenic growth factor whose expression is relatively limited to trophoblast. METHOD OF STUDY: Current literature of PIGF was reviewed, with emphasis on its expression, regulation, role in angiogenesis, and potential function(s) at the maternal-fetal interface. RESULTS: PIGF is abundantly expressed by trophoblast, which implies that it could act in a paracrine manner to modulate vascular development, stability, and/or function within the decidua and placental villi. In addition, expression of the PIGF receptor, fms-like tyrosine kinase (flt-1) receptor, on trophoblast raises the potential for an autocrine role of PIGF in regulating trophoblast growth and/or function. CONCLUSIONS: The potential for PIGF to influence both vascular endothelial cells and trophoblast suggests that aberrant trophoblast production of PIGF could compromise cellular function during gestation and contribute to the vascular and placental pathologies noted in many obstetric complications.

Lymphatic mapping with isosulfan blue dye in squamous cell carcinoma of the head and neck.

OBJECTIVE: To determine whether intraoperative lymphatic mapping with isosulfan blue dye and sentinel lymph node biopsy accurately demonstrates the pathway of regional metastases from mucosal sites in squamous cell carcinoma of the head and neck. DESIGN: A prospective clinical study of intraoperative lymphatic mapping. SETTING: An academic tertiary referral center. PATIENTS: Patients with previously untreated squamous cell carcinoma of the head and neck whose surgical treatment included neck dissection. INTERVENTION: Injection of isosulfan blue dye into the mucosa surrounding squamous cell carcinomas of the upper aerodigestive tract during cervical lymphadenectomy. OUTCOME MEASURES: Correlation of the pathologic findings in the blue sentinel lymph node with those in the remaining cervical lymphatics. RESULTS: No blue-stained cervical lymphatics were identified after injection of the mucosa surrounding the primary squamous cell carcinoma with isosulfan dye. CONCLUSION: The technique of intraoperative lymphatic mapping with isosulfan blue dye requires further study before it can be used for the detection of occult cervical metastases in squamous cell carcinoma of the head and neck.

Neuromuscular hamartomas of the head and neck.

The neuromuscular hamartoma (also referred to as the neuromuscular choristoma or benign triton tumor) is a rare developmental lesion composed of mature elements of both striated muscle and nerve. To date, less than 20 cases have been reported in the English language literature. The majority of these have involved large nerves, such as the sciatic or brachial plexus, but cutaneous lesions have also been reported. We report 2 cases that involve the head and neck and that are among the few described in this location. The majority of cases have been described in infants and young children. However, 1 of our cases (and at least 1 previously reported case) occurred in an adult. While surgical excision has been the most widely used form of therapy, a few cases have been complicated by and/or associated with a second lesion, such as a fibromatosis or lymphangioma.

Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) mRNA are up-regulated in squamous cell carcinoma of the head and neck (SCCHN) tissues. METHODS: Immunohistochemical staining with monoclonal antibodies to TGF-alpha and EGFR was undertaken to identify the cellular origin in tissue obtained from cancer patients and controls and to determine the correlation between mRNA expression levels and two methods of immunohistochemical evaluation. RESULTS: TGF-alpha protein staining occurred in the suprabasal layers and spared the basal layer of normal controls. Conversely, in histologically normal mucosa from SCCHN patients, TGF-alpha was present throughout the epithelium, including the basal layer. EGFR staining was negligible in normal mucosa from control patients without cancer and relatively increased in SCCHN tissues. Increasing staining intensity was correlated with worsening dysplasia and closer proximity to the tumor. Using computerized image analysis to quantify the intensity of immunostaining, the mean optical density (MOD) of TGF-alpha staining in histologically normal mucosa (P = 0.049) and tumors (P = 0.005) from SCCHN patients was significantly higher than in control normal mucosa from noncancer patients (1.9- and 1.7-fold, respectively). EGFR MOD was also greater in the histologically normal mucosa (P = 0.009) and tumors (P = 0.006) from SCCHN patients than in control normal mucosa (1.8- and 1.9-fold, respectively). For both TGF-alpha (P = 0.668) and EGFR (P = 0.116), the MOD was similar for both tumor and histologically normal mucosa from SCCHN patients. CONCLUSIONS: TGF-alpha and EGFR protein expression is increased early in head and neck squamous cell carcinogenesis and can be quantitated by computerized image analysis of immunohistochemical staining. Altered distribution of TGF-alpha protein in histologically normal mucosa from SCCHN patients compared with control mucosa from patients without cancer suggests a switch from a paracrine to an autocrine pathway.

Ameloblastic fibrosarcoma of the jaws. A clinicopathologic and DNA analysis of five cases and review of the literature with discussion of its relationship to ameloblastic fibroma.

Ameloblastic fibrosarcoma, the malignant counterpart of the ameloblastic fibroma, is a rare odontogenic tumor characterized by benign epithelium and a malignant fibrous stroma. We have compared nuclear DNA content of five ameloblastic fibrosarcomas and three ameloblastic fibromas by image analysis. The three ameloblastic fibromas were diploid, whereas 1 of 5 ameloblastic fibrosarcomas was aneuploid. There was no correlation with histologic grade and aneuploidy. These five new cases were also added to a review of the literature, bringing the total cases of reported ameloblastic fibrosarcomas to 51. The ameloblastic fibrosarcoma occurs at a later age (mean, 27.5 years) compared with reported ameloblastic fibromas (mean, 14.6 to 22 years), which supports a step-wise malignant transformation. There was histologic documentation that 44% of ameloblastic fibrosarcomas developed in ameloblastic fibromas. In view of this data and of the reported cumulative recurrence rate of 18.3% for ameloblastic fibroma, it is recommended that ameloblastic fibromas be treated with complete surgical excision and long-term follow up rather than simple curettage or enucleation.