Bret Wehrli

Gardner-associated fibromas (GAF) in young patients: a distinct fibrous lesion that identifies unsuspected Gardner syndrome and risk for fibromatosis.

Gardner syndrome (GS), caused by mutations in the adenomatous polyposis coli (APC) gene, is characterized by polyposis coli, osteomas, and various soft-tissue tumors. If undetected or untreated, virtually all patients develop colonic carcinoma at a young age. Early detection, while essential, can be difficult because of attenuated phenotypes or spontaneous mutations. We present the clinicopathologic features of 11 identical fibromatous lesions that we have termed Gardner-associated fibroma (GAF), which not only appear to be a part of the spectrum of lesions associated with GS but, in some cases, represent the sentinel event leading to its detection. The GAFs occurred in 11 patients (5 boys and 6 girls; age range, 3 months–14 years), were solitary (n = 7) or multiple (n = 4), and occurred in the superficial and deep soft tissues of the paraspinal region (n = 7), back (n = 3), face (n = 2), scalp (n = 2), chest wall (n = 2), thigh (n = 1), neck (n = 1), and flank (n = 1). Histologically, GAFs resemble nuchal-type fibromas (NFs), consisting of thick, haphazardly arranged collagen bundles between which are found occasional bland fibroblasts, and having margins that frequently engulf surrounding structures including adjacent fat, muscle and nerves. After surgical excision, four patients developed recurrences that were classic desmoid fibromatoses (DFs). In one patient with multiple GAFs, one lesion had the features of GAF and DF in the absence of surgical trauma. A family history of GS or polyposis (n = 6) or DF (n = 1) was known at the time of surgery in seven patients. In three patients, the diagnosis of GAF resulted in the diagnosis of unsuspected APC in older family members, with the detection of an occult colonic adenocarcinoma in one parent. In the family of the remaining patient, no stigmata of GS were present. Genetic analysis of this child was performed to investigate the presence of a spontaneous (new) mutation; however, no abnormalities were detected. The significance of GAF is that it serves as a sentinel event for identifying GS kindreds, including those with a high risk for the development of DF, and it may potentially identify children with spontaneous mutations of the APC gene. Because NFs and GAFs resemble one another, we suggest that a subset of NF occurring in multiple sites, unusual locations, or children may be GAF.

Early-stage squamous cell carcinoma of the oropharynx: Radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR) – study protocol for a randomized phase II trial

BackgroundThe incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC.Methods/DesignThe target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required.DiscussionThis study, if successful, will provide a much-needed randomized comparison of the conventional strategy of primary RT vs. the novel strategy of primary TORS. The trial is designed to provide a definitive QOL comparison between the two arms, and to inform the design of an eventual phase III trial for survival outcomes.Trial registrationNCT01590355

Epithelioid angiosarcoma arising in a surgically constructed arteriovenous fistula. A rare complication of chronic immunosuppression in the setting of renal transplantation

Immunosuppression in the setting of solid organ transplantation is associated with the development of a variety of malignant tumors, most commonly squamous carcinomas and non-Hodgkins lymphomas. Sarcomas, apart from Kaposis sarcoma, are relatively infrequent. We recently encountered a 71-year-old man with chronic renal failure, treated by allograft kidney transplantation, who developed a high-grade epithelioid angiosarcoma at the site of a nonfunctioning arteriovenous fistula, previously constructed for hemodialysis. At diagnosis, the patient had numerous satellite nodules of angiosarcoma involving the distal skin, soft tissues, and bones. After a below-elbow amputation, there was a rapid local recurrence at the amputation stump. Currently, the patient is alive with numerous pulmonary metastases, 6 months after amputation. A literature review identified three recently reported identical cases of epithelioid angiosarcoma arising in nonfunctioning arteriovenous fistulae. All three patients had been treated by kidney transplantation for renal failure, suggesting a possible causal association between these events. We performed polymerase chain reaction for human herpes virus 8, the recently recognized herpes virus proposed as a major etiologic agent of Kaposis sarcoma, and possibly some conventional angiosarcomas, but we failed to identify any viral DNA within the tumor.

Intra-lesional interleukin-2 for the treatment of in-transit melanoma†

To investigate the role of intra‐lesional interleukin‐2 (IL‐2) injection for treatment of in‐transit melanoma metastases.

A Pilot Study Comparing HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas by Whole Exome Sequencing

Background. Next-generation sequencing of cancers has identified important therapeutic targets and biomarkers. The goal of this pilot study was to compare the genetic changes in a human papillomavirus- (HPV-)positive and an HPV-negative head and neck tumor. Methods. DNA was extracted from the blood and primary tumor of a patient with an HPV-positive tonsillar cancer and those of a patient with an HPV-negative oral tongue tumor. Exome enrichment was performed using the Agilent SureSelect All Exon Kit, followed by sequencing on the ABI SOLiD platform. Results. Exome sequencing revealed slightly more mutations in the HPV-negative tumor (73) in contrast to the HPV-positive tumor (58). Multiple mutations were noted in zinc finger genes (ZNF3, 10, 229, 470, 543, 616, 664, 638, 716, and 799) and mucin genes (MUC4, 6, 12, and 16). Mutations were noted in MUC12 in both tumors. Conclusions. HPV-positive HNSCC is distinct from HPV-negative disease in terms of evidence of viral infection, p16 status, and frequency of mutations. Next-generation sequencing has the potential to identify novel therapeutic targets and biomarkers in HNSCC.

Biomechanical properties of the facial retaining ligaments.

OBJECTIVE Osteocutaneous facial retaining ligaments play an important role in the aging face. We sought to better characterize the biophysical properties of these ligaments and, in doing so, provide an empirical basis for the natural descent seen in facial aging. METHODS Five fresh frozen cadaver heads yielding 10 hemifaces were dissected to expose the orbital, zygomatic, buccomaxillary, and mandibular osteocutaneous ligaments. Each ligament was assessed and subjected to biomechanical testing. The main outcome measures included ligament dimensions, stiffness, percentage of elongation, and force to initial and ultimate failure. RESULTS Initial and ultimate failure testing revealed the zygomatic ligament to be strongest, followed by the orbital, mandibular, and maxillary ligaments. The zygomatic ligament was also stiffest, followed by the orbital, maxillary, and mandibular ligaments. The percentage of elongation acted as a surrogate marker of elasticity, with the greatest elasticity maintained by the mandibular ligament, followed by the orbital, zygomatic, and buccomaxillary ligaments. Ligament dimensions and biophysical properties did not vary relative to cadaveric hemiface, age, or sex. CONCLUSIONS To our knowledge, this is the first investigation to quantify the biomechanical properties of the facial retaining ligaments. Inherent ligament properties seem to be related to the changes observed in facial aging, although further study is required.

Collagen-rich Tumors of Soft Tissues: An Overview

Although relatively common, soft tissue tumors frequently present diagnostic problems for practicing pathologists. Immunohistochemistry has facilitated the diagnosis of many mesenchymal tumors; however, there is considerable overlap in the staining profiles among cells demonstrating fibroblastic and myofibroblastic differentiation. It has been our experience that soft tissue tumors associated with abundant extracellular collagen deposition commonly cause problems in classification. One reason for this is that tumors displaying this morphology include representatives from different histogenetic families. Specifically, tumors exhibiting fibroblastic, myofibroblastic and even lipomatous differentiation may manifest as a densely collagenous mass. It is the purpose of this review to highlight these collagen-rich soft tissue tumors.

Modulation of ERK5 Is a Novel Mechanism by Which Cdc42 Regulates Migration of Breast Cancer Cells

Members of Rho family GTPases including Cdc42 are known to play pivotal roles in cell migration. Cell migration is also known to be regulated by many protein kinases. Kinetworks KPSS 11.0 phospho‐site screening of Cdc42‐silenced Hs578T breast cancer cells revealed most dramatic change in ERK5 MAP kinase. In the present study, we set out to determine the relationship between Cdc42 and ERK5 and its significance in breast cancer cell migration and invasion. Specific siRNAs were used for knocking down Cdc42 or ERK5 in breast cancer cells. Increased ERK5 phosphorylation in breast cancer cells was achieved by infection of constitutively active MEK5 adenovirus. The cells were then subjected to cell migration or invasion assay without the presence of serum or any growth factor. We found that Cdc42 negatively regulated phosphorylation of ERK5, which in turn exhibited an inverse relationship with migration and invasiveness of breast cancer cells. To find out some in vivo relevance of the results of our in vitro experiments we also examined the expression of ERK5 in the breast cancer tissues and their adjacent normal control tissues by real‐time RT‐PCR and immunocytochemistry. ERK5 expression was found to be reduced in breast cancer tissues as compared with their adjacent uninvolved mammary tissues. Therefore, Cdc42 may promote breast cancer cell migration and invasion by inhibiting ERK5 phosphorylation and ERK5 expression may be inversely correlated with the progression of some breast tumors. J. Cell. Biochem. 116: 124–132, 2015.

Variable expression of the forgotten oncogene E5 in HPV-positive oropharyngeal cancer

BACKGROUND The role of the HPV E6/E7 oncogenes in head and neck squamous cell cancer (HNSCC) has been studied extensively, but the role of the viral E5 protein remains poorly understood. Studies in cervical cancer indicate that E5 increases epidermal growth factor receptor (EGFR) recycling to the cell surface and enhances growth factor signal transduction. OBJECTIVE This study was designed to examine the relationship between HPV E5, EGFR, and survival in HPV-positive HNSCC. STUDY DESIGN A retrospective search of the London Health Sciences Centre pathology database was performed to identify oropharyngeal cancer samples. HPV E5 and EGFR expression was measured by reverse transcriptase real-time PCR. RESULTS The majority of oropharyngeal tumor samples (59/82, 72%) were HPV-16 positive. Among the HPV-positive tumors, highly variable E5 expression was detected from early polycistronic transcripts. Tumors with high E5 expression levels had significantly higher EGFR levels (p=0.03). High E5 levels were correlated with improved recurrence-free survival, but not overall survival (p=0.02 and 0.71, respectively), whereas high EGFR was strongly associated with decreased recurrence-free and overall survival (p<0.001 and 0.006 respectively). Multivariate analysis revealed E5 and EGFR to be the strongest predictors of recurrence-free survival (p<0.01). CONCLUSIONS HPV E5-encoded transcripts are variably expressed in HPV-positive HNSCC and this is correlated with EGFR expression in HPV-positive OPC. However, E5 and EGFR independently predict recurrence-free survival in opposing manners. These findings require further validation to determine if E5 and EGFR are useful biomarkers to stratify treatment intensity for patients with HPV-positive HNSCC.

Sentinel node biopsy as an adjunct to limb salvage surgery for epithelioid sarcoma of the hand

BackgroundEpithelioid sarcomas of the hand are rare, high-grade tumors with a propensity for regional lymphatic spread approaching 40%.Case presentationA 54-year-old male with an epithelioid sarcoma of the palm was treated with neoadjuvant radiation, wide excision, and two-stage reconstruction. Sentinel lymph node biopsy was used to stage the patients axilla. Sentinel node biopsy results were negative. The patient has remained free of local, regional and distant disease for the follow-up time of 16 months.ConclusionThe rarity of this tumor makes definitive conclusions difficult but SLN biopsy appears to be a useful adjunct in the treatment of these sarcomas.