A Case of HPV-Associated Oropharyngeal Squamous Cell Carcinoma with Block-Like, Partial Loss of p16 Expression.

BACKGROUND: Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16. METHODS: A 63 year old male presented with a base of tongue nonkeratinizing squamous cell carcinoma and a large metastatic neck mass. The primary lesion and multiple regions of the metastatic mass were assessed with p16 immunohistochemistry, RNA in situ hybridization for high-risk HPV, and HPV16 genome sequencing. RESULTS: The primary lesion was p16 negative, and the metastatic neck mass had large, confluent regions that were either strongly p16 positive or entirely p16 negative. All of these regions were positive for high-risk HPV with identical HPV16 genomes. CONCLUSION: This unusual case illustrates a potential diagnostic pitfall, and it raises important questions regarding molecular mechanisms and prognostic implications of p16 staining in oropharyngeal squamous cell carcinoma.

Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis.

PURPOSE: A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival. PATIENTS AND METHODS: A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival. RESULTS: A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr = 0.0099]; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr = 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr = 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr = 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41-24.98; Pfdr = 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr = 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr = 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P = 0.008). CONCLUSIONS: HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

The inverse electron-demand Diels-Alder reaction as a new methodology for the synthesis of 225Ac-labelled radioimmunoconjugates.

The inverse electron-demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO) facilitates the efficient radiosynthesis of 225Ac-labelled radioimmunoconjugates in a two-step method, outperforming conventional approaches based on isothiocyanate couplings.

Squamous and Neuroendocrine Specific Immunohistochemical Markers in Head and Neck Squamous Cell Carcinoma: A Tissue Microarray Study.

The performance characteristics of neuroendocrine-specific and squamous-specific immunohistochemical markers in head and neck squamous cell carcinomas (SCC), in particular in oropharyngeal tumors in this era of human papillomavirus (HPV)-induced cases, are not well-established. The differential diagnosis for poorly differentiated SCCs, for nonkeratinizing oropharyngeal SCCs, and for other specific SCC variants such as basaloid SCC and undifferentiated (or lymphoepithelial-like) carcinomas includes neuroendocrine carcinomas. Given that neuroendocrine carcinomas of the head and neck are aggressive regardless of HPV status, separating them from SCC is critically important. In this study, we examined the neuroendocrine markers CD56, synaptophysin, and chromogranin-A along with the squamous markers p40 and cytokeratin 5/6 in a large tissue microarray cohort of oral, oropharyngeal, laryngeal, and hypopharyngeal SCCs with known HPV results by RNA in situ hybridization for the oropharyngeal tumors. Results were stratified by site and specific SCC variant. The neuroendocrine stains were rarely expressed in SCC (<1% overall) with CD56 the least, and chromogranin-A the most, specific markers. Further, p40 and cytokeratin 5/6 were very consistently expressed in all head and neck SCC (>98% overall), including very strong, consistent staining in oropharyngeal HPV-related nonkeratinizing SCC. Undifferentiated (or lymphoepithelial-like) carcinomas of the oropharynx are more frequently p40 or cytokeratin 5/6 negative or show only weak or focal expression. In summary, markers of neuroendocrine and squamous differentiation show very high specificity and sensitivity, respectively, across the different types of head and neck SCC.

Tendinopathic supraspinatus tenocytes may have a neuroendocrine-like function, secreting CGRP, SP and VEGF: a pilot immunohistochemistry study.

We wanted to observe and compare the appearance of neurovascular tissue from tendon ex vivo, in patients with and without painful rotator cuff tendinopathy. Supraspinatus tendons were biopsied from 5 participants with painful tendinopathy and normal tendon from a young male. Slides were stained with haematoxylin and eosin and toluidine blue for histological assessment. Immunohistochemical markers for general nerves (protein gene-product 9.5 and synaptophysin), sensory nerves (calcitonin gene-related peptide; substance-P) and vascularisation (vascular endothelial growth factor) were used. PGP9.5 and CGRP-immunoreactive fibres were associated with vessels in cases and control. Synaptophysinlabelled fibres were observed in close relation to vessels in tendinopathy. PGP9.5, CGRP, SP and VEGF-immunoreaction also labelled tenocyte-like cells in degenerative areas and fibres in regions of fat and collagen. Sensory innervation and vascularity are increased in tendinopathy. The evidence for innervation and vascularity of symptomatic rotator cuff tendon may aid the development of novel investigations and therapies in the management of patients with this ailment.

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

The E. coli DNA Replication Fork.

DNA replication in Escherichia coli initiates at oriC, the origin of replication and proceeds bidirectionally, resulting in two replication forks that travel in opposite directions from the origin. Here, we focus on events at the replication fork. The replication machinery (or replisome), first assembled on both forks at oriC, contains the DnaB helicase for strand separation, and the DNA polymerase III holoenzyme (Pol III HE) for DNA synthesis. DnaB interacts transiently with the DnaG primase for RNA priming on both strands. The Pol III HE is made up of three subassemblies: (i) the αɛθ core polymerase complex that is present in two (or three) copies to simultaneously copy both DNA strands, (ii) the ß2 sliding clamp that interacts with the core polymerase to ensure its processivity, and (iii) the seven-subunit clamp loader complex that loads ß2 onto primer-template junctions and interacts with the α polymerase subunit of the core and the DnaB helicase to organize the two (or three) core polymerases. Here, we review the structures of the enzymatic components of replisomes, and the protein-protein and protein-DNA interactions that ensure they remain intact while undergoing substantial dynamic changes as they function to copy both the leading and lagging strands simultaneously during coordinated replication.

Epidermal Growth Factor Receptor Expression in Spindle Cell Carcinomas of the Head and Neck.

Spindle cell carcinoma (SpCC) is an uncommon head and neck squamous cell carcinoma (SCC) variant consisting of spindled and/or pleomorphic cells with epithelial differentiation. Epidermal growth factor receptor (EGFR) is expressed by >90 % of conventional SCC, and high level expression is associated with a poorer prognosis. Anti-EGFR therapies are commonly used to treat head and neck SCC. However, no studies have evaluated EGFR expression in SpCC. Cases of SpCC were retrieved from department files. The diagnosis required either a biphasic lesion with a squamous neoplastic component, or a purely spindle cell or pleomorphic tumor with immunohistochemical positivity for epithelial markers. EGFR immunohistochemistry was performed and was quantified in quartiles. Medical records were reviewed for clinical follow up information. EGFR was expressed in 21/30 (70 %) cases, including in the squamous component in 18/19 (95 %) and the spindle cell component in only 12/30 (40 %). Where the spindle cell component was positive, the intensity and distribution were lower than for the squamous component. Recurrent tumors were predominantly (80-90 %) of the spindle cell component, and had low (or absent) EGFR expression. Kaplan-Meier survival analysis showed no statistically significant differences in overall or disease free survival between the EGFR expressing and non-expressing groups (p = 0.414 and 0.19, respectively). SpCCs of the head and neck have a poor prognosis, and markedly reduced EGFR expression. EGFR-specific therapies may not be ideal for SpCC patients, which may lack EGFR expression, but further studies are needed.

Distant metastasis in p16-positive oropharyngeal squamous cell carcinoma: a critical analysis of patterns and outcomes.

OBJECTIVE: With good loco-regional control, disease failure in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) mainly results from distant metastasis (DM). Our objective was to characterize the patterns and clinical outcomes of DM in p16-positive OPSCC and compare these to patients with p16-negative disease. METHODS: Primary OPSCC patients who developed DM after completing surgical or non-surgical treatment were identified and p16 status was evaluated. Patterns of DM and post-DM progression-free (PFS) and disease-specific survival (DSS) were assessed. RESULTS: Forty-one of the 66 (62%) patients with DM were p16-positive. DM patterns were not statistically different by p16 status. However, p16-positive patients developed DM later in their course and had longer survival. All p16-negative patients either had progression or died within 24 months of DM detection whereas the 2-year post-DM PFS in the p16-positive group was 20% (95% CI: 8-32.5%, p=0.003). The 3-year post-DM disease-specific survival (DSS) estimate in the p16-positive patients was 16% (95% CI: 7-18%) while all p16-negative patients died within 34 months (p<0.001). p16-negativity, loco-regional disease, and no/palliative versus curative intent treatment were all associated with reduced post-DM DSS in multivariate analysis. CONCLUSIONS: The DM pattern did not differ remarkably between p16-positive and negative OPSCC patients in our practice. In p16-positive OPSCC with pulmonary oligometastatic disease, curative intent treatment and optimized locoregional control for the index primary prolonged survival.

Spindle cell carcinomas of the head and neck rarely harbor transcriptionally-active human papillomavirus.

Spindle cell carcinoma is an uncommon variant of squamous cell carcinoma characterized by spindled or pleomorphic cells which appear to be a true sarcoma but are actually epithelial. Some head and neck squamous cell carcinoma variants can be human papillomavirus (HPV)-related and have improved outcomes. We sought to determine if spindle cell carcinomas are associated with transcriptionally-active HPV. Cases of spindle cell carcinoma were retrieved from department files. Transcriptionally-active HPV was determined by mRNA in situ hybridization for high risk HPV E6 and E7 transcripts and by a surrogate marker, p16 immunohistochemistry, with a 50% staining cutoff. RT-PCR for high risk HPV mRNA was performed on the cases that were technical failures by in situ hybridization. Medical records and follow up information were retrieved for all patients. Of 31 cases, 5 were from the oropharynx, 12 from the oral cavity, and 14 from the larynx or hypopharynx. One purely spindled oral cavity spindle cell carcinoma was HPV positive. It was also diffusely positive for p16. Another laryngeal spindle cell carcinoma was HPV positive in both the squamous and spindle cell components, but was negative for p16. None of the five oropharyngeal spindle cell carcinomas were positive for p16 or HPV RNA. The HPV positive patients both presented at high stage (IV) and died with disease within 2 years of diagnosis. The majority of spindle cell carcinomas of the head and neck, including those arising in the oropharynx, are not related to transcriptionally active HPV. Although the number of cases is too small for any definitive conclusions, for the rare HPV positive spindle cell carcinoma cases, positive viral status does not appear to confer any prognostic benefit.

Perceptions of the painful body: the relationship between body perception disturbance, pain and tactile discrimination in complex regional pain syndrome.

BACKGROUND: Disturbances in body perception are increasingly acknowledged as a feature of complex regional pain syndrome (CRPS). Conventional treatments have limited success particularly among those with long-standing disease. Understanding the relationship between body perception disturbance, pain and tactile acuity might provide insight into alternative avenues for treatment. The aim of this study was to test the hypotheses that (1) body perception disturbance is positively related to pain and (2) decreased tactile acuity is related to increased body perception disturbance. METHODS: A controlled observational design was used to measure these features among those with CRPS of one arm. The extent of body perception disturbance was assessed using the Bath CRPS body perception disturbance scale and pain was measured using the neuropathic pain symptom inventory. Two-point discrimination threshold testing was performed as a measure of tactile acuity. RESULTS: Findings confirmed both hypotheses. Body perception disturbance was found to positively correlate with pain such that those in greater pain had more extensive body perception disturbance (r = 0.57, p < 0.01). Furthermore, a positive correlation was revealed between body perception disturbance and two-point discrimination thresholds (r = 0.5, p < 0.025) so those with greater body perception disturbance had worse tactile acuity. Interestingly, those with longer disease duration had significantly greater body perception disturbance (r = 0.66, p < 0.001). CONCLUSION: Aberrant central processing is suggested as the neural correlate of body perception disturbance and tactile impairment. The exact relationship between body perception disturbance, pain and tactile acuity and how they may be modulated for pain relief requires further exploration.

Lack of association of cadherin expression and histopathologic type, metastasis, or patient outcome in oropharyngeal squamous cell carcinoma: a tissue microarray study.

Altered cadherin expression is important for metastasis in many carcinomas including head and neck squamous cell carcinoma (SCC). We evaluated E- and N-cadherin expression specifically in oropharyngeal SCC and correlated this with clinical and pathologic features. Oropharyngeal SCC patients with clinical follow up information were identified from clinician databases from 1996 through 2007 and tissue microarrays created. Tumors had been previously typed histopathologically as keratinizing, non-keratinizing, or non-keratinizing with maturation, and had known p16 and human papillomavirus status, respectively. Immunohistochemistry was performed on the microarrays, and staining was evaluated for presence and intensity (0 = negative, 1 = weak, 2 = moderate, 3 = strong) both visually and also with digital image analysis software. Of 154 cases, E-cadherin was expressed in 152 (98.7%) and N-cadherin in 17 (11.5%). Neither E- nor N-cadherin expression was statistically significantly associated with histopathologic type (P = 0.082 and P = 0.228, respectively). E-cadherin staining intensity was not statistically significantly associated with nodal or distant metastasis, either visually or by image analysis, (P = 0.098 and P = 0.963 respectively) nor was N-cadherin (P = 0.228 and P = 0.935 respectively). Neither E- nor N-cadherin expression was associated with death from disease (P = 0.995; P = 0.964, respectively). E-cadherin is extensively expressed by oropharyngeal SCC, even the non-keratinizing type. Our results suggest that cadherin expression may not be a predictor for nodal or distant metastasis in these tumors. Mechanisms independent of cadherin expression may be important for metastases in oropharyngeal SCC.

Seromucinous hamartoma of the nasal cavity: a report of two cases and review of the literature.

The sinonasal tract is a complex anatomic site, home to a wide variety of reactive, inflammatory, benign, and malignant lesions. Inflammatory polyps and papillomas are usually easily recognized by pathologists. A poorly understood lesion that has been more clearly defined in recent years is the nasal hamartoma. The epithelial subtypes include seromucinous hamartoma, respiratory epithelial adenomatoid hamartoma, and hybrid lesions. Seromucinous hamartomas have only been recognized and substantially reported over the past few years. They are a diagnostic challenge, needing to be distinguished from low grade adenocarcinomas, and are of interest because most of the basic questions about their pathophysiology remain unanswered. Herein, we present two novel cases of seromucinous hamartoma with features that partly expand the morphologic spectrum of these lesions, discuss the differential diagnosis, and review the literature to compare our findings with previously reported cases with the aim of better understanding this interesting entity.

Acute joint pathology and synovial inflammation is associated with increased intra-articular fracture severity in the mouse knee.

OBJECTIVE: Post-traumatic arthritis is a frequent cause of disability and occurs most commonly and predictably after articular fracture. The objective of this investigation was to examine the effect of fracture severity on acute joint pathology in a novel murine model of intra-articular fracture. DESIGN: Low and high energy articular fractures (n=25 per group) of the tibial plateau were created in adult male C57BL/6 mice. The acute effect of articular fracture severity on synovial inflammation, bone morphology, liberated fracture area, cartilage pathology, chondrocyte viability, and systemic cytokines and biomarkers levels was assessed at 0, 1, 3, 5, and 7 days post-fracture. RESULTS: Increasing intra-articular fracture severity was associated with greater acute pathology in the synovium and bone compared to control limbs, including increased global synovitis and reduced periarticular bone density and thickness. Applied fracture energy was significantly correlated with degree of liberated cortical bone surface area, indicating greater comminution. Serum concentrations of hyaluronic acid (HA) were significantly increased 1 day post-fracture. While articular fracture significantly reduced chondrocyte viability, there was no relationship between fracture severity and chondrocyte viability, cartilage degeneration, or systemic levels of cytokines and biomarkers. CONCLUSIONS: This study demonstrates that articular fracture is associated with a loss of chondrocyte viability and increased levels of systemic biomarkers, and that increased intra-articular fracture severity is associated with increased acute joint pathology in a variety of joint tissues, including synovial inflammation, cortical comminution, and bone morphology. Further characterization of the early events following articular fracture could aid in the treatment of post-traumatic arthritis.

Disseminated Burkholderia gladioli infection in a lung transplant recipient with underlying hypocomplementemic urticarial vasculitis.

Burkholderia gladioli is difficult to definitively identify within the laboratory using phenotypic testing alone. We describe a case of recurrent B. gladioli infection in a lung transplant recipient with underlying hypocomplementemic urticarial vasculitis syndrome, discuss the difficulties encountered with laboratory identification, provide a review of the methodology required for definitive identification, and discuss potential pathophysiologic mechanisms in this patient responsible for the difficulty in treatment.

Ex vivo sentinel lymph node mapping in laparoscopic resection of colon cancer.

AIM: The study examined the feasibility and potential benefit of ex vivo sentinel lymph node (SLN) mapping, including multilevel sectioning (MLS) and immunohistochemistry (IHC) in colon cancer patients undergoing laparoscopic colectomy. The secondary goals were (i) to identify patient and tumour characteristics that might influence the success of the SLN technique, (ii) to investigate the extent of lymphadenectomy required to encompass tumour-positive nonsentinel lymph nodes (NSLN) and (iii) to ascertain the association of SLN status with oncological outcomes. METHOD: SLN mapping was performed after specimen extraction using 1% Isosulfan blue. The SLNs were analysed with H&E staining after MLS, and if negative, IHC was performed. NSLNs were grouped by distance either greater than or less than 4 cm from the tumour. RESULTS: Seventy-one patients completed the study between 2003 and 2007. Using H&E with MLS, the accuracy of SLN mapping was 76%, sensitivity was 52% and the false-negative rate was 48%. Excluding patients with clinically positive lymph nodes resulted in a significant improvement in accuracy to 81% and decreased the false-negative rate to 30%. Furthermore, as the only positive NSLN > 4 cm from the tumour was grossly positive, SLN mapping with a 4-cm mesenteric cuff would have given 100% sensitivity in patients without macroscopically involved nodes. CONCLUSIONS: SLN mapping may be of value in selected patients. It may be possible to accurately stage patients with a 4-cm cuff of mesentery, although further validation of this proposal is required.

Assessing tumor hypoxia by positron emission tomography with Cu-ATSM.

For the last several decades, hypoxia has been recognized to be one of the key factors in tumor aggression and an important impediment to local and distant control of malignant tumors. In addition, hypoxia is a major cause of failure of both radiation therapy and chemotherapy. It has been shown that hypoxia is an independent negative prognostic factor for patient outcome in various solid tumors. Clinical studies using polarographic oxygen electrodes, as a tool for measuring hypoxia, were the first to demonstrate the presence of hypoxia in human tumors and its association with poor prognosis. However, this method is invasive and has technical limitations that prevent its routine clinical use. Over the years, imaging as a noninvasive method has attracted a lot of attention and several radiotracers have been developed for noninvasive evaluation of hypoxia. One of the most promising radiotracers is the copper(II) complex of diacetyl-2,3-bis(N(4)-methyl-3-thiosemicarbazonato) ligand (Cu-ATSM) for imaging with positron emission tomography. In this review, the preclinical evaluation of Cu-ATSM as well as its clinical value in several solid tumors will be discussed.

Rotator cuff tendinopathy/subacromial impingement syndrome: is it time for a new method of assessment?

Disorders of the shoulder are extremely common, with reports of prevalence ranging from 30% of people experiencing shoulder pain at some stage of their lives up to 50% of the population experiencing at least one episode of shoulder pain annually. In addition to the high incidence, shoulder dysfunction is often persistent and recurrent, with 54% of sufferers reporting ongoing symptoms after 3 years. To a large extent the substantial morbidity reflects (i) a current lack of understanding of the pathoaetiology, (ii) a lack of diagnostic accuracy in the assessment process, and (iii) inadequacies in current intervention techniques. Pathology of the rotator cuff and subacromial bursa is considered to be the principal cause of pain and symptoms arising from the shoulder. Generally these diagnostic labels relate more to a clinical hypothesis as to the underlying cause of the symptoms than to definitive evidence of the histological basis for the diagnosis or the correlation between structural failure and symptoms. Diagnosing rotator cuff tendinopathy or subacromial impingement syndrome currently involves performing a structured assessment that includes taking the patient's history in conjunction with performing clinical assessment procedures that generally involve tests used to implicate an isolated structure. Based on the response to the clinical tests, a diagnosis of rotator cuff tendinopathy or subacromial impingement syndrome is achieved. The clinical diagnosis is strengthened with the findings from supporting investigations such as blood tests, radiographs, ultrasound, magnetic resonance imaging (MRI), computed axial tomography (CT), radionucleotide isotope scan, single photon emission computed tomography, electromyography, nerve conduction and diagnostic analgesic injection. This process eventually results in the formation of a clinical hypothesis, and then, in conjunction with the patient, a management plan is decided upon and implemented. This paper focuses on the dilemmas associated with the current process, and an alternative method for the clinical examination of the shoulder for this group of patients is proposed.

Rotator cuff tendinopathy.

PURPOSE: A review was conducted to synthesise the available research literature on the pathogenesis of rotator cuff tendinopathy. RELEVANCE: Musculoskeletal disorders of the shoulder are extremely common, with reports of prevalence ranging from one in three people experiencing shoulder pain at some stage of their lives to approximately half the population experiencing at least one episode of shoulder pain annually. Pathology of the soft tissues of the shoulder, including the musculotendinous rotator cuff and subacromial bursa, is a principal cause of pain and suffering. CONCLUSIONS: The pathoaetiology of rotator cuff failure is multifactorial and results from a combination of intrinsic, extrinsic and environmental factors. The specialised morphology of the rotator cuff, together with the effects of stress shielding, may contribute to the development of rotator cuff tendinopathy. Profound changes within the subacromial bursa are strongly related to the pathology and resulting symptoms. A considerable body of research is necessary to more fully understand the aetiology and pathohistology of rotator cuff tendinopathy and its relationship with bursal pathology. Once this knowledge exists more effective management will become available.