Raman spectroscopy system for real-time diagnosis of clinically significant prostate cancer tissue.

Prostate cancer (PCa) is a significant healthcare problem worldwide. Current diagnosis and treatment methods are limited by a lack of precise in vivo tissue analysis methods. Real-time cancer identification and grading could dramatically improve current protocols. Here, we report the testing of a thin optical probe using Raman spectroscopy (RS) and classification methods to detect and grade PCa accurately in real-time. We present the first clinical trial on fresh ex vivo biopsy cores from an 84 patient cohort. Findings from 2395 spectra measured on 599 biopsy cores show high accuracy for diagnosing and grading PCa. We can detect clinically significant PCa from benign and clinically insignificant PCa with 90% sensitivity and 80.2% specificity. We also demonstrate the ability to differentiate cancer grades with 90% sensitivity and specificity ≥82.8%. This work demonstrates the utility of RS for real-time PCa detection and grading during routine transrectal biopsy appointments.

Cryobiopsy with radial-endobronchial ultrasound (Cryo-Radial) has comparable diagnostic yield with higher safety in comparison to computed tomography-guided transthoracic biopsy for peripheral pulmonary lesions: An exploratory randomised study.

BACKGROUND: Computed tomography-guided transthoracic biopsy (CT-TTB) is the 'gold standard' biopsy for lung nodules. Radial-endobronchial ultrasound (R-EBUS) bronchoscopy is another recommended biopsy but carries a lower diagnostic yield. Addition of cryobiopsy with R-EBUS (Cryo-Radial) has shown promising results. There are no studies comparing CT-TTB with Cryo-Radial biopsy. AIM: The co-primary aims were the diagnostic yeild and safety. The secondary aim: ability to test epidermal growth factor receptor (EGFR). METHODS: A randomised controlled, multicentre exploratory study was conducted at three tertiary hospitals. Patients with nodules >1 cm on CT of the chest were randomised to CT-TTB or Cryo-Radial. With Cryo-Radial, patients had 1-3 cryo-biopsies in addition to at least one R-EBUS biopsy through the 2.6 mm guide sheath. RESULTS: Forty-eight patients were randomised: 22 to CT-TTB and 26 to Cryo-Radial. Sixteen in the CT-TTB and 20 in the Cryo-Radial received the allocated biopsy. The diagnostic yield was CT-TTB 93.8% (15/16) versus Cryo-Radial 85% (17/20) P = 0.61 and the odds ratio was 0.37. For 5/13 (38%), a diagnosis was solely made on cryobiopsy. Eleven (78%) of 14 in CT-TTB versus 7/10 (70%) Cryo-Radial were suitable for EGFR testing P = 0.66, with odds ratio 0.63. Pneumothorax occurrence was 44% (7/16) in CT-TTB versus 4.2% (1/24) in Cryo-Radial. Two (12.5%) of 16 CT-TTB required chest drain insertion. CONCLUSION: Cryo-Radial is comparable in diagnostic yield and ability to perform EGFR testing with a significantly lower risk of pneumothorax, compared with CT-TTB. Cryo-Radial has the additional advantage of mediastinal staging during the same procedure with Linear-EBUS and is a promising first-line tool in the diagnostic method of lung cancer.

The global epidemic of thyroid cancer overdiagnosis illustrated using 18 months of consecutive nodule biopsy correlating clinical priority, ACR-TIRADS and Bethesda scoring.

Low thyroid cancer mortality worldwide has not been altered by decades of increasing radiological, pathological and surgical intervention for thyroid nodules. Ultrasound-based risk stratification of thyroid nodules, such as TIRADS, has been introduced to reduce intervention for the 'global epidemic' of thyroid cancer 'overdiagnosis'. This article illustrates the use of TIRADS at a New Zealand tertiary centre, during its introduction, with all nodules undergoing fine-needle aspiration biopsy (FNAB) correlated with clinical referral priority and cytological Bethesda score. The correlation between TIRADS and Bethesda score was not significant but cytology had a strong association with clinical priority. Accuracy of TIRADS was poor though the risk of malignancy for TIRADS 5 nodules was 5.1 times those rated as TIRADS 3. After TIRADS was introduced, there was no significant trend in the proportion of malignant nodules diagnosed by FNAB. Despite an incomplete TIRADS programme, the ACR targets of malignancy rates were achieved. The number of patients, as well as the number of nodules per patient, referred for FNAB continues to rise. Changing papillary thyroid cancer nomenclature and other control measures by health policymakers, such as adjustments to payment systems, may be justified. Radiologists are wasting precious health resources that can be better deployed. The use of TIRADS is expensive and a symptom of health policy failure. Clear recommendations from professional societies to not report incidental small thyroid nodules may be a useful start. Whether TIRADS merits continuing use and promotion should be further investigated.

USP6 gene rearrangement in nodular fasciitis and histological mimics.

AIMS: Nodular fasciitis is known to be a benign mimic of sarcoma, both clinically and histologically. Accurate diagnosis, particularly on small biopsies, remains a challenge, as the morphology can be varied and the immunophenotype is essentially non-specific. Recently, rearrangement of the ubiquitin-specific protease 6 (USP6) gene has been reported as a recurrent and specific finding in nodular fasciitis. The aim of this this study was to evaluate the diagnostic utility of USP6 fluorescence in-situ hybridization (FISH) analysis in a subset of spindle-cell proliferations in which nodular fasciitis enters into the differential diagnosis. METHODS AND RESULTS: A database search was performed at the Middlemore Hospital Histopathology Department. All in-house cases diagnosed between 2002 and March 2014 in which nodular fasciitis was considered as a differential diagnosis were retrospectively identified. Twenty cases were retrieved, reviewed and categorized as 'definite', 'possible' or 'definitely not' nodular fasciitis by consensus morphological opinion of three experienced pathologists. FISH analysis for USP6 rearrangement was performed in each case, with a commercially available break-apart probe. Of seven cases that were morphologically categorized as 'definite' nodular fasciitis, six were FISH-positive and one was FISH-negative. Of four cases categorized as 'possible' nodular fasciitis, one was FISH-positive and three were FISH-negative. Nine cases categorized as 'definitely not' nodular fasciitis were all FISH-negative. In the morphologically definitive cases, FISH analysis for USP6 had a sensitivity of 86% and specificity of 100% for a diagnosis of nodular fasciitis. The positive predictive value was 100%, and the negative predictive value 90%. CONCLUSIONS: USP6 FISH is a useful ancillary test in cases where nodular fasciitis is a potential diagnostic consideration.

MDM2/CDK4 gene amplification in large/deep-seated 'lipomas': incidence, predictors and clinical significance.

This study of 140 cases assessed the incidence of MDM2/CDK4 gene amplification in lipomatous neoplasms with histological features of a lipoma but which were of clinical concern due to large size (≥50 mm) and/or deep-seated (subfascial) location. Univariate and multivariate statistical analyses were used to identify clinical, radiological and pathological predictors of gene amplification. Differences in local recurrence rates between amplified and non-amplified cases were assessed using survival analysis. The findings indicate that the incidence of MDM2/CDK4 amplification in this setting is low at 5% (95%CI 1.4-8.6%). Variables associated with amplification on univariate analysis were tumour site (thigh, p = 0.004), size (>100 mm, p = 0.033) and presence of equivocal atypia (p = 0.001). Independent predictors on multivariate analysis were size (OR 3.9, 95%CI 1.4-11.3, p = 0.012) and presence of equivocal atypia (OR 12.5, 95%CI 1.9-80.3, p = 0.008). There was no significant difference in local recurrence rates between amplified and non-amplified cases (p = 0.461) based on a median follow-up time of 31 months. Assessment for MDM2/CDK4 amplification, therefore, should be considered in 'lipomas' which are >100 mm in size, show equivocal atypia and arise in the thigh. However, the clinical significance of gene amplification in this setting is unclear and requires confirmation in larger studies.

Microscopic Kaposiform hemangioendothelioma with extensive lymphangiomatosis: an extraordinary example of an unusual entity.

Kaposiform hemangioendothelioma (KHE) is presently classified as a vascular neoplasm of intermediate malignant potential. The clinical course of large, deep-seated tumors is frequently complicated by consumptive coagulopathy and life-threatening hemorrhage, while superficial tumors tend to behave in an indolent manner, with no known reports of distant metastasis. We describe an unusual example of KHE occurring as an incidental microscopic finding, within a background of extensive lymphangioma-like changes. The patient underwent 4 intralesional excisions over a period of 6 years, and the Kaposiform component accounts for less than 5% of the overall tissue excised. The patient remains clinically well with residual disease 5 years after conservative surgery, and there has been no evidence of regional or distant metastasis. Based on existing literature, it appears doubtful that KHE has any metastatic potential at all, which calls into question the appropriateness of its place in the spectrum of malignant vascular neoplasms.

Retroperitoneal schwannoma with monoclonal plasma cell infiltration: an exceptionally rare collision tumor?

Collision tumors within the retroperitoneum are rare. We present the case of a 54-year-old man with an incidental finding of a well-defined iliopsoas mass. He underwent marginal resection via an anterior superior ilio-inguinal approach. Histological examination revealed typical features of a schwannoma surrounded by a notable plasma cell infiltrate. On immunohistochemistry stains, the spindled cells displayed diffuse, strong nuclear and cytoplasmic positivity for S100, whereas epithelial membrane antigen, glial fibrillary acidic protein, and neurofilament stains were uniformly negative. The plasma cell infiltrate was diffusely positive for CD 138, with a majority of them demonstrating positive staining for lambda light chain and negative for kappa light chain. Hematological review found no evidence of marrow plasmacytosis and multiple myeloma was ruled out. At 12 month follow-up, the patient remains free of any recurrence. To our knowledge this is the second case of a schwannoma coexisting with a monoclonal plasma cell infiltrate and the first in the retroperitoneum.

Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer.

Delta-like ligand 4 (Dll4) is a Notch ligand that is predominantly expressed in the endothelium. Evidence from xenografts suggests that inhibiting Dll4 may overcome resistance to antivascular endothelial growth factor therapy. The aims of this study were to characterize the expression of Dll4 in breast cancer and assess whether it is associated with inflammatory markers and prognosis. We examined 296 breast adenocarcinomas and 38 ductal carcinoma in situ tissues that were represented in tissue microarrays. Additional whole sections representing 10 breast adenocarcinomas, 10 normal breast tissues, and 16 angiosarcomas were included. Immunohistochemistry was then performed by using validated antibodies against Dll4, CD68, CD14, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), CD123, neutrophil elastase, CD31, and carbonic anhydrase 9. Dll4 was selectively expressed by intratumoral endothelial cells in 73% to 100% of breast adenocarcinomas, 18% of in situ ductal carcinomas, and all lactating breast cases, but not normal nonlactating breast. High intensity of endothelial Dll4 expression was a statistically significant adverse prognostic factor in univariate (P = 0.002 and P = 0.01) and multivariate analyses (P = 0.03 and P = 0.04) of overall survival and relapse-free survival, respectively. Among the inflammatory markers, only CD68 and DC-SIGN were significant prognostic factors in univariate (but not multivariate) analyses of overall survival (P = 0.01 and 0.002, respectively). In summary, Dll4 was expressed by endothelium associated with breast cancer cells. In these retrospective subset analyses, endothelial Dll4 expression was a statistically significant multivariate prognostic factor.

Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma.

There is currently no prognostic tool that reliably predicts the risk of metastasis in cutaneous squamous cell carcinoma, most of which occur in the head and neck region. Epidermal growth factor receptor has received much interest in recent years with the advent of epidermal growth factor receptor-targeted molecular therapy in clinical oncology. We investigate the role of epidermal growth factor receptor as a biomarker for head and neck cutaneous squamous cell carcinoma. Using immunohistochemistry and fluorescence in situ hybridization, we assessed the epidermal growth factor receptor protein expression and gene copy in 3 groups of head and neck cutaneous squamous cell carcinoma: primary lesions not associated with metastasis (P), primary lesions associated with subsequent metastasis (PM), and metastatic nodal disease (M). Epidermal growth factor receptor overexpression was detected in 36% and 79% of P and PM cases, respectively. Epidermal growth factor receptor overexpression was significantly associated with PM (P = .03) and was found to be an independent prognostic factor for metastasis on multivariate analysis (P = .05). However, epidermal growth factor receptor overexpression was only maintained in 47% of cases in the M group. None of the 27 cases that overexpressed the epidermal growth factor receptor protein showed gene amplification: the results were uninterpretable in 2, and polysomy and balanced disomy were detected in 5 and 20 cases, respectively. These observations may have important prognostic and therapeutic implications for head and neck cutaneous squamous cell carcinoma.

Anaphylactic deaths in Auckland, New Zealand: a review of coronial autopsies from 1985 to 2005.

AIMS: To determine the frequency of anaphylactic deaths amongst coronial autopsy cases performed in the greater Auckland region from 1985 to 2005, and review the circumstances of death and autopsy findings. METHODS: A computerised search for anaphylactic deaths was performed using the Forensic Pathology Department database at Auckland City Hospital. Postmortem reports and police reports were reviewed to determine the circumstances of death. Details recorded included basic demographic data, medical history, agent responsible for the allergic reaction, and pathologic findings at autopsy. RESULTS: A total of 18 cases of anaphylactic deaths were identified for the study period, including nine males and nine females, age range 33-76 years, mean 51.9 years. There were 10 reactions to drugs or contrast media (4 anaesthetic agents, 3 antibiotic, 2 IV contrast media, 1 streptokinase), four to bee/wasp venom, two to seafood, and two undetermined. Death occurred within 1 hour of onset of anaphylaxis in 12 cases. Findings at autopsy included non-specific pulmonary oedema and congestion (n = 13), laryngeal oedema (n = 5), cerebral hypoxia (n = 4) and cutaneous oedema (n = 1). Serum tryptase levels were measured in 15 cases, and were significantly elevated (>20 microg/L) in eight cases. CONCLUSION: Anaphylactic reaction is an uncommon cause of sudden death. In many cases, no specific macroscopic or microscopic findings were detected at autopsy. In the presence of a typical clinical history, postmortem measurement of serum tryptase levels can be a useful diagnostic aid.

Low-grade follicular lymphoma in the dura: rare mimic of meningioma.

Lymphomas rarely present as a localized mass within the dura. We report a case of a 72-year-old woman, normally fit and well, who presented with a sudden episode of grand mal seizure. Imaging studies showed an extra-axial mass arising from the dura, with radiologic features characteristic of a meningioma. The mass was surgically excised, and the histologic features were of a grade 1 follicular lymphoma. Analysis using fluorescent in situ hybridization (FISH) demonstrated t(14:18) translocation. A bone marrow aspirate showed focal infiltration of lumbar vertebra by low-grade follicular lymphoma. Intracranial meningeal involvement by non-Hodgkin lymphoma usually occurs in the form of diffuse leptomeningeal spread. It is seen in high-grade lymphomas, often in association with widespread systemic disease. The majority of cases of dural lymphomas reported in the literature have been primary mucosa-associated lymphoid tissue (MALT)-type lymphomas. Most of these presented as localized dural masses mimicking meningiomas. Low-grade follicular lymphoma, either primary or secondarily involving the dura, appears to be an exceedingly rare occurrence.