Author Correction: Metastatic-niche labelling reveals parenchymal cells with stem features.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Metastatic-niche labelling reveals parenchymal cells with stem features.

Direct investigation of the early cellular changes induced by metastatic cells within the surrounding tissue remains a challenge. Here we present a system in which metastatic cancer cells release a cell-penetrating fluorescent protein, which is taken up by neighbouring cells and enables spatial identification of the local metastatic cellular environment. Using this system, tissue cells with low representation in the metastatic niche can be identified and characterized within the bulk tissue. To highlight its potential, we applied this strategy to study the cellular environment of metastatic breast cancer cells in the lung. We report the presence of cancer-associated parenchymal cells, which exhibit stem-cell-like features, expression of lung progenitor markers, multi-lineage differentiation potential and self-renewal activity. In ex vivo assays, lung epithelial cells acquire a cancer-associated parenchymal-cell-like phenotype when co-cultured with cancer cells and support their growth. These results highlight the potential of this method as a platform for new discoveries.

Peri-tumoural spatial distribution of lipid composition and tubule formation in breast cancer.

BACKGROUND: Response guided treatment in breast cancer is highly desirable, but the effectiveness is only established based on residual cellularity from histopathological analysis after surgery. Tubule formation, a key component of grading score, is directly associated with cellularity, with significant implications on prognosis. Peri-tumoural lipid composition, a potential marker, can be rapidly mapped across the entire breast using novel method of chemical shift-encoded imaging, enabling the quantification of spatial distribution. We hypothesise that peri-tumoural spatial distribution of lipid composition is sensitive to tumour cellular differentiation and proliferative activity. METHODS: Twenty whole tumour specimens freshly excised from patients with invasive ductal carcinoma (9 Score 2 and 11 Score 3 in tubule formation) were scanned on a 3 T clinical scanner (Achieva TX, Philips Healthcare). Quantitative lipid composition maps were acquired for polyunsaturated, monounsaturated, and saturated fatty acids (PUFA, MUFA, SFA). The peri-tumoural spatial distribution (mean, skewness, entropy and kurtosis) of each lipid constituent were then computed. The proliferative activity marker Ki-67 and tumour-infiltrating lymphocytes (TILs) were assessed histologically. RESULTS: For MUFA, there were significant differences between groups in mean (p = 0.0119), skewness (p = 0.0116), entropy (p = 0.0223), kurtosis (p = 0.0381), and correlations against Ki-67 in mean (ρ = -0.5414), skewness (ρ = 0.6045) and entropy (ρ = 0.6677), and TILs in mean (ρ = -0.4621). For SFA, there were significant differences between groups in mean (p = 0.0329) and skewness (p = 0.0111), and correlation against Ki-67 in mean (ρ = 0.5910). For PUFA, there was no significant difference in mean, skewness, entropy or kurtosis between the groups. CONCLUSIONS: There was an association between peri-tumoural spatial distribution of lipid composition with tumour cellular differentiation and proliferation. Peri-tumoural lipid composition imaging might have potential in non-invasive quantitative assessment of patients with breast cancer for treatment planning and monitoring.

Intra-tumoural lipid composition and lymphovascular invasion in breast cancer via non-invasive magnetic resonance spectroscopy.

OBJECTIVES: Despite improved survival due to new treatments, the 10-year survival rate in patients with breast cancer is approximately 75%. Lymphovascular invasion (LVI), a prognostic marker independent from histological grade and stage, can only be fully determined at final histological examination. Lipid composition is deregulated in tumour via de novo lipogenesis, with alteration in lipogenic genes in LVI. We hypothesise alteration in lipid composition derived from novel non-invasive spectroscopy method is associated with LVI positivity. METHODS: Thirty female patients (age 39-78) with invasive ductal carcinoma were enrolled, with 13 LVI negative and 17 LVI positive. Saturated, monounsaturated, polyunsaturated fatty acids and triglycerides (SFA, MUFA, PUFA and TRG) were quantified from ex vivo breast tumours freshly excised from patients on a 3 T clinical MRI scanner, and proliferative activity marker Ki-67 and serotonin derived histologically. RESULTS: There were significantly lower MUFA (p = 0.0189) in LVI positive (median: 0.37, interquartile range (IQR): 0.25-0.64) than negative (0.63, 0.49-0.96). There were significantly lower TRG (p = 0.0226) in LVI positive (1.32, 0.95-2.43) than negative (2.5, 1.92-4.15). There was no significant difference in SFA (p = 0.6009) or PUFA (p = 0.1641). There was no significant correlation between lipid composition against Ki-67 or serotonin, apart from a borderline negative correlation between PUFA and serotonin (r = - 0.3616, p = 0.0496). CONCLUSION: Lipid composition might provide a biomarker to study lymphovascular invasion in breast cancer. KEY POINTS: • Monounsaturated fatty acids in lymphovascular invasion (LVI) positive invasive breast carcinoma were significantly lower than that in LVI negative. • Triglycerides in LVI positive invasive breast carcinoma were significantly lower than that in LVI negative. • Lipid composition from MR spectroscopy reflects the rate of de novo lipogenesis and provides a potential biomarker independent from histological grade and stage.

Lactate concentration in breast cancer using advanced magnetic resonance spectroscopy.

BACKGROUND: Precision medicine in breast cancer demands markers sensitive to early treatment response. Aerobic glycolysis (AG) upregulates lactate dehydrogenase A (LDH-A) with elevated lactate production; however, existing approaches for lactate quantification are either invasive or impractical clinically. METHODS: Thirty female patients (age 39-78 years, 15 grade II and 15 grade III) with invasive ductal carcinoma were enrolled. Lactate concentration was quantified from freshly excised whole tumours with double quantum filtered (DQF) magnetic resonance spectroscopy (MRS), and Nottingham Prognostic Index (NPI), LDH-A and proliferative marker Ki-67 were assessed histologically. RESULTS: There was a significantly higher lactate concentration (t = 2.2224, p = 0.0349) in grade III (7.7 ± 2.9 mM) than in grade II (5.5 ± 2.4 mM). Lactate concentration was correlated with NPI (ρ = 0.3618, p = 0.0495), but not with Ki-67 (ρ = 0.3041, p = 0.1023) or tumour size (r = 0.1716, p = 0.3645). Lactate concentration was negatively correlated with LDH-A (ρ = -0.3734, p = 0.0421). CONCLUSION: Our results showed that lactate concentration in whole breast tumour from DQF MRS is sensitive to tumour grades and patient prognosis.

Occult disease in reduction mammoplasties and prophylactic mastectomies.

The aim of this study was to determine the incidence of occult breast carcinoma and significant breast disease in clinically and radiologically unremarkable breast reduction specimens and prophylactic mastectomies. A retrospective search using specimen type codes was performed in the computerized histopathology archive from April 2007 to April 2016. The pathology results of 505 patients were analyzed (782 specimens). A total of 267 patients underwent simple reduction mammoplasties (10 unilateral), 20 had bilateral prophylactic mastectomies and 218 undertook contralateral symmetrizing or prophylactic mastectomy surgery following a history of breast cancer. Overall, normal (unremarkable) breast tissue was found in 42.6% of patients (n = 215), benign tissue (nonproliferative/proliferative disease without atypia) in 51.1% (n = 258), significant disease (LCIS/proliferative disease with atypia) in 5.5% (n = 28), and malignant disease (invasive/ductal carcinoma in situ) in 0.8% (n = 4). The incidence of significant breast pathology was statistically higher (P value < .0001) in prophylactic mastectomies (12.4%) compared to reduction mammoplasties (2.3%). There was however no significant increase in the incidence of malignancy between prophylactic mastectomies (1.2%) and reduction mammoplasties (0.6%). Even though the clear majority of resected tissue in reduction mammoplasties and prophylactic mastectomies is benign, our findings support the continued need for histological examination of these specimens for occult carcinoma and precursor lesions.

Spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive breast cancer.

Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid mapping of the human whole breast. We set out to elucidate the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive (ER +) breast cancer. Thirteen participants (mean age, 62 ± [SD] 6 years) with ER + breast cancer and 13 age-matched postmenopausal healthy controls were scanned on MRI. The number of double bonds in triglycerides was computed from MRI images to derive lipid composition maps of monounsaturated, polyunsaturated, and saturated fatty acids (MUFA, PUFA, SFA). The spatial heterogeneity measures (mean, median, skewness, entropy and kurtosis) of lipid composition in the peri-tumoural region and the whole breast of participants and in the whole breast of controls were computed. The Ki-67 proliferative activity marker and CD163 antibody on tumour-associated macrophages were assessed histologically. Mann Whitney U or Wilcoxon tests and Spearman's coefficients were used to assess group differences and correlations, respectively. For comparison against the whole breast in participants, peri-tumoural MUFA had a lower mean (median (IQR), 0.40 (0.02), p < .001), lower median (0.42 (0.02), p < .001), a negative skewness with lower magnitude (- 1.65 (0.77), p = .001), higher entropy (4.35 (0.64), p = .007) and lower kurtosis (5.13 (3.99), p = .001). Peri-tumoural PUFA had a lower mean (p < .001), lower median (p < .001), a positive skewness with higher magnitude (p = .005) and lower entropy (p = .002). Peri-tumoural SFA had a higher mean (p < .001), higher median (p < .001), a positive skewness with lower magnitude (p < .001) and lower entropy (p = .012). For comparison against the whole breast in controls, peri-tumoural MUFA had a negative skewness with lower magnitude (p = .01) and lower kurtosis (p = .009), however there was no difference in PUFA or SFA. CD163 moderately correlated with peri-tumoural MUFA skewness (rs = - .64), PUFA entropy (rs = .63) and SFA skewness (rs = .59). There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy.

Atypical fibroxanthoma with pseudoangiomatous features: a histological and immunohistochemical mimic of cutaneous angiosarcoma.

Atypical fibroxanthoma and pleomorphic dermal sarcoma may be difficult to separate from cutaneous angiosarcoma. We aim to study the morphological spectrum of pseudoangiomatous features in these tumors and the value of staining for endothelial markers CD31, CD34, FLI1, and ERG. Eleven atypical fibroxanthomas and 3 pleomorphic dermal sarcomas were identified. All tumors arose on sun-damaged skin of elderly men. Atypical fibroxanthomas were nodular and confined to the dermis, whereas pleomorphic dermal sarcoma invaded into underlying fascia. All tumors were composed of pleomorphic epithelioid and spindle cells showing blood-filled spaces and intratumoral hemorrhage. Intracytoplasmic vacuoles (n = 4), hemosiderin deposition (n = 2), and keloidal stromal change (n = 1) were also noted. Immunohistochemically, CD31 was expressed in 43% of cases, FLI1 in 79% and smooth muscle actin in 50%. Staining for CD34, ERG, S100, HMB-45, desmin, p63 and cytokeratins was negative. Follow up (median, 43.1 months; range 1-100), available for 10 patients, showed no adverse outcome. Pseudoangiomatous features and aberrant expression of CD31 and FLI1 in atypical fibroxanthoma and pleomorphic dermal sarcoma may lead to an erroneous diagnosis of cutaneous angiosarcoma. Negativity for CD34 and ERG, in particular, is a reliable differentiating feature in this setting.

Towards detection of early response in neoadjuvant chemotherapy of breast cancer using Bayesian intravoxel incoherent motion.

Introduction: The early identification of good responders to neoadjuvant chemotherapy (NACT) holds a significant potential in the optimal treatment of breast cancer. A recent Bayesian approach has been postulated to improve the accuracy of the intravoxel incoherent motion (IVIM) model for clinical translation. This study examined the prediction and early sensitivity of Bayesian IVIM to NACT response. Materials and methods: Seventeen female patients with breast cancer were scanned at baseline and 16 patients were scanned after Cycle 1. Tissue diffusion and perfusion from Bayesian IVIM were calculated at baseline with percentage change at Cycle 1 computed with reference to baseline. Cellular proliferative activity marker Ki-67 was obtained semi-quantitatively with percentage change at excision computed with reference to core biopsy. Results: The perfusion fraction showed a significant difference (p = 0.042) in percentage change between responder groups at Cycle 1, with a decrease in good responders [-7.98% (-19.47-1.73), n = 7] and an increase in poor responders [10.04% (5.09-28.93), n = 9]. There was a significant correlation between percentage change in perfusion fraction and percentage change in Ki-67 (p = 0.042). Tissue diffusion and pseudodiffusion showed no significant difference in percentage change between groups at Cycle 1, nor was there a significant correlation against percentage change in Ki-67. Perfusion fraction, tissue diffusion, and pseudodiffusion showed no significant difference between groups at baseline, nor was there a significant correlation against Ki-67 from core biopsy. Conclusion: The alteration in tumour perfusion fraction from the Bayesian IVIM model, in association with cellular proliferation, showed early sensitivity to good responders in NACT. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03501394, identifier NCT03501394.

Cutaneous Sebaceous Carcinoma Presenting as a Large Fungating Breast Tumour in Synchronicity With Primary Carcinomata of the Breasts.

Sebaceous carcinomas are rare malignant tumours which arise from sebaceous glands. They are subclassified into ocular and extraocular subtypes and most commonly occur in the head and neck region. Tumours below the neck occur infrequently, and most commonly resemble benign skin lesions such as pyogenic granulomata and molluscum contagiosum, or malignant skin tumours like basal and squamous cell carcinomas (SCCs). We report a case of an 86-year-old lady presenting with a fungating breast tumour which began as a "mole" and exhibited insidious growth over five years to reach a maximum size of 10 cm. An excision biopsy was performed by the breast surgery team and histopathological analysis revealed a sebaceous carcinoma arising from the skin adnexa. On subsequent follow up, the patient was found to have a 19 mm mass in the left breast and a 20 mm mass in the right breast, which was P5 and P3 on clinical palpation, respectively. Core biopsies of left and right breast lesions showed invasive lobular carcinoma and invasive ductal carcinoma with lobular features respectively; the patient was started on primary letrozole treatment. The patient also went on to have a 2 cm wide local excision of the sebaceous carcinoma scar which was excised down to the pectoralis fascia. This is a unique presentation of a sebaceous gland carcinoma presenting as a fungating breast tumour. These tumours have a high metastatic potential and local recurrence rate, and can co-exist with primary carcinoma of the breast.

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi.

Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

Incidence of male breast cancer in Scotland over a twenty-five-year period (1992-2017).

Male breast cancer (MBC) accounts for around 1% of all breast cancers diagnosed. There are inconsistent reports on the incidence of MBC which some propose may be rising. Here, for the first time, the incidence of MBC in Scotland over 25 years from 1992 to 2017 was examined through interrogating the Information Services Division Scotland database. Results showed MBC incidence rose with age, peaking in the 65-70 and 75-79 age groups. Both the total number and the age-adjusted incidence of MBC increased in Scotland since 1992. This rising trend was most clear in the North of Scotland. Interestingly a higher MBC incidence in some rural areas was also observed. Our findings emphasise the need for a better understanding of MBC risk factors so that improved prevention policies can be applied for patient benefit.

Epithelial sheath neuroma: be aware of benign perineural invasion!

Perineural involvement by epithelial cells is usually considered as a sign of malignancy and is seen in a variety of malignant skin neoplasms. However, there are other benign conditions characterized by the presence of perineural involvement by epithelial cells. We present a case of epithelial sheath neuroma in a 43-year-old male. The clinicopathological features of this newly described entity are discussed together with the differential diagnosis and the different hypotheses of pathogenesis. Both pathologists and dermatologists should be aware of this entity to avoid misdiagnosis of malignancy.

Phaeochromocytoma crisis presenting with profound hypoglycaemia and subsequent hypertension.

A patient was presented with four days of vomiting, abdominal pain and sweating. At presentation the Capillary Blood Glucose (CBG) was 1.7 mmol/L, the Blood Pressure (BP) was 182/102 mmHg, and the pulse 100 bpm. On examination, he was sweaty, pale and cold. The initial differential diagnosis was hypoglycaemia secondary to insulin abuse, hypoadrenalism or insulinoma, the transient hypertension being considered a consequence of sympathetic stimulation. He remained clinically well overnight with a CBG of 10-14 mmol/L following intravenous glucose. The next morning he complained of nausea and abdominal pain. The BP had risen to 203/127 mmHg when he was later reviewed, having been given 10mg intramuscular metoclopramide. Shortly afterwards, he developed acute pulmonary oedema and had become hypoglycaemic again; a phaeochromocytoma crisis was suspected. Treatment with alpha-adrenoceptor blockade with intravenous phenoxybenzamine was advised. However, the patient deteriorated and died in the Intensive Care Unit within two hours. Autopsy examination confirmed a phaeochromocytoma in the left adrenal, with haemorrhage within the head of pancreas, but no evidence of a pancreatic tumour.

q-Space Imaging Yields a Higher Effect Gradient to Assess Cellularity than Conventional Diffusion-weighted Imaging Methods at 3.0 T: A Pilot Study with Freshly Excised Whole-Breast Tumors.

Purpose: To determine whether q-space imaging (QSI), an advanced diffusion-weighted MRI method, provides a higher effect gradient to assess tumor cellularity than existing diffusion imaging methods, and fidelity to cellularity obtained from histologic analysis. Materials and Methods: In this prospective study, diffusion-weighted images were acquired from 20 whole-breast tumors freshly excised from participants (age range, 35-78 years) by using a clinical 3.0-T MRI unit. Median and skewness values were extracted from the histogram distributions obtained from QSI, monoexponential model, diffusion kurtosis imaging (DKI), and stretched exponential model (SEM). The skewness from QSI and other diffusion models was compared by using paired t tests and relative effect gradient obtained from correlating skewness values. Results: The skewness obtained from QSI (mean, 1.34 ± 0.77 [standard deviation]) was significantly higher than the skewness from monoexponential fitting approach (mean, 1.09 ± 0.67; P = .015), SEM (mean, 1.07 ± 0.70; P = .014), and DKI (mean, 0.97 ± 0.63; P = .004). QSI yielded a higher effect gradient in skewness (percentage increase) compared with monoexponential fitting approach (0.26 of 0.74; 35.1%), SEM (0.26 of 0.74; 35.1%), and DKI (0.37 of 0.63; 58.7%). The skewness and median from QSI were significantly correlated with the skewness (ρ = -0.468; P = .038) and median (ρ = -0.513; P = .021) of cellularity from histologic analysis. Conclusion: QSI yields a higher effect gradient in assessing breast tumor cellularity than existing diffusion methods, and fidelity to underlying histologic structure.Keywords: Breast, MR-Diffusion Weighted Imaging, MR-Imaging, Pathology, Tissue Characterization, Tumor ResponseOnline supplemental material is available for this article.Published under a CC BY 4.0 license.

Primary cutaneous amebiasis with a fatal outcome.

We report a fatal case of disseminated amebiasis in a young African woman, which initially presented with an ulcerated cutaneous lesion on the left flank. The causative organism was confirmed by examination of a wet drop preparation from the ulcer discharge and by skin biopsy. The patient was not immunosuppressed and was treated unsuccessfully with metronidazole. Postmortem examination revealed the presence of intestinal amebiasis complicated by a liver abscess.

Pleomorphic LCIS what do we know? A UK multicenter audit of pleomorphic lobular carcinoma in situ.

AIMS: Pleomorphic lobular carcinoma in situ (PLCIS) is a relatively newly described pathological lesion that is distinguished from classical LCIS by its large pleomorphic nuclei. The lesion is uncommon and its appropriate management has been debated. The aim of this study is to review data from a large series of PLCIS to examine its natural history in order to guide management plans. MATERIALS AND METHODS: Comprehensive pathology data were collected from two cohorts; one from a UK multicentre audit and the other a series of PLCIS cases identified from within the GLACIER study cohort. 179 cases were identified of whom 176 had enough data for analysis. RESULTS: Out of these 176 cases, 130 had invasive disease associated with PLCIS, the majority being of lobular type (classical and/or pleomorphic). A high incidence of histological grade 2 and 3 invasive cancers was noted with a predominance of ER positive and HER-2 negative malignancy. When PLCIS was the most significant finding on diagnostic biopsy the upgrade to invasive disease on excision was 31.8%, which is higher than pooled data for classical LCIS and DCIS. CONCLUSION: The older age at presentation, high grade of upgrade to invasive cancer, common association with higher grade tumours suggest that PLCIS is an aggressive form of insitu disease. These findings support the view that PLCIS is a more aggressive form of lobular in situ neoplasia and supports the tendency to treat akin to DCIS.

Heterotopic pancreas mimicking cholangiocarcinoma. Case report and literature review.

CONTEXT: Majority of the patients developing obstructive jaundice have an underlying malignancy. Identification of a benign pathology like heterotopic pancreas as an aetiology is uncommon and usually occurs only subsequent to a major operation. CASE REPORT: We report a case of heterotopic pancreas adjacent to the ampulla of Vater mimicking distal cholangiocarcinoma. A 47-year-old patient presented with abdominal pain and obstructive jaundice. ERCP demonstrated a distal common bile duct stricture suspicious of cholangiocarcinoma. He underwent a pylorus-preserving pancreaticoduodenectomy. Histology showed a nodule of heterotopic pancreatic tissue adjacent to the ampulla. CONCLUSION: We have reviewed the literature on heterotopic pancreas of the periampullary region presenting with biliary obstruction. This is a rare entity and remains difficult to diagnose, despite advances in radiological and endoscopic imaging techniques. For symptomatic patients with an established diagnosis of periampullary heterotopic pancreas, local excision may be sufficient. However, in the absence of unequivocal imaging or histological confirmation of benign pathology, and when there is a suspicion of underlying malignancy, pancreaticoduodenectomy may be the only treatment option, as in this case.