Histopathologic features predictive of metastasis and survival in 230 patients with cutaneous squamous cell carcinoma of the head and neck and non-head and neck locations: a single-center retrospective study.

BACKGROUND: Staging systems for cutaneous squamous cell carcinoma (cSCC) produce inconsistent risk stratification. OBJECTIVE: The aim of this study was to identify further prognostic parameters for better stratification. METHODS: We retrospectively analysed the prognostic significance of clinicopathologic parameters of 230 patients who underwent primary excision of invasive cSCC of the head and neck (n = 115) and non-head and non-neck (n = 115) locations. In addition to known high-risk features, we analysed tumour nest shape, invasion pattern, lymphoid response pattern and tumour budding. RESULTS: On multivariable analysis, lymphovascular invasion (LVI) and high tumour budding predicted worse disease-specific survival, and ulceration, LVI and high tumour budding predicted worse overall survival. Only ulceration was independently associated with risk of nodal metastasis. CONCLUSION: High tumour budding, LVI and ulceration are independently associated with poor outcome in cSCC and may be used to refine cSCC prognostic stratification, which is crucial to optimize clinical decision and to identify patients who are more likely to benefit from more aggressive interventions or clinical trials.

Spitzoid melanoma with histopathological features of ALK gene rearrangement exhibiting ALK copy number gain: a novel mechanism of ALK activation in spitzoid neoplasia.

Spitzoid neoplasms pose diagnostic difficulties because their morphology is not consistently predictive of their biological potential. Recent advances in the molecular characterization of these tumours provides a framework by which they can now begin to be categorized. In particular, spitzoid lesions with ALK rearrangement have been specifically associated with a characteristic plexiform growth pattern of intersecting fascicles of amelanotic spindled melanocytes. We report the case of an 87-year-old man with a 3-cm nodule on his mid-upper back comprised of an intradermal proliferation of fusiform amelanotic melanocytes arranged in intersecting fascicles with occasional peritumoral clefts. Immunohistochemical studies demonstrated diffuse, strong expression of SOX10 and S100 by the tumour cells and diffuse, weak-to-moderate cytoplasmic positivity for anaplastic lymphoma kinase (ALK), suggestive of ALK rearrangement. Fluorescence in situ hybridization revealed no ALK rearrangements but instead revealed at least three intact ALK signals in 36% of the tumour cells, confirming ALK copy number gain. To our knowledge, this is the first reported case of a plexiform spitzoid neoplasm exhibiting ALK copy number gain instead of ALK rearrangement. This case suggests that ALK copy number gain is a novel mechanism of ALK activation but with the same characteristic histopathological growth pattern seen among ALK-rearranged spitzoid neoplasms.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Active animal health surveillance in European Union Member States: gaps and opportunities.

Animal health surveillance enables the detection and control of animal diseases including zoonoses. Under the EU-FP7 project RISKSUR, a survey was conducted in 11 EU Member States and Switzerland to describe active surveillance components in 2011 managed by the public or private sector and identify gaps and opportunities. Information was collected about hazard, target population, geographical focus, legal obligation, management, surveillance design, risk-based sampling, and multi-hazard surveillance. Two countries were excluded due to incompleteness of data. Most of the 664 components targeted cattle (26·7%), pigs (17·5%) or poultry (16·0%). The most common surveillance objectives were demonstrating freedom from disease (43·8%) and case detection (26·8%). Over half of components applied risk-based sampling (57·1%), but mainly focused on a single population stratum (targeted risk-based) rather than differentiating between risk levels of different strata (stratified risk-based). About a third of components were multi-hazard (37·3%). Both risk-based sampling and multi-hazard surveillance were used more frequently in privately funded components. The study identified several gaps (e.g. lack of systematic documentation, inconsistent application of terminology) and opportunities (e.g. stratified risk-based sampling). The greater flexibility provided by the new EU Animal Health Law means that systematic evaluation of surveillance alternatives will be required to optimize cost-effectiveness.

Use of New Techniques in Addition to IHC Applied to the Diagnosis of Melanocytic Lesions, With Emphasis on CGH, FISH, and Mass Spectrometry.

Melanoma remains one of the most aggressive forms of cutaneous malignancies. While its diagnosis based on histologic parameters is usually straight forward in most cases, distinguishing a melanoma from a melanocytic nevus can be challenging in some instances, especially when there are overlapping clinical and histopathologic features. Occasionally, melanomas can histologically mimic other tumors and even demonstration of melanocytic origin can be challenging. Thus, several ancillary tests may be employed to arrive at the correct diagnosis. The objective of this review is to summarize these tests, including the well-established and commonly used ones such as immunohistochemistry, with specific emphasis on emerging techniques such as comparative genomic hybridization, fluorescence in situ hybridization and imaging mass spectrometry.

Systematic review of surveillance systems and methods for early detection of exotic, new and re-emerging diseases in animal populations.

In this globalized world, the spread of new, exotic and re-emerging diseases has become one of the most important threats to animal production and public health. This systematic review analyses conventional and novel early detection methods applied to surveillance. In all, 125 scientific documents were considered for this study. Exotic (n = 49) and re-emerging (n = 27) diseases constituted the most frequently represented health threats. In addition, the majority of studies were related to zoonoses (n = 66). The approaches found in the review could be divided in surveillance modalities, both active (n = 23) and passive (n = 5); and tools and methodologies that support surveillance activities (n = 57). Combinations of surveillance modalities and tools (n = 40) were also found. Risk-based approaches were very common (n = 60), especially in the papers describing tools and methodologies (n = 50). The main applications, benefits and limitations of each approach were extracted from the papers. This information will be very useful for informing the development of tools to facilitate the design of cost-effective surveillance strategies. Thus, the current literature review provides key information about the advantages, disadvantages, limitations and potential application of methodologies for the early detection of new, exotic and re-emerging diseases.

Thickness of superficial basal cell carcinoma (sBCC) predicts imiquimod efficacy: a proposal for a thickness-based definition of sBCC.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in the white population. It is an important driver of healthcare costs and causes significant morbidity. Topical imiquimod is a good noninvasive treatment alternative for surgical excision in superficial BCC (sBCC). However, there are currently no uniform histological definitions of sBCC. A definition based on tumour thickness might be a good alternative. OBJECTIVES: To determine whether tumour thickness in sBCC is a predictor of treatment failure. METHODS: We retrospectively examined 127 histological biopsy specimens of sBCC treated primarily with imiquimod five times a week for 6 weeks. Mean follow-up was 34 months (range 3-91). Recurrence was evaluated clinically with histological verification. RESULTS: Among nonrecurrent cases the median tumour thickness was 0·26 mm (range 0·09-0·61), while for recurrent cases the median tumour thickness was 0·57 mm (range 0·41-1·41, P < 0·0001). Among lesions ≤ 0·40 mm in thickness, none recurred, whereas for lesions > 0·40 mm the recurrence rate was 58% (P < 0·0001). CONCLUSIONS: We recommend the use of tumour thickness to define the superficial pattern in pathology reports for BCC as this can help to determine treatment response of sBCC to imiquimod.

Spitzoid and non-spitzoid melanoma in children: a prognostic comparative study.

BACKGROUND: Spitzoid melanoma is a rare melanoma subtype often developing in children with unknown biological potential. OBJECTIVES: To compare the clinical and histopathological factors that influence the biological behaviour between spitzoid and non-spitzoid childhood melanoma, to establish if the spitzoid subset of melanoma has different prognosis than other types of childhood melanomas. METHODS: A comparison of the prognostic significance of clinical and pathological findings between 38 spitzoid (SM) and 99 non-spitzoid melanomas (N-SM) in children and teenagers younger than 18 years referred to UT - MD Anderson Cancer Center during the period 1992-2007. RESULTS: Children with SM were significantly younger than those with N-SM, had more frequently multiple melanocytic nevi, nodular melanoma subtype with vertical growth phase, high Breslow thickness and mitotic rate, positive sentinel lymph node biopsy and more advanced stage. N-SM had more often associated nevus. However, the mortality rate in the SM group was lower (5.9%) than in the N-SM group (12.0%). This study has two major limitations. Small size of both groups does not allow reaching statistically significant differences regarding mortality. Using metastatic potential as an inclusion criterion for SM could result in a sample selection bias of the most aggressive group of SM. CONCLUSIONS: Although SM patients had poorer prognostic factors than N-SM patients, slightly lower mortality rate was detected in the SM group. This less aggressive behaviour could be due to lower potential for widespread distant metastases than conventional melanomas or younger age of children with SM.

Identification of suitable areas for West Nile virus outbreaks in equid populations for application in surveillance plans: the example of the Castile and Leon region of Spain.

The introduction and rapid spread of West Nile virus (WNV) into new areas such as the American continent, associated also with the severity of the disease in humans and equids has increased concerns regarding the need to better prevent and control future WNV incursions. WNV outbreaks in equids usually occur under specific climatic and environmental conditions and, typically, before detection of WNV cases in humans. Targeting surveillance strategies in areas and time periods identified as suitable for WNV outbreaks in equids may act as an early-warning system to prevent disease in both equids and humans. This study used a GIS-based framework to identify suitable areas and time periods for WNV outbreak occurrence in one of the most important areas of equid production in Spain, i.e. Castile and Leon. Methods and results presented here may help to improve the early detection and control of future WNV outbreaks in Spain and other regions.

Agreement of dermatopathologists in the evaluation of clinically difficult melanocytic lesions: how golden is the 'gold standard'?

BACKGROUND: The 'gold standard' for the diagnosis of melanocytic lesions is dermatopathology. Although most of the diagnostic criteria are clearly defined, the interpretation of histopathology slides may be subject to interobserver variability. OBJECTIVES: The aim of this study was to determine the variability among dermatopathologists in the interpretation of clinically difficult melanocytic lesions. METHODS: This study used the database of MelaFind®, a computer-vision system for the diagnosis of melanoma. All lesions were surgically removed and sent for independent evaluation by four dermatopathologists. Agreement was calculated using kappa statistics. RESULTS: A total of 1,249 pigmented melanocytic lesions were included. There was a substantial agreement among expert dermatopathologists: two-category kappa was 0.80 (melanoma vs. non-melanoma) and three-category kappa was 0.62 (malignant vs. borderline vs. benign melanocytic lesions). The agreement was significantly greater for patients ≥40 years (three-category kappa = 0.67) than for younger patients (kappa = 0.49). In addition, the agreement was significantly lower for patients with atypical mole syndrome (AMS) (kappa = 0.31) than for patients without AMS (kappa = 0.76). LIMITATIONS: The data were limited by the inclusion/exclusion criteria of the MelaFind® study. This might represent a selection bias. The agreement was evaluated using kappa statistics. This is a standard method for evaluating agreement among pathologists, but might be considered controversial by some statisticians. CONCLUSIONS: Expert dermatopathologists have a high level of agreement when diagnosing clinically difficult melanocytic lesions. However, even among expert dermatopathologists, the current 'gold standard' is not perfect. Our results indicate that lesions from younger patients and patients with AMS may be more problematic for the dermatopathologists, suggesting that improved diagnostic criteria are needed for such patients.

Use of modifying phrases in surgical pathology reports: is there a different understanding between pathologists and treating physicians?

When not all the histopathologic and clinical features necessary for a pathology diagnosis are present in a particular specimen, pathologists may use modifying phrases to convey various degrees of certainty, e.g., "consistent with…" and "suggestive of…." However, it is unclear whether pathologists use such phrases consistently or whether treating physicians fully understand their intended meaning. A questionnaire concerning six common modifying phrases ("consistent with, suggestive of, suspicious for, highly consistent with, highly suggestive of, some features of") was sent to all physicians from a single institution who either issued or routinely received surgical pathology reports. Physicians were asked to rank their understanding of each phrase on a printed scale between 1 ("no evidence of") and 10 ("diagnostic of"). One hundred sixty physicians (74.3%) responded. Despite wide variation, there was a hierarchy (from more to less diagnostic): highly consistent > highly suspicious > consistent > suspicious > suggestive > some features (p < 1 × 10-7). There were no significant differences between pathologists and treating physicians (p = 0.72) or attendings and residents (p = 0.9). Pathologists and treating physicians share an overall common understanding of their hierarchical relationship, albeit with wide ranges. Based upon our results, we propose to use only three qualifying phrases to convey the degree of certainty for a particular diagnosis: "suggestive of" (> 25 ≤ 50% certainty), "suspicious for" (> 50 ≤ 75%), and "consistent with" (> 75%). The phrase "no evidence of" should probably be used only when there is ≤ 5% confidence in a diagnosis, and conversely, "diagnostic of" should probably be used only when there is ≥ 95% confidence in a diagnosis.

Multimethod imaging, staging, and spectrum of manifestations of metastatic melanoma.

The incidence of melanoma has been steadily increasing. Imaging plays an important role in tumour assessment as metastatic melanoma can involve multiple organs. Computed tomography (CT) is currently the most widely used technique for tumour staging, surveillance and assessment of therapeutic response, but ultrasound, magnetic resonance imaging (MRI) and positron-emission tomography (PET)-CT also play important roles in the imaging of this tumour. In this article, we review the pathways of spread, staging according to the recently updated TNM classification, pathology, typical and atypical imaging features at common and uncommon sites, and treatment of metastatic melanoma.

Short communication: characterization of microflora in Mexican Chihuahua cheese.

This work was performed to identify the bacterial species present in 10 Chihuahua cheeses obtained from commercial producers in Mexico using 16S rRNA gene analysis. As expected, some of the agar media initially used for isolation were not very selective, supporting the growth of several unrelated bacterial species. Sequence analysis identified potential pathogens, including Escherichia coli and Staphylococcus aureus, in all raw milk samples and 2 pasteurized milk samples. Streptococcus thermophilus and Lactococcus lactis ssp. lactis were identified in 9 and 6 samples, respectively, and would serve as acidifying agents during cheese production. Lactobacilli were identified in all cheeses, with the most prevalent being Lactobacillus plantarum identified in 7 raw milk and 1 pasteurized milk cheeses. Leuconostoc mesenteroides and Streptococcus macedonicus were identified in 4 raw milk cheeses and both were present in all pasteurized milk samples, suggesting that they may play a role in the development of traditional Chihuahua cheese attributes.

Lymphomatoid papulosis and associated lymphomas: a retrospective case series of 84 patients.

AIMS: To determine incidence and risk factors for developing lymphoma in patients with lymphomatoid papulosis (LyP), and to identify putative triggers amenable to treatment. METHODS: The prognostic effect of severity of LyP, viral infection by history or serology, beta-2-microglobulin level, lactic dehydrogenase (LDH) level, and CD4 : CD8 ratio were evaluated using logistic regression models. Responses to prophylactic or palliative treatment were assessed. RESULTS: In total, 84 patients (38 men, 46 women, median age at diagnosis 48.5 years) were identified. Of these, 34 (40%) were also diagnosed with one or more lymphomas: 16 (19%) had mycosis fungoides, 15 (17%) had primary cutaneous anaplastic large-cell lymphoma (pcALCL), 2 had both MF and pcALCL, and 1 had MF with large cell transformation and 1 had peripheral T-cell lymphoma. Of the 61 people presenting with LyP alone, only 11 (18%) subsequently developed lymphoma, with a median onset of 17.6 years (95% CI: 4, not obtained). Men were 2.5 times more likely than women to develop lymphoma (P = 0.04). Exposure to Epstein-Barr virus (EBV) was associated with an increase in incidence of 4.8 times (P = 0.16). Treatment for a putative infectious trigger resulted in improvement for 15 of 24 patients (63%). CONCLUSION: Referral bias may explain the higher (40%) incidence of lymphoma in this population of LyP patients, compared with the 10-20% incidence commonly cited in the literature. In the subset of patients presenting with LyP alone, only 18% later developed lymphoma. Male patients or patients with prior EBV infection may have a higher risk for developing lymphoma, and some patients improved with treatment of putative infectious triggers.

A novel AKT3 mutation in melanoma tumours and cell lines.

Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

[Sarcoidosis and fibrolamellar carcinoma of the liver]. / Sarcoidosis y carcinoma fibrolamelar del hígado.

The case of 20-years female patient with the diagnosis of sarcoidosis associated to fibrolamellar carcinoma of the liver is presented. Clinical features, diagnosis and treatment of these entities are exposed. The criteria of several researchers about the relation between sarcoidosis and neoplasic diseases are stood out. Sarcoidosis associated to fibrolamellar hepatocarcinoma is very uncommon.

[Splenic lymphoma of the marginal zone without peripheral hairy lymphocytes]. / Linfoma esplénico de la zona marginal sin linfocitos vellosos en periferia.

This paper reports on a case of a 34-year male patient diagnosed for splenic lymphoma of the marginal zone, a rare entity in our milieu. Features of the disease are described. Early diagnosis is a must for optimum treatment of such a pathology, whose onset can be giant splenomegalia. All possible causes are to be considered.

[Benchmarking in patient identification: An opportunity to learn]. / Benchmarking en la identificación de pacientes: una oportunidad para aprender.

OBJECTIVE: To perform a benchmarking on the safe identification of hospital patients involved in "Club de las tres C" (Calidez, Calidad y Cuidados) in order to prepare a common procedure for this process. MATERIAL AND METHODS: A descriptive study was conducted on the patient identification process in palliative care and stroke units in 5medium-stay hospitals. The following steps were carried out: Data collection from each hospital; organisation and data analysis, and preparation of a common procedure for this process. RESULTS: The data obtained for the safe identification of all stroke patients were: hospital 1 (93%), hospital 2 (93.1%), hospital 3 (100%), and hospital 5 (93.4%), and for the palliative care process: hospital 1 (93%), hospital 2 (92.3%), hospital 3 (92%), hospital 4 (98.3%), and hospital 5 (85.2%). CONCLUSIONS: The aim of the study has been accomplished successfully. Benchmarking activities have been developed and knowledge on the patient identification process has been shared. All hospitals had good results. The hospital 3 was best in the ictus identification process. The benchmarking identification is difficult, but, a useful common procedure that collects the best practices has been identified among the 5 hospitals.