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Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases ( p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

Presence of C. acnes in granulomas is not unique to sarcoidosis but can also be found in patients with HP or EGPA. C. acnes may be involved in the pathogenesis of those granulomatous diseases in a mitogenic way. https://bit.ly/3pU0PeC., Competing Interests: Conflicts of interest: E. Beijer has nothing to disclose. Conflicts of interest: K. Seldenrijk has nothing to disclose. Conflicts of interest: B. Meek has nothing to disclose. Conflicts of interest: J. Damen has nothing to disclose. Conflicts of interest: M.J.R. Quanjel has nothing to disclose. Conflicts of interest: J.C. Grutters has nothing to disclose. Conflicts of interest: M. Veltkamp has nothing to disclose., (Copyright ©The authors 2021.)

Several studies demonstrated that Propionibacterium acnes may be involved in sarcoidosis pathogenesis. Presence of P. acnes was found in granulomas of the majority of Japanese sarcoidosis patients. However, presence of P. acnes in tissue has never been related to sarcoidosis phenotypes and clinical outcome. Therefore, the aims of our study were to demonstrate whether P. acnes can be detected in granulomas of Dutch sarcoidosis patients and to investigate whether its presence is related to a clinical phenotype and/or course of disease. Sections of formalin-fixed paraffin-embedded tissue blocks of 76 sarcoidosis patients were examined by immunostaining with a P. acnes- specific monoclonal antibody (PAB antibody) using a Ventana BenchMark ULTRA. Clinical outcome status (COS) was determined and classified into two phenotype groups: A: resolved, minimal or persistent disease without treatment (COS 1-6) and B: persistent disease with need for treatment (COS 7-9). P. acnes was detected in samples of 31 patients (41%) and located within granulomas in samples of 13 patients (17%). The frequency of P. acnes detected in granulomas at diagnosis was significantly higher in patients with phenotype B compared to patients with phenotype A (29% versus 0%, p=0.021). Presence of P. acnes in granulomas can be confirmed in Dutch sarcoidosis patients. It is intriguing that presence of P. acnes in granulomas is more frequently found in patients with chronic disease requiring treatment. This adds to the rationale that a subgroup of sarcoidosis patients might benefit from antibiotic therapy., Competing Interests: Conflict of interest: E. Beijer has nothing to disclose. Conflict of interest: K. Seldenrijk has nothing to disclose. Conflict of interest: Y. Eishi has nothing to disclose. Conflict of interest: K. Uchida has nothing to disclose. Conflict of interest: J. Damen has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: M. Veltkamp has nothing to disclose., (Copyright ©ERS 2021.)

Aims: The histopathological diagnosis of low-grade dysplasia (LGD) in Barrett's oesophagus (BO) is associated with poor interobserver agreement and guidelines dictate expert review. To facilitate nationwide expert review in the Netherlands, a web-based digital review panel has been set up, which currently consists of eight 'core' pathologists. The aim of this study was to evaluate if other pathologists from the Dutch BO expert centres qualify for the expert panel by assessing their performance in 80 consecutive LGD reviews submitted to the panel., Methods: Pathologists independently assessed digital slides in two phases. Both phases consisted of 40 cases, with a group discussion after phase I. For all cases, a previous consensus diagnosis made by five core pathologists was available, which was used as reference. The following criteria were used: (1) percentage of 'indefinite for dysplasia' diagnoses, (2) percentage agreement with consensus diagnosis and (3) proportion of cases with a consensus diagnosis of dysplasia underdiagnosed as non-dysplastic. Benchmarks were based on scores of the core pathologists., Results: After phase I, 1/7 pathologists met the benchmark score for all quality criteria, yet three pathologists only marginally failed the agreement with consensus diagnosis (score 68.3%, benchmark 69%). After a group discussion and phase II, 5/6 remaining aspirant panel members qualified with all scores within the benchmark range., Conclusions: The Dutch BO review panel now consists of 14 pathologists, who-after structured assessments and group discussions-can be considered homogeneous in their review of biopsies with LGD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Clinical significance of the pT4 category in colon cancer is increasing with several therapeutic implications. The aim of this study was to evaluate variability in diagnosing pT4a colon cancer. Twelve pathologists classified 66 preselected scanned Hematoxylin/Eosin-stained slides with tumor cells at a distance of 25-1500 μm (n = 22), 0-25 μm (n = 22), or on (n = 22) the peritoneal surface. Inter- and intraobserver variability were calculated using Kappa statistics. For interlaboratory variability, pathology reports of pT3 and pT4a colon cancer were extracted from the Dutch Pathology Registry between 2012 and 2015. The proportion of pT4a (pT4a/(pT3+pT4a)) was compared between 33 laboratories. Potential risk of understaging was assessed by determining the average number of blocks taken from pT3 and pT4a N0-2M0 tumors with metachronous peritoneal metastasis. Interobserver variability among 12 pathologists was 0.50 (95%CI 0.41-0.60; moderate agreement). Intraobserver variability (8 pathologists) was 0.71 (substantial agreement). A total of 7745 reports with pT3 or pT4aN0-2M0 colon cancer from 33 laboratories were included for interlaboratory analysis. Median percentage of pT4a was 15.5% (range 3.2-24.6%). After adjustment for case mix, 8 labs diagnosed pT4a significantly less or more frequently than the median lab. Metachronous peritoneal metastases were histologically verified in 170 of 6629 pT3 and in 129 of 1116 pT4a tumors, with a mean number of blocks of 4.03(SD 1.51) and 4.78 (SD 1.76) taken from the primary tumors, respectively (p < 0.001). A substantial variability in diagnosing pT4a colon cancer exists, both at pathologist and laboratory level. Diagnosis of pT4a stage appears to be challenging and there is a need for standardizing assessment of this pathological entity.

Background: Esophagectomy for submucosal (T1b) esophageal adenocarcinoma (EAC) is performed in order to optimize patient outcomes given the risk of concurrent lymph node metastases (LNM). However, not seldom, comorbidity precludes these patients from surgery. Therefore, the aim of our study was to assess the course of follow-up after treatment in submucosal EAC patients undergoing surgery versus conservative therapy and to evaluate the incidence of metastatic disease., Methods: Between 2001 and 2012, all patients undergoing diagnostic endoscopic resection for EAC in two centers were reviewed. Only patients with histopathologically proven submucosal tumor invasion were included. Submucosal EACs were divided into tumors that were removed radically (R0) and irradically (R1). Subsequently, in the R0 group, EACs were classified as either low risk (LR; submucosal invasion <500 nm, G1-G2, no LVI) or high risk (HR; deep submucosal invasion >500 nm, G3-G4 and/or LVI). Metastatic disease was defined as LNM in surgical resection specimen and/or evidence of malignant disease during follow-up (FU)., Results: Sixty-nine patients with a submucosal EAC were included [23 R1-resections and 46 R0-resection (14 R0-LR and 32 R0-HR)]. Twenty-six patients underwent surgical treatment (1 R0-LR, 12 R0-HR and 13 R1). None of the 14 R0-LR patients developed metastatic disease after a median FU of 60 months. In the R0-HR group and R1 group, metastatic disease was diagnosed in 16 and 30 % of patients, respectively. Surgical patients tended to have a better overall survival than non-surgical patients (p = 0.09). Tumor-related deaths, however, were 12 % in both groups., Conclusions: In LR submucosal EAC, the risk of metastatic disease appears to be very low. In deep submucosal EAC (either R0- or R1-resection), the rate of metastatic disease is lower than reported in earlier surgical series. Given the reasonable disease-free survival and high background mortality, conservative management of these patients seems to be a valid alternative for surgery in selected cases.

Objective: This study investigates the predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) for good pathological response at different time points during and after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer., Background: Preoperative CRT followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer. The use of standard radical surgery in good treatment responders after CRT is being questioned., Methods: Patients with locally advanced rectal adenocarcinoma were treated with preoperative CRT followed by surgery. DW-MRI scans were performed before CRT, during the third week of CRT, 4 weeks post-CRT and presurgery. Tumor apparent diffusion coefficient (ADC) values were acquired from the DW-MRI scans. After surgery the pathological tumor regression grade was assessed according to the classification by Mandard et al [Cancer. 1994;73:2680-2686]. Patients with pathological complete or near-complete response (tumor regression grade 1-2) were classified as good responders (GRs)., Results: Twenty-two patients participated of which 9 were GRs (41%). Pre-CRT ADC values were lower in good versus moderate/poor responders (P = 0.04). ADC values during CRT and four weeks post-CRT were higher in GR. ADC values presurgery did not differ between response groups. For all time points the relative ADC increase (ΔADC) compared to the ADC pre-CRT was higher in GR (P < 0.001). The ΔADC during CRT and four weeks post-CRT were the best predictive parameters for pathological good response., Conclusions: This study shows that DW-MRI is feasible to select good treatment responders during preoperative CRT for locally advanced rectal cancer.

Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified six children and one adolescent with cervical lymphadenopathy showing prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and four adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED-2-IG PCR analysis. Haemophilus influenzae was identified in all six cases of pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in three pNMZLs and 28 non-specific reactive cervical lymph nodes of age-matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 years). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules, the expanded germinal centres and variably sized marginal zones were colonized by activated B-cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In four cases tested, this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD+ marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL., (Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Objective: The experiences on the treatment of seven consecutive patients with large-cell neuroendocrine carcinoma (LCNEC) were studied, observed over 6 years from 1992. Since LCNEC was recognized as a separate histological entity, only very few series have been reported. Together with the carcinoids (atypical and typical) and the small-cell lung carcinoma (SCLC), it forms the spectrum of neuroendocrine tumors., Methods: Between 1992 and 1997, seven patients who underwent surgical resection were diagnosed as LCNEC postoperatively. Mean age was 65 years (range 54-77 years), five patients were male, all patients were heavy smokers. One patient was staged as IA, four as IB, one as IIIB and one as IV., Results: In five patients, preoperative diagnosis was unknown, in one squamous cell carcinoma and in one adenocarcinoma was suspected. There were four lobectomies, two bilobectomies and one resection of the lingular division with a wedge resection of the upper division of the left upper lobe. Three patients received adjuvant chemotherapy and one, adjuvant radiotherapy. Survival ranged from 7 to 39 months. There are no patients currently alive., Conclusions: LCNEC is a high-grade neuroendocrine tumor with a poor prognosis. In our patients, after surgical resection or multimodality treatment, all have developed widespread metastatic disease with a rapidly fatal course. Due to the rarity of this tumor, the incidence, prognosis and optimal treatment remain to be determined.

By a combination of reversed transcription and subsequent polymerase chain reaction (RNA-PCR), 23 cytologically normal cervical scrapings, positive for the presence of human papillomavirus type 16 (HPV 16) DNA, were analyzed for the presence of transcripts originating from the E6 region of the viral genome. This region is thought to be involved in transformational, tumorigenic events. No mRNAs of the E6 region were detectable using the most sensitive PCR-mediated procedure currently available. Since it was previously shown that in cytological abnormal cervical scrapings about one-half of the samples positive for HPV 16 DNA express mRNAs of the E6 region, a difference between normal and abnormal cervical scrapings, when the HPV 16 is present, exists. The observed difference between cytologically normal and abnormal, HPV-DNA-positive cervical scrapes may eventually be used as a prognostic marker for screening of women at risk for the development of cervical carcinoma. However, firm establishment of the putative correlation between tumor progression and the presence of E6 transcripts requires extensive follow-up analysis of HPV-positive patients.