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ObjectiveEndometrial cancer surgical staging includes lymph node assessment which can lead to lower extremity lymphedema. The aim of this study was to estimate prevalence after sentinel lymph node biopsy versus lymphadenectomy.MethodsConsecutive patients who underwent minimally invasive surgery at the Mayo Clinic, Rochester, Minnesota, USA, between January 2009 and June 2016 for newly diagnosed endometrial cancer were mailed our validated 13 item lower extremity lymphedema screening questionnaire. We also ascertained via questionnaire whether the patient was ever diagnosed with lower extremity lymphedema.ResultsAmong 378 patients included in the analysis, 127 (33.5%) had sentinel lymph node biopsy with or without side specific lymphadenectomy (sentinel lymph node cohort) and 251 (66.4%) underwent bilateral lymphadenectomy prior to sentinel lymph node biopsy implementation at our institution or as 'backup' after sentinel lymph node mapping (lymphadenectomy cohort). The prevalence of lower extremity lymphedema was 41.5% (157/378), with 69 patients (18.3%) self-reporting a lower extremity lymphedema diagnosis after their endometrial cancer surgery at a median of 54.3 months (interquartile range 31.2–70.1 months), and an additional 88 patients (23.3%) identified by the screening questionnaire. The prevalence of lower extremity lymphedema was significantly higher in the lymphadenectomy cohort compared with the sentinel lymph node group (49.4% (124/251) vs 26.0% (33/127); pConclusionsSentinel lymph node biopsy was associated with a decreased risk of post-treatment lymphedema compared with lymphadenectomy in patients who underwent surgical staging for endometrial carcinoma.

ObjectiveLow grade serous ovarian cancers characterize a unique clinical pattern and likely less frequent incidence of lymphatic metastasis. The expression level of Ki67 is associated with differences in prognosis and therapy outcome. However, its expression in combination with lymphovascular space invasion has not been evaluated in the prediction of lymphatic metastasis.MethodsPatients with low grade serous ovarian cancer were identified in an institutional database. Patients with primary low grade serous ovarian cancer diagnosed and/or treated at our center between September 2000 and December 2018 were identified. Receiver operator characteristics curve analysis was performed to find the cut-off values of per cent Ki67 to discriminate patients with lymph node metastasis. The association between the presence of lymphovascular space invasion and lymph node involvement was analyzed.ResultsA total of 109 patients with primary low grade serous ovarian cancer were identified in our institution's database. Of these, 72 (66.1%) patients underwent primary surgery with pelvic and para-aortic lymph node dissection. Complete data for Ki67 expression and lymphovascular space invasion were obtained for 61 (84.7%) of these patients. Among them, 37 (60.7%) patients had lymph node metastasis. The presence of lymphovascular space invasion was associated with an increased risk of lymph node metastases (odds ratio (OR)=12.78, 95% confidence interval (CI) 3.15 to 51.81; p65 years, peritoneal carcinomatosis, and ascites>500 mL, lymphovascular space invasion remained a significant risk factor for lymphatic metastases (OR=35.11, 95% CI 2.38 to 517.69; p=0.010). Ki67 ≥6% was associated with a higher risk of lymphovascular space invasion (OR=3.67, 95% CI 1.26 to 10.64; p=0.017). No significant correlation between Ki67 expression level and nodal metastases was found (OR=2.19, 95% CI 0.76 to 6.26; p=0.14). Neither presence of lymphovascular space invasion or nodal metastases was associated with a statistically poorer prognosis.ConclusionsWe showed an association between lymphovascular space invasion, Ki67 expression, and risk of lymph node metastasis in primary low grade ovarian cancer. Further prospective trials evaluating lymphovascular space invasion and Ki-67 as predictors of lymph node metastasis are needed.

ObjectiveTo achieve the full potential of sentinel lymph node (SLN) detection in endometrial cancer, both presumed low- and high-risk groups should be included. Perioperative resource use and complications should be minimized. Knowledge on distribution and common anatomical sites for metastatic SLNs may contribute to optimizing the concept while maintaining sensitivity. Proceeding from previous studies, simplified algorithms based on histology and lymphatic anatomy are proposed.MethodsData on mapping rates and locations of pelvic SLNs (metastatic and non-metastatic) from two previous prospective SLN studies in women with endometrial cancer were retrieved. Cervically injected indocyanine green was used as a tracer and an ipsilateral re-injection was performed in case of non-display of the upper and/or lower paracervical pathways. A systematic surgical algorithm was followed with clearly defined SLNs depicted on an anatomical chart. In high-risk endometrial cancer patients, removal of SLNs was followed by a pelvic and para-aortic lymphadenectomy.Results423 study records were analyzed. The bilateral mapping rates of the upper and lower paracervical pathways were 88.9% and 39.7%, respectively. 72% of all SLNs were typically positioned along the upper paracervical pathway (interiliac and/or proximal obturator fossa) and 71 of 75 (94.6%) of pelvic node positive women had at least one metastatic SLN at either of these positions. Women with grade 1–2 endometroid cancers (n=275) had no isolated metastases along the lower paracervical pathway compared with two women with high-risk histologies (n=148).ConclusionSLNs along the upper paracervical pathway should be identified in all endometrial cancer histological subtypes; removal of nodes at defined typical positions along the upper paracervical pathway may replace a site-specific lymphadenectomy in case of non-mapping despite tracer re-injection. Detection of SLNs along the lower paracervical pathway can be restricted to high-risk histologies and a full pre-sacral lymphadenectomy should be performed in case of non-display.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) occurs in approximately 9% of non-Hodgkin B cell lymphoma. However, it occurs only rarely within the colon. The presentation is often asymptomatic, and can have multiple endoscopic appearances, including a single or multinodular polypoid lesion. Furthermore, small biopsies can make histological evaluation challenging. The 2016 WHO classification update includes many molecular features of entities and expands the differential diagnosis of lymphoid lesions of the colon. In addition to immunohistochemistry, molecular methods may be tempting to use for small difficult cases. Furthermore, treatment approaches are varied for this entity, and not well studied. Therefore, an updated review on MALT lymphoma of the colon is needed.

Pelvic and para-aortic lymphadenectomy is routinely performed in early ovarian cancer to define the stage of the disease. However, it may be associated with increased blood loss, operative time, and length of hospitalization. The sentinel lymph node technique has been shown to be safe and feasible in vulvar, uterine, and cervical cancer. Data detailing feasibility and outcomes of sentinel lymph node mapping in ovarian cancer are scarce.To summarize the studies evaluating the feasibility of sentinel lymph node detection from the ovary, examining the technique and detection rate.A systematic search of the literature was performed using PubMed and Embase from June 1991 to February 2019. Studies describing the sentinel lymph node technique and lymphatic drainage of the ovaries were incorporated in this review. Ten articles were selected, comprising a total of 145 patients. A variety of agents were used, but the primary markers were technetium-99m radiocolloid (Tc-99m), patent blue, or indocyanine green, and the most common injection site was the ovarian ligaments.The overall sentinel lymph node detection rate was 90.3%.We propose a standardized technique sentinel lymph node mapping in ovarian cancer, using indocyanine green, or Tc-99m and blue dye as alternative tracers, injected in both the suspensory and the infundibulopelvic ligament of the ovary.

Hypothyroidism is a well-known cause of pericardial effusion (with an incidence of 3%–37%) and can cause cardiac tamponade in severe cases. In this review, we present the current knowledge on the epidemiology of hypothyroid-induced pericardial diseases, the mechanism through which low thyroid hormone levels affect the pericardium, the associated clinical manifestations, diagnostic tests and management options. Hypothyroidism causes pericardial effusion through increased permeability of the epicardial vessels and decreased lymphatic drainage of albumin, resulting in accumulation of fluid in the pericardial space. Interestingly, autoimmunity does not seem to play a major role in the pathophysiology, and a majority of effusions are asymptomatic due to slow fluid accumulation. The diagnosis is generally made when the pericardial disease is associated with an elevated thyroid-stimulating hormone level, and other secondary causes are excluded. Management consists of thyroid replacement therapy, along with pericardial drainage in case of tamponade.In conclusion, hypothyroidism-induced pericardial diseases are underdiagnosed. Initiating treatment early in the disease process and preventing complications relies on early diagnosis through systematic screening per guidelines.

PurposeTo report the clinical manifestations of 199 patients with suspected conjunctival lymphoma, the associations between these features and the pathological diagnoses, and the prognosis of conjunctival lesions during long-term follow-up.MethodsWe conducted a retrospective chart review of 199 patients who underwent conjunctival biopsy on suspicion of conjunctival lymphoproliferative disease between January 2008 and June 2015. We focused on slit-lamp findings in the conjunctiva and the pathological diagnoses.ResultsIn total, 261 specimens of 199 patients were included in this study. The median age of patients was 42 years (range, 16–87 years), and those over 60 years of age constituted 17.1% of all patients. The proportion finally diagnosed with mucosa-associated lymphoid tissue (MALT) lymphomas was 58.2%. In these patients, the most common slit-lamp findings were the ‘salmon patch’ appearance (73.7%), followed by a follicular appearance (14.5%) and a nodular or subconjunctival mass (6.6%). Bilateral ocular manifestations were more common in patients with disease with the follicular appearance, as compared with patients with the salmon-patch appearance.ConclusionConjunctival MALT lymphoma presents in various ways, not only with the salmon-patch appearance. Therefore, biopsy should be considered if suspicion is raised, even though the conjunctival lesion does not exhibit the typical appearance of MALT lymphoma. In cases of follicular lesions responding poorly to topical steroids, a conjunctival MALT lymphoma may be suspected, given that chronic inflammation may precede neoplasia in patients with extranodal marginal zone lymphoma.

Background Lymph node status is one of the most important prognostic factors in endometrial cancer and crucial for deciding adjuvant therapy. Objective The aim of the study was to assess the different models used to predict lymphatic nodal disease. Search Strategy A literature search was conducted to detect the relevant studies. Inclusion Criteria Relevant papers comparing the preoperative modality with the final histopathological results including randomized clinical trials, case-control studies, and any publications with a minimum of 50 patients in the report. Results Molecular-based predictors are still far from a practical application. Preoperative radiological scans (positron emission tomography, computed tomography, magnetic resonance imaging, and ultrasound) have shown the best predictor of lymphatic dissemination. However, there is currently no ideal model available, which can be used within standard clinical care. Conclusions Surgical staging still remains the criterion standard in the determination of lymph node status in endometrial cancer.

We present the case of a 53-year-old woman with silicone breast implants who underwent excision of an abdominal melanoma and sentinel lymph node biopsy. Two lymph nodes were excised; both lying in the breast parenchyma adjacent to the intact right breast capsule. The lymph node histology revealed a subcapsular melanoma deposit along with silicone lymphadenopathy in the sentinel node. This case highlights that sentinel lymph nodes can be located in alternative locations to the common lymphatic basins and, therefore, the importance of preoperative lymphoscintigraphy. We also discuss subclinical breast implant rupture as a causative factor for silicone lymphadenopathy.

We report a case of an elderly woman, presenting with vesicouterine fistula and enlarged axillary lymph nodes. She had been diagnosed with cervical squamous cell carcinoma (SCC) in April 2015, for which she had received brachytherapy and concurrent chemoradiation therapy. The presence of enlarged axillary lymph nodes raised a suspicion for breast cancer with axillary metastases, but the bilateral mammograms did not show any discrete lesion in both breasts. The biopsy from axillary lymph node showed metastatic SCC, with block positivity for P16, confirming the origin from known cervical primary. Axillary lymph nodes are the least likely to be involved by tumours arising in the pelvis, as the lymphatic drainage of this region goes directly to the systemic circulation via the para-aortic lymph nodes and thoracic ducts. A complete clinical history is essential in such cases, to avoid misdiagnosis. Positron emission tomography CT helps in this regard.

Supplemental digital content is available in the text., Objective Limited data have been obtained in regard to pulmonary metastasis (PM) in patients with stage I endometrial cancer. The aims of the study were (1) to present the clinical and pathological characteristics of patients with PM in the setting of stage I endometrioid-type endometrial cancer (EEC) and (2) to define possible factors that may be used to predict PM. Methods Six hundred thirty patients with stage I EEC, including 12 with PM, 19 with extra-PM (EPM), and 599 with no recurrence, were observed. Paired samples of primary and metastatic tumors from a patient were used for exome sequencing to identify potential gene mutations associated with PM. Results There was no significant difference in the age, Ki-67, lymphatic vascular space invasion, and grade 3 among the 3 groups (P > 0.05). More squamous epithelial differentiation was observed in PM (7/12), as compared with patients with EPM (1/19) (P < 0.05) and no recurrence (20/599) (P < 0.05). The tumor size of the patients with PM was bigger than that of nonrecurrent patients (29.8 ± 16.6 vs 18.5 ± 16.3 mm, P < 0.05). More percentage of patients with deep myometrial invasion (IB) were found in PM (6/12) (P < 0.05) as compared with patients with EPM (3/19) (P < 0.05) and no recurrence (76/599). CDH10, ARID1A, and EMT-associated gene mutations were identified in metastatic tumor tissue but not in primary tumors from a patient with EEC and lung metastases. Conclusions Squamous epithelial differentiation, large tumor size, and deep myometrial invasion might be risk factors for PM in patients with stage I EEC. CDH10, ARID1A, and EMT-associated gene mutation may promote the initiation of lung recurrence. However, further studies are needed to determine the precise mechanisms associated with lung metastasis in these patients.

ObjectiveThe aim of this study was to evaluate the effectiveness of histological grade, depth of myometrial invasion, and tumor size to identify lymph node metastasis (LNM) in patients with endometrioid endometrial cancer (EC).MethodsA retrospective computerized database search was performed to identify patients who underwent comprehensive surgical staging for EC between January 1993 and December 2015. The inclusion criterion was endometrioid type EC limited to the uterine corpus. The associations between LNM and surgicopathological factors were evaluated by univariate and multivariate analyses.ResultsIn total, 368 patients were included. Fifty-five patients (14.9%) had LNM. Median tumor sizes were 4.5 cm (range, 0.7–13 cm) and 3.5 cm (range, 0.4–33.5 cm) in patients with and without LNM, respectively (P = 0.005). No LMN was detected in patients without myometrial invasion, whereas nodal spread was observed in 7.7% of patients with superficial myometrial invasion and in 22.6% of patients with deep myometrial invasion (P < 0.0001). Lymph node metastasis tended to be more frequent in patients with grade 3 disease compared with those with grade 1 or 2 disease (P = 0.131).ConclusionsThe risk of lymph node involvement was 30%, even in patients with the highest-risk uterine factors, that is, those who had tumors of greater than 2 cm, deep myometrial invasion, and grade 3 disease, indicating that 70% of these patients underwent unnecessary lymphatic dissection. A precise balance must be achieved between the desire to prevent unnecessary lymphadenectomy and the ability to diagnose LNM.

AimsThe loss, or decreased expression, of nectin-like molecule 4 (Necl-4; an immunoglobulin-like cell adhesion molecule) is reported to be associated with the development and progression of certain types of cancer. We investigated the clinicopathological significance of Necl-4 expression in patients with pancreatic ductal adenocarcinoma (PDAC).MethodsImmunohistochemical analyses of Necl-4 (n=258) and E-cadherin (n=256) expression were performed using tissue microarray blocks of PDAC samples. Necl-4 expression of 38 pancreatic intraepithelial neoplasia (PanIN) lesions included in tissue microarray cores was also evaluated. Necl-4 and E-cadherin expression was considered positive if >30% of cells were stained, and negative if ≤30% of cells were stained.ResultsNecl-4 expression was positive in 45.7% (n=118) and negative in 54.3% (n=140) of PDAC cases. Necl-4 staining was positive in 96.7% (n=29) and negative in 3.3% (n=1) of low-grade PanIN cases, and positive in 62.5% (n=5) and negative in 37.5% (n=3) of high-grade PanIN cases. The number of cases with positive Necl-4 expression decreased in the order low-grade PanIN>high-grade PanIN>PDAC (p30 mm, perineural invasion, lymphatic involvement, lymph node metastasis (pN1), an advanced TNM (tumour, node, metastases) stage (stage IIB–IV), an advanced histological grade (G2/3), and shorter overall survival. E-cadherin staining was positive in 46.1% (n=118) and negative in 53.9% (n=138) of PDAC cases. Necl-4 expression correlated positively with E-cadherin expression (r=0.405, pConclusionsThe results suggest that Necl-4 is associated with carcinogenesis and aggressiveness of PDAC.

Background Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. Methods Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. Results Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. Conclusions In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.

Lower extremity lymphedema, characterized by accumulation of interstitial fluid, soft tissue swelling, and chronic inflammation, remains a common complication after lymphadenectomy performed in the setting of gynecologic cancer.[1][1] While the overall incidence of lower extremity lymphedema is

An 11-year-old boy with a history of atopy and allergic rhinitis under treatment with sublingual immunotherapy was referred following several episodes of food impaction. Diagnosis of eosinophilic oesophagitis, chronic gastritis and gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated to Helicobacter pylori were confirmed. Results of the extension study were negative and the lymphoma was resolved with eradicating treatment for H. pylori. No improvement was observed in the oesophagitis after the withdrawal of immunotherapy and treatment with high proton pump inhibitor doses or following the omission of several foods to which subclinical sensitisation was confirmed. Oesophagitis was finally resolved by removing cow's milk protein. After 10 years, neither eosinophilic oesophagitis nor MALT lymphoma was observed.Gastric MALT lymphoma associated to H. pylori is a rare disorder in children. Although coexisting H. pylori infection is common in patients with eosinophilic oesophagitis, the association of gastric MALT lymphoma with eosinophilic oesophagitis has not been reported before.

Gorham-Stout disease (GSD) is an extremely rare musculoskeletal disease of unknown aetiology characterised by non-neoplastic proliferation of vascular and lymphatic channels causing massive osteolysis, typically affecting younger individuals. Chylothorax is a known complication of GSD which is postulated to occur from thoracic spine involvement leading to pleural or thoracic duct invasion. In our case, bilateral chylothorax developed in a 60-year-old woman without any thoracic spine involvement of her disease, challenging the proposed mechanism. Despite bilateral pleural drainage and escalating doses of sirolimus, she ultimately developed respiratory failure and shock and succumbed to her illness. Overall survival of GSD is unknown, but when complicated by chylothorax, prognosis is typically poor. GSD represents a diagnostic and management challenge due to the paucity of knowledge surrounding its aetiology and management. These patients require multidisciplinary coordinated care. It is also important to note its high mortality when associated with chylothorax in particular.

BackgroundTo better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.MethodsHumanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.ResultsPET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative.Conclusion89Zr-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of 89Zr-pembrolizumab whole-body distribution in patients.

A 1-week-old female infant presented with a transilluminating neck lump that increased in size with crying. The presumptive diagnosis was lymphatic malformation, but imaging raised the possibility of an abscess or necrotic tumour. A biopsy revealed a likely developmental cyst with local inflammatory change. Microlaryngoscopy revealed a fourth branchial pouch sinus, which was cauterised. The sinus and neck lump resolved without need for further treatment.

Background:Tumour necrosis factor (TNF) induced signaling events are important in lymphoid organ development and function, both in health and in immune-mediated inflammatory diseases such as arthritis. Important receptors involved in this process include TNF receptors (R) I and II that exert distinct functions. Mice overexpressing transmembrane (tm)TNF develop various features of chronic inflammation, including arthritis, that are mediated via TNFRI and/or TNFRII.Objectives:To investigate the importance of TNFRI and TNFRII in spleen and peripheral lymph node (PLN) morphology in mice overexpressing tmTNF.Methods:Spleen and PLN were collected from 13 week old mice with the following genotypes: WT, tmTNF transgenic heterozygotes (tmTNF tg HET), WT x TNFRI-/-, tmTNF tg HET x TNFRI-/-, WT x TNFRII-/-and tmTNF tg HET x TNFRII-/-. Spleens were cut and stained by immunofluorescence for B and T cell markers, imaged by confocal microscopy and analyzed using FIJI software. PLN were used for whole mount tissue staining for B and T cell markers, cleared, 3D imaged by light sheet microscopy and analyzed using Imaris software.Results:Although no macroscopic differences were observed, spleens of tmTNF tg HET animals exhibited an altered morphology characterized by smaller follicles (69,73 ± 72,25 µm2) compared to spleens of WT mice (139,3 ± 71,36 µm2), which was accompanied by a decrease in central T cell areas as measured by % of the total follicle (15,22 ± 9,685; WT 26,60 ± 10,46). WT mice lacking either TNFRI or TNFRII had a morphology comparable to WT (follicle size: TNFRI 234,0 ± 166,9 µm2; TNFRII 154,2 ± 87,92 µm2; % of T cell area: TNFRI 27,81 ± 11,03; TNFRII 28,14 ± 19,66). tmTNF tg x TNFRI-/-exhibited a normal spleen architecture (follicle size: 239,2 ± 250,5 µm2; % of T cell area: 29,92 ± 11,46), whereas the spleen follicles of tmTNF tg x TNFRII-/-mice had T cell areas (17,31 ± 8,88) that were comparable to tmTNF tg HET mice.The size of PLN of tmTNF tg HET mice (3,74 ± 1,31 mm3) was increased compared to WT (2,41 ± 0,60 mm3), also in combination with deficiency of TNFRI (3,98 ± 2,07 mm3) or TNFRII (4,01 mm3). tmTNF tg HET mice had an increase in absolute B cell volume (0,86 ± 0,33 mm3) vs WT (0,51 ± 0,07 mm3) but no change in B cell area as % of total PLN volume. The increased B cell volume was critically dependent on TNF-RII (tmTNF tg HET x TNFRII-/-(14,87). Interestingly, whereas B cell area morphology of tmTNF tg HET, tmTNF tg HET x TNFRII-/-and WT x TNFRII-/-PLN was similar to WT, TNFRI deficiency caused profound alterations in the morphology of the B cell areas that appeared as one peripheral layer of B cells covering a central T cell area rather than properly developed follicles.Conclusion:The current study demonstrates that overexpression of tmTNF leads to an aberrant spleen architecture, characterized by smaller follicles and a decrease in central T cell areas, which is critically dependent on TNFRI. In addition, overexpression of tmTNF results in enlarged PLN and increased total B cell volume, which is dependent on TNFRII, whereas TNFRI is more important in the proper organization of B cell follicles. Overall, this study employing different state-of-the-art (3D) imaging techniques highlights the importance of tmTNF-TNFR-induced signaling events in secondary lymphoid organ morphology and function, and reveals distinct roles for TNFRI and II. Advancing our knowledge in this field might provide a better understanding of the pathophysiology of TNF-associated diseases such as arthritis, which may be important to develop new or improved treatment strategies.Disclosure of Interests:None declared

Background:Lymphoma was one of the most severe complications of primary Sjögren’s syndrome (pSS). Lymphomas often developed in organs where pSS is active, such as salivary glands. The enlargement of salivary glands is considered a predictive factor in previous studies. It is clarified that salivary gland ultrasound can visually and clearly demonstrate the parenchyma structure, which is a feasible method for SS diagnosis. However, there are no specific ultrasound features of salivary gland lymphoma and no early ultrasonic alarming system have been reported.Objectives:To descript the characteristic ultrasound features and assess ultrasonic alarming value of salivary gland lymphoma in patients with pSS.Methods:We followed a cohort of 63 patients with pSS from March 2017 to September 2019 and salivary gland ultrasound was performed every three months. All patients were examined by grey-scale and color Doppler ultrasound (US). The size, echostructure and vascularity of salivary glands were analyzed. US-guided core-needle biopsy (US-CNB) was used for the diagnosis of salivary gland lymphoma.Results:In 63 patients with pSS, parotid enlargement occurred in 11 patients and none of them had submandibular gland enlargement. During the follow-up, 2 patients with parotid enlargement demonstrated recovery of size and echostructure improved. The remaining 9 patients had permanent parotid swelling and echostructure unchanged. US-CNB was performed in these 9 patients and histological and immunohistochemical findings of the cores suggested parotid lymphoma. Compared with other patients, these 9 patients revealed marked, permanent parotid enlargement of the unilateral or bilateral or asymmetric parotid. The parotid lymphoma ultrasonography was characterized by multiple, relatively large, well-demarcated hypoechoic (>6mm) with increased vascularity.Conclusion:Ultrasonographic assessment of salivary gland helped to alarm the occurrence of lymphoma in pSS patients. Marked, permanent and asymmetric parotid enlargement with multiple, relatively large, well-demarcated hypoechoic in echostructure seemed to be characteristic for parotid lymphoma in pSS patients.References:[1]Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796-803.[2]Nocturne G, Mariette X. Sjögren’s Syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol. 2015;168(3):317-27.[3]Alunno A, Leone MC, Giacomelli R, Gerli R, Carubbi F. Lymphoma and lymphomagenesis in primary Sjögren’s syndrome. Front Med (Lausanne). 2018;5:102.[4]Orita Y, Sato Y, Kimura N, Marunaka H, Tachibana T, Yamashita Y, et al. Characteristic ultrasound features of mucosa-associated lymphoid tissue lymphoma of the salivary and thyroid gland. Acta Otolaryngol. 2014;134(1):93-9.Disclosure of Interests:None declared

Background:In patients with primary Sjögren’s syndrome (pSS), both minor and major salivary glands are targets of the disease. Infiltration of salivary glands by immune cells is characteristic for pSS. However, significant inter- and intra-individual variation exists in the size and composition of the infiltrates. Potential differences between minor and major salivary glands in immune cell presence and inflammatory pathway activation are unclear. This knowledge is essential for clinical trial design and precision therapy.Objectives:To compare the transcriptome of paired labial and parotid salivary gland tissue of patients with pSS and non-SS sicca controls.Methods:Thirty-nine pSS patients and 20 age- and sex-matched non-SS sicca controls, who participated in a prospective diagnostic cohort[1], were included. All pSS patients fulfilled 2016 ACR-EULAR criteria. RNA was isolated from formalin-fixed, paraffin-embedded labial and parotid gland tissue sections from the same individuals. Complementary DNA libraries were prepared and sequenced. Biopsies with evidence of sclerosing chronic sialoadenitis or mucosa-associated lymphoid tissue lymphoma were excluded in the current analysis. For differential gene expression analysis, patients were subdivided in four categories: I) non-SS sicca without lymphocytic infiltration, II) non-SS sicca with aspecific infiltration, III) pSS with negative biopsy (focus scoreResults:Principal component analysis (PCA) showed that only pSS patients with a positive biopsy (group IV) could be separated from the non-SS sicca patients based on gene expression. When comparing the labial and parotid gland transcriptome, resp. 798 and 1461 DEGs (FDR-adjusted p-value1) were identified between groups I and IV. The top differentially regulated genes were mostly related to T and B cells.CXCL13, CCR6, MS4A1(CD20), FCRL4andDAZLwere among the genes with the highest positive fold change in both glands of biopsy-positive pSS patients. Overall, there was a moderate to strong correlation between fold changes in labial and parotid glands (R2=0.58, p-valueConclusion:The transcriptome of labial and parotid gland tissue from pSS patients with a positive biopsy is overall comparable, while salivary gland tissue from biopsy-negative pSS patients shows a comparable gene expression profile to non-SS sicca controls. These results indicate that different treatment strategies may be necessary for biopsy-negative and biopsy-positive pSS patients.References:[1]van Nimwegen JF,et al.Validation of the ACR-EULAR criteria for primary Sjögren’s syndrome in a Dutch prospective diagnostic cohort.Rheumatology (Oxford) 2018;57:818–25.Disclosure of Interests:Gwenny M. Verstappen: None declared, Lu Gao Employee of: BMS, Sarah A. Pringle: None declared, Silvia C. Liefers: None declared, Bert van der Vegt Consultant of: Advisory board member for Philips and Visiopharm., Vishal Patel Employee of: BMS, Sarah Hu Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sumanta Mukherjee Employee of: BMS, Arjan Vissink: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant of: Consultant for Bristol-Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Speaker for Bristol-Myers Squibb and Novartis., Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant of: Consultant for Bristol-Myers Squibb, Speakers bureau: Speaker for Bristol-Myers Squibb, Roche and Janssen-Cilag

Background:Auto-antibodies in rheumatoid arthritis (RA) are often present years before disease onset but their mere presence does not seem enough to induce RA. Because several nested-case control studies have shown that autoantibody-response maturation precedes disease onset, it is suggested that it plays a role in disease triggering. At present, it is undetermined whether autoantibody-response maturation occurs in the symptomatic phase preceding clinical arthritis (i.e. Clinically Suspect Arthralgia, CSA), or whether it occurs even earlier in the asymptomatic phase. Secondly, if autoantibody-response maturation is a final step towards clinical disease development, maturation is expected to be present in the patients that progress from CSA to RA, but not in CSA-patients that do not progress.Objectives:To better understand the timeframe of autoantibody-response maturation and its relation to development of RA, we investigated autoantibody-response maturation in patients with CSA that did and did not progress to clinically apparent inflammatory arthritis (IA).Methods:In serum from 148 CSA-patients, we determined the presence and levels of three autoantibodies (ACPA, anti-CarP and AAPA), with three isotypes each (IgM, IgG, IgA), resulting in 9 autoantibody measurements per patient per time-point. Measurements were performed on sera obtained at first presentation at the outpatient clinic and when patients developed IA or else after two years. In-house ELISA was used for all measurements. Three analyses were performed, in patients that progressed to IA (n=56) and in patients that did not progress (n=92) separately. First, in patients negative for all measurements at baseline, we determined the frequency of conversion to seropositivity. Second, in patients with at least one positive test at baseline, we studied the frequency of autoantibody positivity over time. Finally, we determined the change in autoantibody levels in patients positive for the respective autoantibodies at baseline. Frequencies and medians were reported. Statistical significance was tested with Fisher’s Exact test and GEE, taking into account that measurements within one autoantibody type (ACPA, anti-CarP or AAPA) can be correlated.Results:First we studied patients negative for all antibodies at baseline (54% of patients that progressed to IA and 76% of patients that did not progress). 17% of patients that progressed to IA became positive over time, compared to 6% of the patients that did not develop IA (p=0.12). Then we studied patients in whom at least one autoantibody was present at baseline and evaluated autoantibody-positivity over time. In patients that progressed to IA, the number of autoantibodies detected at baseline did not change significantly during follow-up (median 1.5 (IQR 1-3, max. 6) to 1.0 (IQR 1-4, max. 6) (p=0.18)). In the patients with CSA that did not progress similar findings were made (1.0 (IQR 1-2, max. 4) at baseline and 1.0 (IQR 0-2, max. 5) after 2-years (p=0.07)). Increase in number of positive measurements over time took place in only few patients: in 15% of the patients that progressed to IA and in 18% from those that did not progress (p=1.00). Likewise, autoantibody levels did not significantly change over time, both in patients that progressed and in patients that did not progress.Conclusion:The presence of IgM, IgG and IgA ACPA, anti-CarP and AAPA, as well as autoantibody levels, did not significantly increase over time in patients with CSA; this was similar for patients that did and did not develop clinical arthritis. These findings suggest that antibody-response maturation occurs before presenting with symptoms and also that broadening of the autoantibody response is not specific for progression from arthralgia to RA.Disclosure of Interests:None declared

Primary Sjogren’s syndrome is a systemic autoimmune disease characterised by chronic inflammation of exocrine glands, primarily the salivary and lacrimal glands. In the glands, ectopic lymphoid tissue may form, with germinal centre-like structures promoting B-cell DNA rearrangements and Ro/SSA and La/SSB autoantibody production.1 The presence of autoantibodies correlate with disease severity and influence long-term outcome.2 High circulating levels of BAFF also contributes to the polyclonal B-cell activation, and increased plasmablast differentiation and hypergammaglobulinaemia are common.3 4 The autoantibodies can induce production of type I interferons, which further a positive feed-forward loop of chronic B-cell activation.3 Patients with primary Sjogren’s syndrome have a 5–15 times higher risk of lymphoma than the general population, corresponding to a lifetime risk of 5%–10%.5 The malignancies are commonly B-cell non-Hodgkin lymphomas, predominantly marginal zone lymphomas. However, whether there is an increased risk of multiple myeloma in Sjogren’s syndrome has not been unequivocally defined (see online supplementary text).6 Considering the abundance and activity of …

ObjectiveThe aim of this study was to provide detailed knowledge of the metastatic lymph node (LN) locations and to determine factors predicting para-aortic LN metastasis in endometrial cancer patients at risk (intermediate/high) for LN involvement.MethodsA prospective case series with planned data collection was conducted in a total of 173 patients who treated with systematic pelvic para-aortic lymphadenectomy up to the renal vessels. All the LNs removed from pelvic and para-aortic basins—low or high according to the level of the inferior mesenteric artery—were evaluated separately. Logistic regression analyses were performed to determine the impact of variables on para-aortic metastasis.ResultsLymph node metastasis was observed in 21.9% of the patients, pelvic LN involvement in 17.9%, para-aortic LN involvement in 15.0%, both pelvic and para-aortic LN involvement in 10.9%, and isolated para-aortic LN involvement in 4.0%. The most common metastatic LN locations were the external iliac (50.0%), obturator (50.0%), and low precaval regions (36.8%). The least common location of metastasis was the high precaval region (5.3%). Among patients with para-aortic LN metastasis, 42.3% had metastasis above the inferior mesenteric artery. The number of metastatic pelvic LNs greater than or equal to 2 was the only independent predictor of para-aortic metastasis in multivariate analysis (odds ratio, 23.38; 95% confidence interval, 1.35-403.99; P = 0.030), with 96.94% sensitivity, 95.87% specificity, 98.6% positive predictive value, and 97.0% negative predictive value.ConclusionsThe current study supports the idea that in patients at risk of LN involvement, the systematic lymphadenectomy should be performed up to the renal vessels due to the high rate of upper level involvement.

Background Corneal (lymph) angiogenesis is a predominant risk-factor for immune rejection after transplantation. Techniques to regress pre-existing pathological corneal lymphatic vessels prior to transplantation are missing so far. Therefore we analysed the possibility to regress corneal lymphatic vessels by photodynamic therapy (PDT), after intrastromal verteporfin injection. Methods Combined hemangiogenesis and lymphangiogenesis was induced in female BALB/c mice using the murine model of suture-induced inflammatory neovascularisation. Thereafter, the treatment group received an intrastromal injection of verteporfin (controls: phosphate buffered saline (PBS)) followed by PDT. Corneas were excised at different time points (1 day, 5 days and 10 days) after PDT and corneal whole mounts were stained with CD31 and LYVE-1 to quantify hemangiogenesis and lymphangiogenesis. Results Whereas blood vessels showed no significant reduction after PDT, lymphatic vessels could significantly be reduced with PDT after intrastromal verteporfin injection: 1 day after PDT, lymphatic vessels were reduced by 62% (p=0.20). After 5 days and 10 days, lymphatic vessels were reduced by 51% and 48% (p Conclusions This study for the first time shows that PDT after corneal intrastromal verteporfin injection can selectively regress lymphatic vessels. This may become a new ‘preconditioning strategy’ to reduce pre-existing corneal lymphatic vessels prior to transplantation and thereby reduce allograft rejection in high-risk patients.

A 26-year-old man undergoing therapy with 45 mg ustekinumab (Stelara) for chronic psoriasis vulgaris was referred by his general practitioner to an infectious diseases department for fatigue, fever, night sweating, generalised lymphadenomegaly and unexplained weight loss. Physical examination revealed bilateral occipital, cervical, axillary and inguinal lymphadenomegalies in addition to splenomegaly. Preliminary investigation revealed elevated Plasmodium lactate dehydrogenase and an inversion of the CD4/CD8 ratio. Whole-body spiral CT scanning with and without contrast showed splenomegaly and highlighted supradiaphragmatic and subdiaphragmatic lymphadenopathies. A complete Infectious Disease Test Panel revealed high levels of anti-Toxoplasma gondiiantibodies. Immunoglobulin G avidity was negative. Peripheral blood lymphocyte phenotyping was performed to exclude underlying lymphatic neoplasia. The diagnosis of severe acute toxoplasmosis infection in the setting of immune response modifiers was made. Ustekinumab was suspended indefinitely and the patient underwent monthly serological tests to monitor the immune response until all symptoms resolved and the serological testing was negative for Toxoplasma.

We report a preterm neonate who had a large cervical cystic hygroma and right chylothorax. She was operated on day-21 and a near-complete resection of cystic hygroma was done. She developed refractory hypoxemia and shock post surgery and died after 24 hours. During autopsy, the chest cavity was found to be filled with chyle. Histopathological examination showed dilated lymphatics in the pleura, hepatic capsule, serosa of stomach and intestines, peri-pancreatic regions, peri-renal capsule and peri-adrenal tissues suggestive of generalised lymphatic dysplasia. Clinical exome sequencing did not reveal any pathogenic mutation in the genes involved in primary lymphatic dysplasia, noonan syndrome or rasopathies.

General lymphatic anomaly (GLA) is a very rare disorder, characterised by multifocal lymphatic malformations into various tissues that is due to congenital abnormalities of lymphatic development. No treatment has ever proved its efficiency.We report a 22-year-old man with recurrent bronchial casts due to thoracic involvement of GLA. After a 6-month treatment with sildenafil (20 mg three times a day), a phosphodiesterase 5 inhibitor, chest CT scan showed a complete regression of ground-glass opacities and lung function test results improved substantially and remained stable for 1 year. The treatment was well tolerated.This observation suggests that sildenafil may be a therapeutic approach to be tested in thoracic involvement of GLA.

Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphomas of the breast with mammary amyloidosis are exceedingly rare entities. This report describes the case of women with long-standing Sjögren’s syndrome presenting with breast MALT lymphoma and amyloïd light-chain (AL) amyloidosis. Breast microcalcification needle biopsy made the positive diagnosis. This unusual finding should be kept in mind. It emphasises the need for careful clinical examination of nodes and extranodal organs supposedly affected in patients with autoimmune disease.

We report a case of a 79-year-old woman with urinary incontinence who presented at a urogynaecology appointment. Her medical history included rheumatoid arthritis (RA) treated with methotrexate (MXT) for 22 years. A polypoidal lesion was protruding from the meatus urethrae. The histoimmunocytology confirmed a primary superficial spreading malignant melanoma. The tumour was extensively excised, but 8 months later, due to a lymphatic nodal swelling, a positron emission tomography/CT was performed showing a process suspicious of malignant melanoma and multiple distant metastasis. The subsequent treatment was palliative and 1 year later, the patient died. The aetiology of malignant melanomas in the urethra is poorly understood. There is consistent evidence that RA is associated with a number of cancers, but it remains controversial whether this risk is increased with MXT. This case emphasises the importance of gynaecological examination even in patients with only weak symptoms from the pelvic region, especially in patients undergoing immunosuppressive treatment.

Parkes Weber syndrome (PWS) is a rare disorder characterised by arteriovenous (AV) fistula, along with capillary, lymphatic, venous malformations and limb hypertrophy. Stewart-Bluefarb syndrome is a variant of acroangiodermatitis, which is associated with congenital AV malformation/fistulas. It usually begins early in life, unilaterally over lower extremities presenting as violaceous to dusky coloured macules, papules or plaques with tendency to ulcerate. We are reporting a case of AV malformation fulfilling the triad of PWS and presenting with acroangiodermatitis.

Pruritus is a debilitating symptom that can be associated with cutaneous involvement by an underlying malignancy. We report the case of a 68-year-old woman with a history of triple-negative breast cancer who presented with extensive, localised cutaneous metastasis complicated by incapacitating, treatment-refractory pruritus localised to the anatomic regions involved by her metastatic disease. Physical examination revealed an indurated, ecchymotic, ulcerated plaque circumferentially encasing her thorax. Histopathological examination revealed substantial dermal lymphatic involvement and dilation as well as dermal collagen infiltration by tumour cells and nodules. The clinical and pathological findings were consistent with a diagnosis of carcinoma en cuirasse. Mirtazapine, a noradrenergic antidepressant with antiserotonin and antihistamine activity, was started and led to rapid, sustained relief of the patient's pruritus. Mirtazapine may be a useful systemic agent for the palliative relief of pruritus associated with cutaneous infiltration by an underlying malignancy.

ObjectiveTo evaluate the clinical feasibility of sentinel lymph node (SLN) technique and the role of single-photon emission computed tomography with CT (SPECT/CT) compared to lymphoscintigraphy for detection of SLN in vaginal cancer.MethodsThe study was performed in a prospective, unicentric setting. Patients with vaginal carcinoma were scheduled for surgery and SLN labeling by peritumoral injection of 10-MBq technetium Tc 99m nanocolloid and patent blue. After 30 minutes, lymphoscintigraphy and SPECT/CT were carried out. We evaluated the number of SLNs in lymphoscintigraphy, SPECT/CT, and intraoperative histology of SLN and non-SLN as well as the impact of these results to therapeutic approach.ResultsBetween January 2009 and December 2012, the SLN technique was used for 7 of 11 patients treated due to vaginal cancer. Detection rate was 100% (7/7). Lymphoscintigraphy and SPECT/CT showed at least one SLN in each patient. Lymphoscintigraphy detected 2.6 SLNs (range, 2–4 SLNs) per patient compared to 4.3 SLNs (range, 2–8 SLNs) in SPECT/CT (P= 0.053). Sentinel lymph nodes were detected in all patients during surgery with a mean number of 4.3 (range, 1–5). Pelvic SLNs were detected in all 6 patients with infiltration of middle or proximal vaginal third (100%). If the distal vaginal third was additional (3/7 patients) or exclusively (1/7 patients) infiltrated, the inguinal SLN detection rate was 33% and 100%, respectively. All patients with nodal metastases had at least one SLN positive for tumor. There were no false negatives. In 2 (29%) of 7 patients, treatment approach was modified owing to affected SLN.ConclusionThe SLN technique was favorably used in vaginal cancer in this series. It assists in identifying an inguinal and/or pelvic lymphatic drainage. When performed accurately (technetium Tc 99m nanocolloid, lymphoscintigraphy and/or SPECT/CT, blue dye), this technique predicts regional nodal status. This allows tumor stage–adjusted therapy. Single photon emission computed tomography/CT improves preoperative planning and facilitates detection, thus enhancing the clinical value of the SLN technique and improving the oncologic safety of surgery.

Objective To report clinical, histopathological and molecular features of ‘salmon patch’-like conjunctival lesions in paediatric and adolescent patients, and discuss management of these patients and outcome. Methods Patients who presented between 2000 and 2011 with a conjunctival ‘salmon-patch’-like lesion in the plical area, were identified by chart review. Clinical parameters, demographic characteristics and details of ophthalmic imaging were collected, and the effect of treatment examined. Results Eleven patients aged 6–21 years, presented with an elevated pink conjunctival mass in the plical area of one or both eyes. Nine patients underwent an excisional biopsy that histopathologically disclosed extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (also termed ‘MALT lymphoma’) in two cases and reactive lymphoid hyperplasia (RLH) in seven cases. Molecular diagnosis showed polyclonal B cells in six patients, monoclonal B cells in two patients, and a questionable status in one patient. Systemic examination disclosed localised ocular adnexal disease in the patients with MALT lymphoma, and none had either local or systemic recurrence during follow-up. Two other patients were treated with antiallergic medication with resolution of the lesion, and were therefore diagnosed clinically with RLH. Conclusions It is clinically difficult to differentiate between conjunctival RLH and MALT lymphoma in the paediatric and adolescent population. Both lesions are rare in this age group, particularly MALT lymphoma. Molecular analysis of excised lesions does not always correlate with histopathology. A short treatment course with antiallergic drops may sometimes assist diagnosis without compromising the patients due to the indolent nature of lymphoma in that area.

Objective Pterygium is a common, benign fibrovascular disease of the human ocular surface that can impair vision and restrict ocular mobility if not removed. Surgical excision is the most common form of treatment; however, non-surgical therapeutics are being developed, which target the angiogenic component of this disease. Nestin is a class VI intermediate filament protein expressed in neuroepithelium with an emerging role in angiogenesis and tumourigenesis. Given the tumour-like and angiogenic features of pterygia, we postulated that nestin partakes in its development. Methods and Results Formalin-fixed, paraffin-embedded pterygia and donor-matched conjunctiva (n=22) were obtained, sectioned and stained for nestin by immunohistochemistry and immunofluorescence. Immunoreactivity for nestin was semi-quantified and microvessel density counted. Significantly, higher nestin expression was identified in pterygium epithelial cells and blood vessels compared with matched normal conjunctiva. Interestingly, a high proportion of the pterygium specimens displayed nuclear staining for nestin within the basal and suprabasal epithelium. Immunofluorescence was used to simultaneously detect nestin in CD31 + blood vessels; however, this protein was absent from Lyve-1 + lymphatic vessels. In addition, blood and lymphatic vessel density was significantly higher in pterygia compared with corresponding control conjunctiva. Conclusions These results demonstrate for the first time the expression of nestin in the pterygium vasculature and indicate that this protein may play a central role in the angiogenic response, which characterises this disease. Targeting nestin pharmacologically could be considered as an alternative or adjuvant therapeutic strategy.

The carcinogenic potential of trichloroethylene (TCE) continues to generate much controversy, even after the US Environmental Protection Agency raised its classification to 'carcinogenic to humans'. We conducted a meta-analysis of published cohort and case-control studies exploring occupational TCE exposure in relation to five different lymphatic and haematopoietic cancers: non-Hodgkin's lymphoma (NHL, N=24), Hodgkin's lymphoma (HL, N=13), multiple myeloma (MM, N=11), leukaemia (N=12) and chronic/small lymphocytic leukaemia (CLL/SLL, N=7). Studies published between 1950 and 2011 were identified through a PubMed Medline search. All studies included in analyses were classified as those that assessed either occupational TCE exposure specifically ('TCE-exposure' studies) or a broader classification of all chlorinated solvents ('chlorinated solvent-exposure' studies). A significantly raised summary estimate for NHL was seen for all cohort and case-control 'TCE-exposure' studies combined (N=19; relative risk (RR)=1.32, 95% CI 1.14 to 1.54; I(2)=25.20; p-heterogeneity=0.12) and for cohort 'TCE-exposure' studies (N=10; RR=1.52, 95% CI 1.29 to 1.79; I(2)=7.09; p-heterogeneity=0.63). A non-significant but raised summary estimate was seen for NHL case-control 'TCE-exposure' studies. No significant association with NHL risk was detected overall for any 'chlorinated solvent-exposure' studies. Summary estimates for occupational TCE exposure were not associated with risk of HL, MM, leukaemia or CLL/SLL. Our updated meta-analysis of NHL, which incorporates new analytical results from three cohort and four case-control studies, supports an association between occupational TCE exposure and NHL.

Blood and lymphatic vessel invasion (BLVI) has been long recognised as a category I prognostic factor in colorectal carcinomas (CRC) along with the pT and pN categories of the Tumour-Node-Metastasis system, preoperative carcinoembryonal antigen levels and the residual tumour (R) classification.1 Small vessel involvement includes the invasion of capillary-type vessels (figure 1A), where a reliable distinction between lymphatic and blood capillaries cannot be made on H&E-stained or general endothelial marker (eg, CD31, CD34) immunostained sections. Theoretically, the two types of capillary invasion lead to different consequences: lymphatic vessel invasion (LI) precedes and may be predictive of lymph node metastasis, whereas blood capillaries may be the source of systemic dissemination.2–4 The development of lymphatic endothelial markers like podoplanin (D2-40) or lymphatic endothelial hyaluronan receptor (LYVE-1) enables a distinction between lymphatic and blood capillaries: lymphatics can be defined as D2-40, LYVE-1, CD31 and CD34 positive capillaries, whereas blood capillaries are D2-40 and LYVE-1 negative but can be highlighted by CD31 or CD34 antibodies.4–7 Without such a distinction, small vessel invasion is best recorded as (lympho-)vascular invasion (LVI) or angiolymphatic invasion.1 The impact of LI or LVI is mainly seen in patients with conservative removal (eg, polypectomy) of invasive carcinomas without a resection allowing the histopathologic assessment of the lymph nodes. Figure 1 Types of vessel invasion in colorectal carcinomas. (A) Small vessel (ie, capillary) invasion corresponding to (lympho-)vascular invasion. (B and C) Venous invasion (VI) stained by orcein and elastica van Gieson, respectively. Right to the vein invaded by carcinoma is an accompanying artery, which helps the recognition of VI. (D) Invasion of an artery. ((A) CD34 ×400, (B) Orcein ×100, (C) Elastica van Gieson ×100, (D) Orcein ×100). This figure is only reproduced in colour in the online version. By contrast, large vessel invasion includes venous invasion (VI) …