Update and audit of the St George's classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis.

Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, there may be internal lymphatic dysfunction, for example, chylous reflux, or lymphatic malformations, including the thorax or abdomen. A number of causal germline or postzygotic gene mutations have been discovered. Some through careful phenotyping and categorisation of the patients based on the St George's classification pathway/algorithm. The St George's classification algorithm is aimed at providing an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling and associated clinical features. This has enabled the identification of new causative genes. This update brings the classification of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classification for vascular anomalies. The St George's algorithm considers combined vascular malformations and primary lymphatic anomalies. It divides the types of primary lymphatic anomalies into lymphatic malformations and primary lymphoedema. It further divides the primary lymphoedema into syndromic, generalised lymphatic dysplasia with internal/systemic involvement, congenital-onset lymphoedema and late-onset lymphoedema. An audit and update of the algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.

A random forest classifier for lymph diseases.

Machine learning-based classification techniques provide support for the decision-making process in many areas of health care, including diagnosis, prognosis, screening, etc. Feature selection (FS) is expected to improve classification performance, particularly in situations characterized by the high data dimensionality problem caused by relatively few training examples compared to a large number of measured features. In this paper, a random forest classifier (RFC) approach is proposed to diagnose lymph diseases. Focusing on feature selection, the first stage of the proposed system aims at constructing diverse feature selection algorithms such as genetic algorithm (GA), Principal Component Analysis (PCA), Relief-F, Fisher, Sequential Forward Floating Search (SFFS) and the Sequential Backward Floating Search (SBFS) for reducing the dimension of lymph diseases dataset. Switching from feature selection to model construction, in the second stage, the obtained feature subsets are fed into the RFC for efficient classification. It was observed that GA-RFC achieved the highest classification accuracy of 92.2%. The dimension of input feature space is reduced from eighteen to six features by using GA.

Lymphocytic interstitial pneumonia and other benign lymphoid disorders.

Nonneoplastic pulmonary lymphoid disorders consist of a complex spectrum of diseases for pathologists and pulmonologists alike. Advances in our understanding of these disorders in recent years have led to revisions in the classification scheme. This review summarizes the clinicoradiological and pathological features of several benign pulmonary lymphoid disorders as well as the current knowledge regarding their pathogenesis. The disorders discussed include lymphocytic interstitial pneumonitis, follicular bronchiolitis, nodular lymphoid hyperplasia, inflammatory pseudotumor, Castleman disease, immunoglobulin G4-related disease in the lung, and posttransplant lymphoproliferative disease.

[Primitive thoracic lymphatic disease in adults]. / Pathologie lymphatique thoracique primitive de l'adulte.

Primary thoracic lymphatic diseases are both infrequent and probably under diagnosed. Current classification distinguishes lymphangioma (solitary tumor), lymphangiectasies (dilatation), lymphangiomatosis (proliferation) and lymphatic dysplasia syndrome (dysplasia). Classifications' efforts and radiologic progress may lead to an improvement in the management of these patients.

Distribution of PD-1+ lymphocytes in reactive lymphadenopathies.

OBJECTIVES: Programmed death-1 (PD-1) is physiologically expressed by germinal center (GC)-associated helper T cells. It has been proposed that an increase in PD-1+ cells outside GC could indicate pattern I angioimmunoblastic T-cell lymphoma (AITL). METHODS: We studied the distribution of PD-1+ cells in reactive lymphadenopathies (LA), including HIV-associated and dermatopathic LA (n = 5, each), Castleman (n = 3), Kikuchi (n = 2) and Rosai-Dorfman diseases (n = 1), sarcoidoses (n = 7) and follicular hyperplasias (n = 8). RESULTS: The highest concentrations of PD-1+ cells in GC were found in Castleman and Rosai-Dorfman diseases (mean 57 and 50% of total cells, respectively), and the lowest in HIV-associated LA (mean 6%). The highest proportions in paracortices were found in Castleman disease, and in HIV-associated and dermatopathic LA (mean 7, 3 and 2%, respectively). PD-1+ cells predominated in the pale zones of GC in follicular hyperplasia. In HIV-associated LA, PD-1+ cells showed marked marginalization in the GC. No paracortical PD-1+ cells were found in sarcoidoses and Rosai-Dorfman disease. CONCLUSIONS: The varying distribution of PD-1+ cells in defined LA might indicate a functional relevance of these cells in the respective entities. Since increased numbers of PD-1+ cells outside GC are observed in various LA, this finding might not be entirely specific for pattern I AITL.

Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease.

IgG4-related disease sometimes involves regional and/or systemic lymph nodes, and often clinically and/or histologically mimics multicentric Castleman's disease or malignant lymphoma. In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. None of these cases were associated with human herpes virus-8 or human immunodeficiency virus infection, and there was no T-cell receptor or immunoglobulin gene rearrangement. Histologically, systemic IgG4-related lymphadenopathy was classified into two types by the infiltration pattern of IgG4-positive cells: interfollicular plasmacytosis type and intra-germinal center plasmacytosis type. The interfollicular plasmacytosis type showed either Castleman's disease-like features or atypical lymphoplasmacytic and immunoblastic proliferation-like features. By contrast, the intra-germinal center plasmacytosis type showed marked follicular hyperplasia, and infiltration of IgG4-positive cells mainly into the germinal centers, and some cases exhibited features of progressively transformed germinal centers. Interestingly, eight of our nine (89%) cases showed eosinophil infiltration in the affected lymph nodes, and examined patients showed high elevation of serum IgE. Laboratory examinations revealed elevation of serum IgG4 and soluble interleukin-2 receptors. However, the levels of interleukin-6, C-reactive protein, and lactate dehydrogenase were within normal limits or only slightly elevated in almost all patients. One patient showed a high interleukin-6 level whereas C-reactive protein was within the normal limit. Autoantibodies were examined in five patients and detected in four. Compared with the previously reported cases of multicentric Castleman's disease, our patients with systemic IgG4-related lymphadenopathy were significantly older and had significantly lower C-reactive protein and interleukin-6 levels. In conclusion, in our systemic IgG4-related lymphadenopathy showed pathologic features only partially overlapping those of multicentric Castleman's disease, and serum data (especially C-reactive protein and interleukin-6) are useful for differentiating the two. Our findings of eosinophil infiltration in the affected tissue and elevation of serum IgE may suggest an allergic mechanism in the pathogenesis of systemic IgG4-related lymphadenopathy.

Children with significant cervical lymphadenopathy: clinicopathological analysis and role of fine-needle aspiration in Indian setup.

OBJECTIVE: To study the clinicopathological profile of children from India with cervical lymphadenopathy and the role of fine-needle aspiration cytology with special emphasis on tuberculosis as a cause. METHODS: A total of 89 children in the age group of 10 months to 12 years, presenting to our hospital from April 2004 to March 2005, were included. All the patients underwent thorough clinical and investigational assessment vis-à-vis cervical lymphadenopathy. Outcome measurements included clinical status and ability of conventional tests to categorize different types of lymphadenopathy and their utility in diagnosing tubercular lymphadenitis. Interobserver variability was analyzed measuring kappa test and was found to be in agreement. RESULTS: Reactive hyperplasia was the most common type of lymphadenitis, followed by granulomatous involvement. Unilateral posterior triangle lymph nodes were the most commonly affected in the tubercular cervical lymphadenopathy group. Fine-needle aspiration followed by Ziehl-Neelsen staining, histopathology and culture in combination were able to perform the diagnosis in 85.7% of cases affected with tubercular etiology. CONCLUSIONS: Fine-needle aspiration is a valuable diagnostic tool in the management of children with the clinical presentation of enlarged cervical lymph nodes. The technique reduces the need for more invasive and costly procedures, especially in a Third World country. Culture and histopathology, however, should be considered in cases where repeated fine-needle aspiration cytology is non-diagnostic.

Crianças com linfadenopatia cervical significativa: análise clínico-patológica e papel da aspiração por agulha fina no contexto indiano / Children with significant cervical lymphadenopathy: clinicopathological analysis and role of fine-needle aspiration in Indian setup

OBJETIVO: Estudar o perfil clínico-patológico de crianças indianas com linfadenopatia cervical e o papel da citologia aspirativa por agulha fina com ênfase especial na tuberculose como causa. MÉTODOS: Foram incluídas 89 crianças com faixa etária de 10 meses a 12 anos, admitidas em nosso hospital de abril de 2004 a março de 2005. Todos os pacientes foram submetidos a completa avaliação clínica e investigativa em relação à linfadenopatia cervical. Medidas de desfecho incluíram estado clínico e a capacidade de testes convencionais em categorizar tipos diferentes de linfadenopatia e sua utilidade no diagnóstico de linfadenite tuberculosa. A variabilidade interobservador foi analisada através do teste de kappa, tendo boa concordância. RESULTADOS: A hiperplasia reativa foi o tipo mais comum de linfadenite, seguida da granulomatosa. Os linfonodos do triângulo posterior unilateral foram o grupo afetado com maior freqüência no grupo de linfadenopatia cervical tuberculosa. A aspiração por agulha fina, seguida da coloração de Ziehl-Neelsen, histopatologia e cultura em associação, obteve sucesso em realizar o diagnóstico em 85,7 por cento dos casos de etiologia tuberculosa. CONCLUSÕES: A aspiração por agulha fina é uma ferramenta diagnóstica valiosa no tratamento de crianças com apresentação clínica de linfonodos cervicais aumentados. A técnica reduz a necessidade de procedimentos mais invasivos e dispendiosos, principalmente em países em desenvolvimento.Cultura e histopatologia, entretanto, devem ser consideradas em casos nos quais a citologia aspirativa por agulha fina não é diagnóstica.

OBJECTIVE: To study the clinicopathological profile of children from India with cervical lymphadenopathy and the role of fine-needle aspiration cytology with special emphasis on tuberculosis as a cause. METHODS: A total of 89 children in the age group of 10 months to 12 years, presenting to our hospital from April 2004 to March 2005, were included. All the patients underwent thorough clinical and investigational assessment vis-à-vis cervical lymphadenopathy. Outcome measurements included clinical status and ability of conventional tests to categorize different types of lymphadenopathy and their utility in diagnosing tubercular lymphadenitis. Interobserver variability was analyzed measuring kappa test and was found to be in agreement. RESULTS: Reactive hyperplasia was the most common type of lymphadenitis, followed by granulomatous involvement. Unilateral posterior triangle lymph nodes were the most commonly affected in the tubercular cervical lymphadenopathy group. Fine-needle aspiration followed by Ziehl-Neelsen staining, histopathology and culture in combination were able to perform the diagnosis in 85.7 percent of cases affected with tubercular etiology. CONCLUSIONS: Fine-needle aspiration is a valuable diagnostic tool in the management of children with the clinical presentation of enlarged cervical lymph nodes. The technique reduces the need for more invasive and costly procedures, especially in a Third World country. Culture and histopathology, however, should be considered in cases where repeated fine-needle aspiration cytology is non-diagnostic.

The benign lymphoepithelial cyst and a classification system for lymphocytic parotid gland enlargement in the pediatric HIV population.

OBJECTIVES/HYPOTHESIS: The objectives of this study are to present a series of parotid gland benign lymphoepithelial cysts (BLEC) in HIV-positive children and to propose a three-tiered classification system for HIV-associated lymphocytic parotid gland enlargement. STUDY DESIGN: The authors conducted a retrospective case series and literature review. METHODS: The authors conducted a retrospective chart review of four pediatric patients with HIV-associated parotid gland BLEC who presented to a tertiary care university medical center. RESULTS: Four pediatric HIV-positive patients (four girls; age range, 7-17 years [mean age, 12.8 years]) were diagnosed with parotid gland BLEC. Two patients presented with acute parotitis and the others presented with asymptomatic enlargement of the parotid glands. Three patients had bilateral parotid gland BLEC. The other patient demonstrated persistent generalized lymphadenopathy (PGL) of the intraparotid and cervical lymph nodes and early BLEC limited to the left parotid gland. One patient also displayed parotid gland microcalcifications and cystic changes in the adenoids, neither of which have been described previously in the setting of HIV-associated BLEC. Computed tomography was performed on all patients, and one patient underwent fine needle aspiration to confirm the diagnosis. All patients opted for observation and antiretroviral medication therapy as long-term treatment. Based on these findings and a review of the literature, we propose a three-tiered classification system for lymphocytic parotid gland enlargement in the HIV population: 1) PGL, 2) benign lymphoepithelial lesions (BLEL), and 3) BLEC. CONCLUSIONS: This series equals the largest pediatric series of HIV-associated parotid gland BLEC in the English literature. One patient in our series also demonstrated PGL; there were no cases of BLEL. A classification system based on morphology is proposed to help resolve the confusion in terminology used to describe this entity. Most pediatric HIV-infected patients with parotid gland BLEC can be treated with observation and antiretroviral medication therapy. For others, who are symptomatic or more concerned about their cosmetic appearance, sclerotherapy may offer a reasonable option. Radiation therapy and surgery should be reserved for select cases.

Current concepts in lymphatic malformation.

A lymphatic malformation (LM) is the most common form of congenital vascular malformation (CVM). The new Hamburg classification of CVM distinguishes the truncular (T) form from the extratruncular (ET) form of LMs. Both are consequences of a developmental arrest at the different stages of lymphangiogenesis as a result of defective genes. The purpose of this review was to evaluate the current management results of both forms of LMs. A retrospective review of the clinical data of 315 patients with a diagnosis of LMs treated between September 1994 and December 2001 was performed. Lymphoscintigraphy was the most frequent diagnostic test. The patients with the ET form were treated with sclerotherapy with OK-432 and/or ethanol. Combinations of CDP (complex decongestive physiotherapy) and/or compressotherapy were used to treat all the T-form patients. In addition, surgery, either reconstructive or ablative, was offered to patients with the T form who failed to respond to the proper CDP. A multidisciplinary team performed the management of LM, and the results were evaluated every 6 months. Among 797 patients with CVM, 315 were confirmed to have LMs, either as the T form (226) or the ET form (89). Another 66 LMs were diagnosed with hemolymphatic malformations (HLM). Most of the ET forms (89/315) were the cystic type (70/89), while the T forms included aplasia and/or an obstruction (204/226). The ET form was most frequent in the head, neck, and thorax (69/89). The T form was located most frequently to the extremities (202/226), mostly to the lower limb (180/202). Two hundred and twenty-six T forms belonged to the various clinical stages: stages I-32, II-104, III-48, IV-18, and an unclear stage-24. The ET form was treated with sclerotherapy using OK-432 (108/120) and absolute ethanol (12/120). Among the 11 patients with the multiple ET form, 7 patients underwent perioperative sclerotherapy with OK-432 and a subsequent surgical excision. The clinical response of the T form at the extremity to CDP was excellent to good in a majority of clinical stages I to II (121/136) but decreased to a good to fair degree in stages III to IV (31/66). The additional surgical therapy, either reconstructive (10/19) or ablative (9/19), provided limited success in improving CDP efficacy, owing mainly to poor compliance. The long-term outcome of the initial success through self-motivated home-maintenance care during the follow-up period of up to 48 months was totally dependent on patient compliance. OK-432 sclerotherapy to 51 ET forms has shown excellent results on 88.9% of the cystic type (40/45) and 50% (3/6) of the cavernous type (minimum follow-up for 24 months). Seventeen ET forms in 7 patients were treated with a preoperative OK-432 sclerotherapy and a subsequent surgical excision, which provided good to excellent results in 14 for a minimum of 24 months. Primary lymphedema, which is the T form of LMs, can be managed safely by a combination of CDP with compressotherapy. Patients with good compliance can benefit from additional surgical therapy, either reconstructive or ablative. The ET form, particularly the cystic type, can be treated with various scleroagents that are preferably less toxic as the primary therapy. A surgical excision with or without perioperative sclerotherapy provides good results for patients with the localized cavernous type of the ET form. A multidisciplinary team approach is essential for the proper care of LM.

Ketron-Goodman disease, Woringer-Kolopp disease, and pagetoid reticulosis.

In this historical review I will synopsize the original articles by Lloyd W. Ketron and M.H. Goodman who described Ketron-Goodman disease, by Frederic Woringer and Pierre Kolopp who described Woringer-Kolopp disease, and by Otto Braun-Falco and colleagues who described pagetoid reticulosis. In their publications, each of these authors reported on one patient. I will review the clinical picture of the three patients, their histopathology, and the pathogenesis of each disease as suggested by the above authors. Then the views of others that have written on the subject recently will be reviewed particularly as to their conception of the diseases. Publications that describe the histopathology of the patch (early) stage of mycosis fungoides will be redacted to compare it to the histopathology of Ketron-Goodman disease, Woringer-Kolopp disease, and pagetoid reticulosis. I will discuss whether any or all of them are diseases sui generis, whether they are one, two, or three entities, or whether any or all are but forms of mycosis fungoides.

[Classification of vascular anomalies (tumours and malformations). Clinical characteristics and natural history]. / Clasificación de las anomalías vasculares (tumores y malformaciones). Características clínicas e historia natural.

Vascular anomalies are divided into tumours and malformations. Haemangiomas are the most frequent amongst the former. Not normally present at birth, except in a premonitory form, they grow for 10-12 months due to hyperplasia, to subsequently undergo a progressive involution for a period that might last from ten to twelve years. They have an incidence of up to 12% in newborns; they are more common amongst girls; and are divided into superficial, deep and compound. Congenital haemangiomas and those that do not undergo involution are considered to be rare entities. Vascular malformations, with a lower incidence than haemangiomas, are always present at birth, they grow by hypertrophy and never undergo involution. According to the classification of the ISSVA, vascular malformations are divided - depending on the vessel affected - into capillary or venular (port-wine stain), venous, lymphatic, arteriovenous and combined or complex. Each of these has certain defining clinical and haemodynamic peculiarities. Within the final group are included some with a low flow, such as the Klippel-Trenaunay syndrome (venous and lymphatic venular vascular malformation associated with the muscular-skeletal hypertrophy of an extremity), and others with a high flow, such as the Parkes-Weber syndrome.

[Pathogenesis and treatment strategies for lymphorrhea and lymphocele after vascular surgeries on the lower extremities]. / Patogenez i taktika lecheniia limforei i limfotsele posle sosudistykh operatsii na nizhnikh konechnostiakh.

From 1995 to 2003 lymphatic complications (lymphorrhea and lymphocele) after different vascular surgeries on the lower extremities were seen in 57 (4.6%) patients. All the methods of therapeutic and surgical treatment of lymphorrhea and lymphocele are presented. Problems of surgical policy and some aspects of pathogenesis of these complications are regarded. Ethiopathogenetic classification of lymphatic complications is proposed. Creation of lymphovenous anastomosis is regarded as the most promising method. This surgery was performed in 31 patients, efficacy was 96.8%. The method permits one to stop inflow of lymph into lymphatic cavity and to avoid lymphedema after surgery. Other methods of treatment have various efficacy.

[Diseases of the pulmonary lymphatic system in children]. / Pathologies des lymphatiques pulmonaires chez l'enfant.

Diseases of the lymphatic system in children include a group of exceptional conditions difficult to manage. The anatomy of lymphatic system is complex in the lung. Variable from one subject to another, its complex physiology plays an important role in air-blood exchanges occurring in the lung. In the pulmonary interstitium and in the pleura, the lymphatic system acts like an overflow valve capable of regulating variations in interstitial fluid. The presence or development of dysplasic lymphatics causes leakage, dilatation, and reflux of the lymph through incontinent valves leading to chylothorax and/or fluid overload in the pulmonary interstitium. Symptomatic care is usually proposed, based on a fat-free diet supplemented with light-chain triglycerides and liposoluble vitamins. Other therapeutic options can be proposed. Medical options include cytotoxic agents, somatostatin, and interferon-alpha. Surgery may also be useful, but an assessment of therapeutic efficacy is very difficult due to partial effects and the small number of cases studied.