Chylothorax as Rare Manifestation of Pleural Involvement in Waldenström Macroglobulinemia: Mechanisms and Management.

Here we report the clinical, pathological, and immunological features of a rare case of Waldenström macroglobulinemia (WM) with pleural infiltrations. An atypical chylothorax, successfully treated by videothoracoscopy, represented the main clinical feature of this case of low-grade lymphoplasmacytic lymphoma. Pleuropulmonary manifestations are rare (from 0 to 5% of cases) in WM, with chylothorax observed in just seven patients worldwide. In addition to describing this uncommon clinical presentation, we investigate hypothetical pathogenetic mechanisms causing chylothorax and through an up-todate review of available literature furnish helpful suggestions for diagnosis and management of chylothorax in WM patients.

Chyloperitoneum: Diagnostic and Therapeutic Options.

Chyloperitoneum is not rare and is often associated with other chylous disorders particularly in more complex clinical conditions. An accurate diagnostic study is indispensable to plan the correct therapeutic approach, and we examined the long-term outcomes of our experience in the management of primary and secondary chyloperitoneum in fifty-eight patients (50 adults and 8 children; 34 primary and 24 secondary forms). Diagnostic assessment consisted of aracentesis, whole body lymphoscintigraphy, lymphangio-MR, and lymphangio-CT (LAG-CT). The management of chyloperitoneum consisted initially of non-operative procedures (MCT diet, TPN, octreotide). Surgical treatment was performed in patients not responsive to conservative methods and involved different options using surgical and microsurgical approaches. Microsurgical techniques included chylousvenous shunts connecting chyliferous vessels and mesenteric veins. Fibrin glue or platelet gel injection at the site of the chylous leakage was also used to treat one case of refractory secondary chyloperitoneum. Patients were followed clinically and instrumentally (echography and labs tests) for 6 months to over 5 years. We found that LAG-CT was the primary diagnostic modality to provide precise topographic information concerning the site, cause, and extension of chylous pathology, all of which allowed proper planning of therapeutic procedures. Thirty-four patients did not have a relapse of the chyloperitoneum and 22 patients had a persistence of a small quanitity of ascites with no protein imbalance. We observed early relapse of chylous ascites in 2 cases that required a peritoneal-jugular shunt leading to good outcomes. An accurate diagnostic study (above all LAG-CT) and a microsurgical approach proved to represent an effective management of chyloperitoneum refractory to non-operative treatment.

Dermatological consultations in an observation unit of an emergency department in Italy.

BACKGROUND: Dermatological emergencies exist and should not be underestimated. On the other hand, many accesses to the emergency department (ED) of patients with dermatological conditions are unjustified. OBJECTIVE: Our main objective is to describe dermatological conditions seen in an ED observation unit (EDOU). Secondly, our aim is to identify alarm symptoms and signs of 'true emergencies'. METHODS: We conducted a prospective study, including dermatological patients admitted to EDOU of the University Hospital of San Martino, Genoa, Italy, in 3 years. RESULTS: Overall 372 patients were studied. The most common condition seen was infection (41.67%) (mainly bacterial), followed by atypical exanthem (13.98%) and vasculitis (11.29%). The highest rate of cases peaked in May (13%); infectious diseases showed two peaks (spring and autumn). CONCLUSION: Given constraints involved in health care today, it is crucial to understand which dermatological presentations are 'true emergencies'. In such a scenario knowing the epidemiology of dermatological emergencies and the alarming skin signs and symptoms might be useful.

INTERMITTENT NEGATIVE PRESSURE THERAPY IN THE COMBINED TREATMENT OF PERIPHERAL LYMPHEDEMA.

Intermittent negative pressure devices were initially developed by NASA to enhance blood perfusion and combat a reduction in orthostatic tolerance. Investigational studies have demonstrated that the pressure differential produces changes in the blood and cardiac systems and also documented changes in weight and cellulite in obese patients. Although the mechanisms are not known, previous investigation has also reported changes in lymphedematous limbs. These initial results suggested to us that the inclusion of intermittent negative pressure into a lymphedema treatment protocol would be beneficial. We subsequently undertook a study of 50 patients with lymphedema adding intermittent negative pressure to our CLyFT protocol and compared them to the CLyFT protocol without intermittent negative pressure. We found a significant difference between the groups with an additional 7% reduction in lymphedema volume (p = 0.008). Our study results indicate that the inclusion of intermittent negative pressure therapy into the CLyFT protocol was beneficial and further incorporation into other protocols should be investigated.

OPTIMIZING THE STAGING OF MELANOMA PATIENTS FOR THEIR BEST SURGICAL MANAGEMENT.

Interval nodes (IN) are defined as lymph nodes that lie along the course of lymphatic collecting vessels between a primary tumor site and a draining node field. Sometimes INs contain metastases and a consensus on their surgical management is needed. Therefore, to optimize the surgical management of melanoma patients with metastatic lymphatic involvement, especially when the sentinel lymph node biopsy identifies an unusual drainage field, we identified patients treated at the Department of Plastic and Reconstruction Surgery of Bari between July 1994 and December 2012 identified with a primary-cutaneous melanoma who underwent lymphoscintigraphy and subsequent positive-IN the lymphadenectomy to evaluate the impact of this procedure on overall survival and disease-free-period. 51 patients presented INs, and lymphadenectomy (LA) of the subsequent lymphatic field was performed in 13 subjects with positive-IN. In 4 cases additional lymphatic metastases were detected in the usual basin beyond the IN+. Recurrence-free period and survival rate at 5 years were higher in patients with positive-IN who underwent LA than in subjects who underwent LA due to positive lymph nodes in the usual field. Immediate lymphadenectomy of the subsequent lymphatic field in patients with positive-INs may afford patients earlier stage treatment of their disease and improved prognosis.

Chylopericardium: a case report demonstrating utility of lymphography combined with 3D computed tomography for corrective surgical treatment using VATS.

We present a case of a 58 year-old woman with primary chylopericardium associated with chylothorax. Chylopericardium is a condition in which chylous fluid containing a high concentration of triglycerides accumulates in the pericardial cavity, and it can form for many different reasons. 3D computed tomography with lymphography precisely depicted the specific location of the lymphatic leak in this patient, which was successfully repaired using targeted video assisted thoracic surgery (VATS).

Lymphoscintigraphy patterns in newborns and children with congenital lymphatic dysplasia.

We performed lymphoscintigraphy on 31 patients (newborns and children) affected by congenital lymphatic dysplasia according to our previously published protocol. Congenital lymphatic dysplasia may present with various degrees of clinical severity, ranging from nonimmune hydrops fetalis with visceral effusions to lymphedema alone. We recommend that lymphoscintigraphy should be strongly considered in all patients with signs of lymphatic dysplasia, including those with minimal and initial signs of lymphatic impairment, in order to obtain a very early diagnosis and to start treatment. Lymphoscintigraphy is safe and useful in the diagnosis of lymphatic dysplasia in the newborn and children. Moreover, it is well tolerated by patients and well accepted by their parents.

Dynamics of pleural fluid effusion and chylothorax in the fetus and newborn: role of the lymphatic system.

Pleural fluid effusion particularly chylothorax is a relatively rare occurrence in the newborn, but when it occurs it is often life-threatening. In this article, we describe and illustrate the morphologic features of the visceral and parietal pleura including pleural lymphatics and the physiology and pathophysiology of pleural fluid balance. The role and function of the lymphatic system in controlling the volume and composition of pleural liquid are detailed and a conceptual scheme presented. Finally, the crucial role of inadequate lymphatic drainage (either functional overload from an imbalance in Starling forces or mechanical insufficiency from lymphatic dysplasia) is emphasized.

Surgical prevention and treatment of lymphedema after lymph node dissection in patients with cutaneous melanoma.

Despite the development of minimal access dissection techniques, use of superficial groin dissection alone, and other recommendations to reduce morbidity in melanoma treatment, the incidence of lymphedema is still significant. The purpose of the current study was to assess the efficacy of microsurgical methods to limit the morbidity of inguinal lymphadenectomy. We conducted a retrospective review of patients who underwent groin dissection for melanoma treatment from February 2006 to April 2009. A total of 59 melanoma patients with positive groin lymph nodes comprised 18 patients (T-group) with melanoma in the trunk and 41 patients (E-group) who had melanoma in an extremity and currently have lymphedema. The T-group patients underwent primary prevention of lymphedema with microsurgical lymphatic-venous anastomoses (LVA) performed simultaneously with groin dissection. The E-group patients underwent LVA to treat the secondary lymphedema after an accurate oncological and lymphological assessment. Limb volume measurements and lymphoscintigraphy were performed pre- and postoperatively to assess short and long term outcome. No lymphedema occurred after microsurgical primary preventive approach in the T- group. Significant (average 80% reduction of pre-op excess volume) reduction of lymphedema resulted after microsurgical treatment for secondary leg lymphedema. Post-operative lymphoscintigraphy in 35 patients demonstrated patency of microsurgical anastomoses in all cases with an average follow-up of 42 months. Study results demonstrate that microsurgical LVA primary prevention prevented lymphedema after inguinal lymphadenectomy in the T-group patients. In addition, lymphatic-venous multiple anastomoses proved to be a successful treatment for clinical lymphedema with particular success if treated at the early stages.

Addition of Intermittent Pneumatic Compression to Conventional Treatment Improves Volume Reduction Before Lymphatic Surgery for Lower Limb Lymphedema: A Pilot Study.

This study assesses the impact of an advanced intermittent pneumatic compression device (IPC - Lympha Press® Optimal Plus) when added to Complete Decongestive Therapy (CDT) compared to CDT alone on volume reduction of limbs with lymphedema. The goal is to maximally reduce edema in preparation for microsurgery. Fifty subjects scheduled for Multiple Lymphatic-Venous Anastomosis (MLVA) were randomly (sequentially) assigned to experimental or control group: 25 (21 females and 4 males) in the experimental IPC group and 25 (20 females and 5 males) in the control group. The two groups were similar in age, sex distribution, and type of lymphedema. Results indicate the IPC group reported greater volume loss than the control group (p= 0.00137) comparing final vs. initial limb volume. The average percentage edema volume loss achieved with added IPC was two times greater (11.7%) than in the control group (5.0%). When differences in treatment duration were accounted for, the IPC group achieved consistently greater proportional volume loss (12.83% vs 6.30%) than conservative therapy alone. In our pilot study, IPC added to CDT resulted in greater proportional volume loss and provides better preparation for MLVA surgery.

Immunodeficiency due to chylous dysplasia: diagnostic and therapeutic considerations.

Among primary immunodeficiencies, common variable immunodeficiency (CVID) is defined by an impaired production of immunoglobulins characterized by low levels of plasma immunoglobulins and an altered antibody response. The case reported here was initially interpreted as a CVID. A 20 year old male suffered from diarrhea, weight loss, and malnutrition. Accurate diagnostic assessment uncovered a protein-losing enteropathy. Conventional oil contrast lymphangiography accurately documented the underlying problem and established the appropriate therapeutic approach. The operation consisted of multiple antigravitational ligatures of dilated and incompetent chylous vessels and chylous vessel-mesenteric vein microanastomoses. Serum albumin and leukocyte counts normalized by 1 week after operation and remained stable with time. There were no more episodes of diarrhea, and the patient regained weight. Accurate diagnostic assessment and particularly lymphangiography may be necessary to properly define difficult cases of immunodeficiency due to intestinal protein loss and to plan a corrective therapeutic functional approach.

Are there lymphatic vessels in the placenta?

The role of lymphatics in placentation has been scantily studied and the true existence of placental lymphatics is under debate. Numerous blood and lymphatic-lineage molecule markers are now available and they are expressed in human placental tissue. D2-40 expression at the placental stromal level seems to indicate that network-forming, podoplanin-expressing cells may act as a reticular-lymphatic-like conductive network. This exciting area at the intersection of perinatology and lymphology needs further investigation.

Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study.

This retrospective study was carried out at eight Neonatal Intensive Care Units (NICU) Centers worldwide on 33 newborns presenting at birth with pleural, pericardial, or abdominal chylous effusions. Diagnosis of chylous effusion is based on findings of fluid with a milk-like appearance, a concentration of triglycerides in pleural effusion >1.1 mmol/l, and a total cell count >1,000 cells/ml with a predominance of >80% lymphocytes. Thirty-three newborns met the inclusion criteria and were studied. Six subjects who presented at birth with fetal effusion were treated by in-utero pleuro-amniotic shunt. Five of these patients are alive at follow-up. At birth, pleural drainage was performed in 29/33 patients and abdominal drainage was carried out in 3/33. Total parenteral nutrition (TPN) was given to 32/33 patients; 19/23 patients were fed a medium-chain triglycerides (MCT). No adverse effects were observed. Eight patients were treated with Octreotide at dosages ranging from 1 to 7 mcg/kg/hour for 8 to 35 days. All patients showed decreased chylous production. Two patients were treated by pleurodesis. Twenty-two babies are alive after at least 6 months follow-up, 9/33 are deceased, and 2 were lost to follow-up. Clinical conditions of survivors are basically good except for lung involvement [chronic lung disease (CLD) or lung lymphangiectasia] and lymphedema. All patients were using a MCT diet at follow-up with good control of chylous effusion. Visceral chylous effusions of the fetus and neonate are rare disorders, and there currently is only partial agreement on decision-making strategies. We suggest the need for an international prospective trial in an effort to establish the efficacy and effectiveness of diagnostic and therapeutic options described in this article.

Perinatal deaths and lymphatic system involvement: a diagnostic flow-chart applying immunohistochemical methods.

A diagnostic flow chart is presented for use in case of perinatal death or still birth with non-immune hydrops fetalis, visceral effusions, or increased nuchal translucency. Immunohistochemical staining with CD-31, CD-34, D2-40, and smooth muscle actin is recommended.

Congenital lymphatic dysplasia in Kabuki syndrome: first report of an unusual association.

Kabuki syndrome was first described in Japan in 1981 as a rare disorder of unknown cause. Its main features include characteristic facies, postnatal growth retardation, and mental delay. To date, there is no molecular marker for Kabuki syndrome, which is considered genetically heterogeneous and still is a clinically-based diagnosis. Here we describe the first case of a patient affected by Kabuki syndrome associated with lymphatic dysplasia. We suggest accurate evaluation of all Kabuki patients as early as possible in order to diagnose lymphedema or other clinical manifestations of lymphatic system involvement. Early identification of lymphatic system maldevelopment provides the best chance for reducing the risk of developing progressive lymphedema with associated tissue changes (fibrosis, sclerosis, and fat deposition).

Lymphovenous anastomosis for the treatment of lymphedema: A systematic review of the literature and meta-analysis.

Lymphovenous anastomosis (LVA) has been described as an effective treatment for early stages of lymphedema (LE). The aim of this study was to deepen the evaluation of the effectiveness of LVA by performing a metaanalysis to provide information about its utility in specific anatomical sites, clinical stages, duration of lymphedema, and surgical technique. A systematic literature search using PubMed/Medline, Google Scholar, and Cochrane Database was performed in November 2019. Only original studies in which exclusively LVA was performed for primary and/or secondary lymphedema in humans were eligible for data extraction. A meta-analysis was performed on articles with a well-defined endpoint and a subgroup analysis was conducted in relation to surgical technique, duration of lymphedema, stage of pathology. Forty-eight studies, including 6 clinical trials and 42 lowrisk bias observational studies were included in our meta-analysis. 1,281 subjects were included and the majority of articles reported a pre-post analysis. Lymphaticovenular anastomosis appears to result effectively in treatment of lymphedema with an odds ratio of 0.07 (CI: 0.04, 0.13, p<0.001). All subgroup metaanalyses were statistically significant for LVAs specifically with regard to anatomical site, clinical stage, duration of LE, or type of microsurgical procedure (p<0.05). Our meta-analysis confirmed the efficacy of LVAs for the treatment of lymphedema, even when subgroup analysis was performed for clinical stage, duration of pathology, anatomical site of lymphedema, or type of microsurgical procedure. Further prospective trials with a common clearly defined outcome measure are warranted for an unbiased evaluation.

Congenital lymphatic dysplasias: genetics review and resources for the lymphologist.

Diagnosing congenital lymphatic dysplasia and counseling the parents of babies with possible genetic conditions represents a difficult task. This article attempts to provide a guide to establishing genetic tools and a reference library for use in the diagnostic work-up of congenital lymphatic diseases. The tools that are outlined herein are not meant to replace genetic counseling; their role is merely to facilitate the interaction between lymphologist and geneticist. These tools are a way of identifying lymphatic dysplasias at a very early stage.

Selective D2-40 lymphatic endothelium immunoreactivity in developing human fetal skin appendages.

D2-40 is a novel monoclonal antibody that recognizes a 40,000 Da O-linked sialoglycoprotein podoplanin. Although its use is becoming more common, little work has been done with human foetuses. We initiated an evaluation of D2-40 antibody immunoreactivity in developing cutaneous adnexa of human fetuses at various gestational ages. Starting from a retrospective cohort of 1,098 human fetal autopsies we identified and selected a total of 48 fetuses ranging from the 12th week gestational age to term appropriate for this study. We demonstrated that the gems of the hair follicles were D2-40 negative in fetuses from the 12th to 15th week gestation, positive in fetuses between the 16th and 20th week of gestation, negative in fetuses from the 21st week gestation to term. Normal adult controls were also negative. This is the first report to demonstrate intense D2-40 immunoreactivity in the gems of hair follicles of developing human skin.

Prospective evaluation of a prevention protocol for lymphedema following surgery for breast cancer.

Lymphedema is a common complication of axillary dissection and thus emphasis should be placed on prevention. Fifty-five women who had breast-conserving surgery or modified radical mastectomy for breast cancer with axillary dissection were randomly assigned to either the preventive protocol (PG) or control group (CG) and assessments were made preoperatively and at 1, 3, 6, 12 and 24 months postoperatively. Arm volume (VOL) was used as measurement of arm lymphedema. Clinically significant lymphedema was confirmed by an increase of at least 200 ml from the preoperative difference between the two arms. The preventive protocol for the PG women included preoperative upper limb lymphscintigraphy (LS), principles for lymphedema risk minimization, and early management of this condition when it was identified. Assessments at 2 years postoperatively were completed for 89% of the 55 women who were randomly assigned to either PG or CG. Of the 49 women with unilateral breast cancer surgery who were measured at 24 months, 10 (21%) were identified with secondary lymphedema using VOL with an incidence of 8% in PG women and 33% in CG women. These prophylactic strategies appear to reduce the development of secondary lymphedema and alter its progression in comparison to the CG women.

The role of lymphoscintigraphy in the diagnosis of lymphedema in Turner syndrome.

Lymphedema can be present in patients affected by Turner syndrome (TS) with the dorsum of the hands and feet most commonly affected. This lymphedema results from underdevelopment of the lymphatic system before birth, and it usually decreases during childhood. The aim of our study was to evaluate the role of lymphoscintigraphy as a diagnostic tool in patients with TS to assess possible impairments in the lymphatic system. Eighteen patients with TS were karyotyped to confirm diagnosis and were evaluated by lymphoscintigraphy. Lymphatic dysfunction was demonstrated in 15/18 patients. Lymphoscintigraphic studies showed: 1) lymphatic channels, 2) collateral lymphatic channels, 3) interrupted lymphatic structures, and 4) lymph nodes of the deep lymphatic system. Our data demonstrate that lymphoscintigraphy should be mandatory not only in patients affected by Turner syndrome with signs of lymphatic dysplasia but also in those with minimal or absent signs of lymphatic impairment in order to obtain a very early diagnosis and to provide substantial information for possible medical or surgical treatment.