Cutaneous Lymphatic Malformations Research Articles

Erythematous capillary-lymphatic malformations mimicking blood vascular anomalies.

Superficial erythematous cutaneous vascular malformations are assumed to be blood vascular in origin, but cutaneous lymphatic malformations can contain blood and appear red. Management may be different and so an accurate diagnosis is important. Cutaneous malformations were investigated through 2D histology and 3D whole-mount histology. Two lesions were clinically considered as port-wine birthmarks and another 3 lesions as erythematous telangiectasias. The aims were (i) to demonstrate that cutaneous erythematous malformations including telangiectasia can represent a lymphatic phenotype, (ii) to determine if lesions represent expanded but otherwise normal or malformed lymphatics, and (iii) to determine if the presence of erythrocytes explained the red color. Microscopy revealed all lesions as lymphatic structures. Port-wine birthmarks proved to be cystic lesions, with nonuniform lymphatic marker expression and a disconnected lymphatic network suggesting a lymphatic malformation. Erythematous telangiectasias represented expanded but nonmalformed lymphatics. Blood within lymphatics appeared to explain the color. Blood-lymphatic shunts could be detected in the erythematous telangiectasia. In conclusion, erythematous cutaneous capillary lesions may be lymphatic in origin but clinically indistinguishable from blood vascular malformations. Biopsy is advised for correct phenotyping and management. Erythrocytes are the likely explanation for color accessing lymphatics through lympho-venous shunts.

TOPICAL TACROLIMUS 0.1% FOR TREATMENT OF CUTANEOUS MICROCYSTIC LYMPHATIC MALFORMATIONS

Microcystic lymphatic malformations as described in the international literature form a subgroup of low-flow congenital vascular malformations (VM) resulting from irregular embryological development. Microcystic lesions normally manifest as an accumulation of lymph- and blood-filled vesicles that, when externalized, cause skin maceration with consequent pain and potential infection resulting in the impairment of the patient's quality of life. There is no consensus on a standardized algorithm nor clear guidelines for successful treatment of this type of lymphatic malformation, and treatment options employed often result in ambivalent and transient outcomes with a high rate of recurrence. The topical formulation of tacrolimus is a well-known FDAapproved anti-T cell agent that was recently identified as a potent activator of ALK1, which is involved in several processes and functions including angiogenesis. We investigated if topical administration of tacrolimus may be an effective therapy for directly targeting cutaneous microcystic lymphatic malformations as a complement to systemic treatment. The study enrolled four patients with cutaneous microcystic lymphatic malformations: three male (ages: 13,15,18) and one female (age: 30). Two of the patients presented lesions on their backs, one patient on the left hand and one on the left lower limb. All four patients received treatment with topical tacrolimus 0.1% twice a day for 10 weeks on a previously selected area for application. Weekly clinical follow-ups were conducted along with close physician-patient contact. All patients displayed a satisfactory response after treatment. Lymphorrhea and bleeding were stopped in all cases and the esthetic aspect of lesions improved in two patients. To date, all patients presented no clinically significant changes to the size or extension of the lesion. Topical tacrolimus treatment is a promising and reasonable option for microcystic lymphatic malformations. Our results encourage further exploration in larger populations with the consideration that it is a safe and effective alternative or complementary therapy to systemic treatment.

Sensitive detection of Cre-mediated recombination using droplet digital PCR reveals Tg(BGLAP-Cre) and Tg(DMP1-Cre) are active in multiple non-skeletal tissues.

In humans, somatic activating mutations in PIK3CA are associated with skeletal overgrowth. In order to determine if activated PI3K signaling in bone cells causes overgrowth, we used Tg(BGLAP-Cre) and Tg(DMP1-Cre) mouse strains to somatically activate a disease-causing conditional Pik3ca allele (Pik3caH1047R) in osteoblasts and osteocytes. We observed Tg(BGLAP-Cre);Pik3caH1047R/+ offspring were born at the expected Mendelian frequency. However, these mice developed cutaneous lymphatic malformations and died before 7weeks of age. In contrast, Tg(DMP1-Cre);Pik3caH1047R/+ offspring survived and had no cutaneous lymphatic malformations. Assuming that Cre-activity outside of the skeletal system accounted for the difference in phenotype between Tg(BGLAP-Cre);Pik3caH1047R/+ and Tg(DMP1-Cre);Pik3caH1047R/+ mice, we developed sensitive and specific droplet digital PCR (ddPCR) assays to search for and quantify rates of Tg(BGLAP-Cre)- and Tg(DMP1-Cre)-mediated recombination in non-skeletal tissues. We observed Tg(BGLAP-Cre)-mediated recombination in several tissues including skin, muscle, artery, and brain; two CNS locations, hippocampus and cerebellum, exhibited Cre-mediated recombination in >5% of cells. Tg(DMP1-Cre)-mediated recombination was also observed in muscle, artery, and brain. Although we cannot preclude that differences in phenotype between mice with Tg(BGLAP-Cre)- and Tg(DMP1-Cre)-mediated PIK3CA activation are due to Cre-recombination being induced at different stages of osteoblast differentiation, differences in recombination at non-skeletal sites are the more likely explanation. Since unanticipated sites of recombination can affect the interpretation of data from experiments involving conditional alleles, we recommend ddPCR as a good first step for assessing efficiency, leakiness, and off-targeting in experiments that employ Cre-mediated or Flp-mediated recombination.

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial

BackgroundCutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.MethodsThis French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2.DiscussionFor patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.Trial registrationClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018–001359-11.

Klippel-Trenaunay Syndrome

Klippel-Trenaunay syndrome or KTS is a complex vascular syndrome associated with overgrowth occurring as a result of somatic mutations in the PIK3CA gene. Patients are diagnosed on the basis of physical findings, sometimes with supportive imaging, of commonly a segmental anomaly with a cutaneous port-wine stain, lymphatic and venous malformations and overgrowth. The severity of the component vascular malformations and the degree of overgrowth varies from patient to patient which demands care given by a multi-professional team with regular follow-up in a specialist clinic. Some patients may present with acute life-threatening problems, often as a result of veno-thromboembolic events (VTEs) especially following surgical and invasive radiological procedures. Awareness of such problems is vital and prophylactic measures to reduce such risks are paramount. The interventional radiologist is vital to the care team as he/she can undertake procedures including endovascular closure of significant venous anomalies which predispose to such VTEs. Although these procedures can be lengthy and complex, they can now provide a minimally invasive means to reduce the risk from life-threatening and sometimes fatal VTEs. The results however from such interventions will require long-term studies which to date are unavailable.

Carbon Dioxide Laser for the Treatment of Microcystic Lymphatic Malformations (Lymphangioma Circumscriptum): A Systematic Review

Lymphangioma circumscriptum (LC) is a rare, superficial, cutaneous lymphatic malformation. Management is difficult because of high recurrence rates, regardless of the treatment modality chosen. The carbon dioxide (CO2 ) laser may offer a less-invasive option than surgery that provides satisfactory functional and cosmetic results. To systematically review the efficacy and safety of the CO2 laser for the treatment of LC. The terms "lymphangioma circumscriptum" and "microcystic lymphatic malformation" were combined with "treatment," "laser," and "carbon dioxide" during separate searches in the PubMed database. The articles retrieved were then evaluated based on set criteria. We identified 16 studies (11 case reports, 5 case series) with a total of 28 separate patients who had been treated for LC using a CO2 laser. Eight patients remained disease free from 4months to 3years, 10 experienced partial recurrence, and two experienced complete recurrence. Various laser parameters were reported, and adverse effects were generally minor and infrequent, such as dyspigmentation and mild scarring. Available evidence indicates that the CO2 laser is a safe and efficacious option for the treatment of LC, particularly in large lesions that may not be amenable to surgical intervention.

Acral hemosideric lymphatic malformation

Cutaneous lymphatic malformations represent a group of heterogeneous diseases caused by developmental defects of lymphatic system. The purpose of this study was to report the clinical, histopathological and immunohistochemical features of a distinctive lymphatic malformation. Twelve patients with similar clinical and histopathological features were included in this study. Immunohistochemical staining of CD31, D2-40, Prox1 and Wilms tumor 1 (WT-1) were performed on all lesions. All cases were either congenital lesions or developed during the first 2 years of life. All presented as red to brown papules or nodules on acral sites. Histopathologically, the lesions consisted of a dermal proliferation of flat or slit-like vessels lined with a single layer of endothelial cells. Hemosiderin or extravascular red blood cells were present in all cases. The constituent vessels expressed CD31, D2-40 and Prox1 and lacked expression of WT-1. On the basis of the clinical, histopathological and immunohistochemical findings, our cases represent a unique type of lymphatic malformation that we believe is distinct from previously reported vascular proliferations. We propose the name of acral hemosideric lymphatic malformation for this entity.

A case of lymphangioma circumscriptum successfully treated with electrodessication following failure of pulsed dye laser

Lymphangioma circumscriptum is the most common cutaneous lymphatic malformation. It presents as a well-circumscribed, localized region of vesicles that can ooze and drain lymphatic and sanguineous fluid. The vesicles cause significant morbidity and psychological distress from itching, pain, drainage, and secondary infection. We report a case of a 16-year-old female with a life-long history of a weeping, hemorrhagic, and painful lesion on her right buttock causing significant emotional distress. We initially attempted therapeutic treatment with pulsed dye laser. The lesion appeared unchanged after two trials and we subsequently used three sessions of electrodessication to cauterize the aberrant vessels. The lesion largely resolved without complications and is no longer causing pain or emotional distress.

Malformations lymphatiques kystiques cutanées localisées (ou lymphangiomes cutanés)

Cutaneous cystic lymphatic malformations consist of dilatations of various sizes, developed from the lymphatic system. Various clinical presentations exist, which are more or less complex and severe. MRI is the best examination to determine the extent of deep lesions. Therapeutic decisions usually follow multidisciplinary consultations. In localized superficial forms, whether surgical excision or abstention is required. In macrocystic forms, sclerotherapy is the first-line treatment.

Acral Angiokeratomas in a Patient with Turner Syndrome

Several types of vascular anomalies have been described in patients with Turner syndrome, including cutaneous lymphatic malformations, vascular anomalies of the heart and aorta, acral venous malformations, and intestinal vascular anomalies. Angiokeratomas have rarely been reported in patients with Turner syndrome. Here, we describe a 14-year-old girl with Turner syndrome who presented with a 2-year history of tender bluish-black keratotic acral papules. Biopsy showed acral skin with focal epidermal acanthosis that was centered on a dilated superficial vessel, consistent with an angiokeratoma. Lysosomal enzyme assays were normal, and she did not demonstrate any other features of a lysosomal storage disorder.

Volume rendering and fusion of MRI/MRA data in the diagnosis and management planning of Klippel–Trenaunay syndrome

Klippel–Trenaunay syndrome (KT) is a rare triad of an enlarged extremity, cutaneous vascular malformations, and venous and lymphatic malformations. MR imaging is very useful for evaluation of the extent of venous and lymphatic malformations in KT syndrome. MRV has proven useful in evaluation of abnormalities in the deep venous circulation in the lower extremities. We present some unique examples of advanced image fusion and volume rendering techniques which may prove extremely beneficial in diagnostic and surgical planning.

Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: A novel clue to the pathogenesis of a rare syndrome

Gorham-Stout disease is an unusual, progressive syndrome of unknown etiology characterized by mono- or polyostotic osteolysis most often affecting children and young adults. The onset is insidious and the disease progresses to extensive and potentially disabling osteolysis often unresponsive to therapeutic intervention. Although bone and soft tissue lesions are the most frequent manifestations of Gorham-Stout disease, skin lesions can occur and may provide a clue to the pathogenesis of this rare syndrome. Our aim was to describe characteristics of vascular skin lesions of this rare condition using magnetic resonance imaging and histomorphological analysis. The case of a 36-year-old man with Gorham-Stout disease of the left leg and foot is reported. This case was remarkable for its prominent lymphatic vascular malformations involving the skin and soft tissues adjacent to the diseased bone-a previously undescribed abnormality, which preceded osteolysis for several years. Magnetic resonance imaging played a key role in defining the extent of disease in skin and soft tissues. It is difficult to assess the true incidence of hemangiomatosis in the earlier reports on Gorham-Stout disease in which hemangiomatous cutaneous lesions were mentioned but not described or illustrated. A vascular process with angiomatous histological features is considered to be the pathological hallmark of Gorham-Stout disease, but the specific type of this vascular process is still under debate. Our report highlights a lymphatic malformative nature of Gorham-Stout disease, thereby contributing to a better understanding and characterization of this rare disease entity.

Cutaneous Manifestations and Massive Genital Involvement in Hennekam Syndrome

We describe a 16-year-old boy with intestinal lymphangiectasia, lymphedema of the limbs and genitalia, mild mental retardation, and facial anomalies (Hennekam syndrome) and cutaneous lesions. Severe edema in the genital area created a gigantic mass that included the scrotum and penis. Numerous grouped red-violaceous pseudo-vesicular lesions and plaques, as well as verrucous brown papules, were present on the penis and scrotum. The prepuce was hypertrophic, with severe phimosis. Histologic analysis revealed dilated lymphatic vessels lined by a discontinuous layer of flat endothelial cells in the papillary dermis and extending down to the reticular dermis. Dilated blood vessels were also present but no cellular abnormalities were identified. A diagnosis of superficial cutaneous lymphatic malformations was made. To the best of our knowledge, this is the first detailed cutaneous histologic investigation in a patient with Hennekam syndrome. We assume that the onset of cutaneous lesions in our patient was likely triggered by a generalized worsening of his lymphedema.

Malformations capillaires associées à un angiome caverneux cérébral

Capillary malformations such as benign hereditary telangiectasia are a familial affection, of dominant autosomal transmission, characterized by the progressive development of cutaneous telangiectasia during childhood. The association with cutaneous vascular, arteriovenous or lymphatic malformations is exceptional and has only recently been described.A 5 year-old girl presented with widespread erythematous, predominantly telangiectasic, congenital and acquired macules when she was one year-old. Her history was marked by right temporal cerebral hemorrhage at the age of 4, revealing a right temporal cavernoma-like vascular malformation. The familial history of telangiectasic macules and clinical and histological examination led to the diagnosis of benign hereditary telangiectasia.This case report raises doubt on the exclusively cutaneous nature of benign hereditary telangiectasic-type capillary malformations. Moreover, it illustrates the possibility of a particular clinical form of this affection, associating classical telangiectasia and post-wine stain-type macules. The recent localization of the locus implied in this affection in 5q14 in the same chromosomic space as the CMC1 locus incriminated in familial capillary malformations, suggests that these two affections are in fact phenotype variations of a single and same clinical entity.

Lymphangioma of the penis: a rare anomaly

Lymphatic malformations are known to affect any part of the body. However, lymphangiomas involving the penile skin are rare. We report a case of a cutaneous lymphatic malformation of the penis.

Cutaneous Vascular Malformations in Disappearing Bone (Gorham-Stout) Disease

A34-YEAR-OLD MAN WAS REFERRED TO OUR HOSPITAL for evaluation of extensive and slowly progressive vascular skin lesions and recurrent episodes of local cutaneous infection. He had a history of cutaneous lymphatic malformations of the left lower extremity since he was 14 years old. After sustaining minor trauma at age 21 years, the patient was hospitalized for diffuse left leg pain without associated constitutional symptoms. The patient had no personal or family history of systemic vascular malformations. A definite diagnosis was not made. During the following year, the patient developed difficulty walking and severe progressive bone pain in his left leg, which was exacerbated by physical activity. He was referred to a radiology center with special expertise in the diagnosis of bone disease for further evaluation. Radiographs taken at this center showed extensive resorption of the lower left femoral shaft and the metatarsal bones of the left foot (FIGURE 1A). Histological examination of the bone lesions revealed a widespread vascular malformation with ectatic, thin-walled, sinusoidal vessels in zones where bone structures had almost completely disappeared (Figure 1B). These pathomorphological features were consistent with Gorham-Stout disease. The patient received fractionated irradiation of the bone lesions, and 12 months later, the patient’s symptoms and the radiologic appearance of the involved bones had improved. On evaluation at our hospital 10 years later, the patient had numerous skin-colored papules, 1 mm to 1 cm in diameter, on the medial aspect of the left thigh with an underlying palpable soft tissue mass extending from the gluteal region to the popliteal fossa (FIGURE 2A) and dilated vascular channels on his left foot, 2 to 3 cm in diameter (Figure 2B). Magnetic resonance imaging showed a continuous vascular malformative process from the skin into the adjacent connective tissue, striated muscle, and fat, which were riddled with diffuse and intercommunicating vascular networks (Figure 2C). Radiographsandcomputed tomographyscansof adjacentboneswere unremarkable. Biopsy specimens from papular lesions on the left leg showed lymphatic vascular malformation (Figure 2D).

Cutaneous lymphatic malformation with secondary fat hypertrophy

Lymphatic malformations are a type of vascular anomaly. They are uncommon and can present in various ways. Associated hypertrophy of the soft tissue and bone have been described in association with deep lymphatic connections, but late-onset localised fat hypertrophy in the absence of deep connections has not been previously described. We present a case of cutaneous lymphatic malformation of the thigh and buttock with secondary fat hypertrophy. The lesion had been present since childhood but enlarged rapidly during adolescence. MRI excluded deep connections and lipoma. Liposuction was used to debulk the area with a satisfactory result.

CUTANEOUS LYMPHATIC MALFORMATION OF THE PENIS AND SCROTUM

No AccessJournal of UrologyPediatric Urology1 Oct 1999CUTANEOUS LYMPHATIC MALFORMATION OF THE PENIS AND SCROTUM B. SADIKOĞLU, İ. KURAN, H. ÖZCAN, and A. GÖZÜ B. SADIKOĞLUB. SADIKOĞLU More articles by this author , İ. KURANİ. KURAN More articles by this author , H. ÖZCANH. ÖZCAN More articles by this author , and A. GÖZÜA. GÖZÜ More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)68336-XAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "CUTANEOUS LYMPHATIC MALFORMATION OF THE PENIS AND SCROTUM." The Journal of Urology, 162(4), pp. 1445–1446 References 1 : Genitalia, penile scrotal lymphedema and scrotal gangrene. In: . Baltimore: Williams & Wilkins1997: 189. chapt. 21. Google Scholar 2 : Tumors of lymph vessels. In: . Philadelphia: Mosby1995: 683. chapt. 26. Google Scholar 3 : Lymphangioma circumscriptum. A clinicopathological review. Ann. Plast. Surg.1981; 7: 318. Google Scholar 4 : Reconstruction of the scrotum using a tissue expander. Urologe1994; 33: 159. Google Scholar 5 : The potential of mild testicular heating as a safe, effective and reversible contraceptive method for men. Int. J. Androl.1994; 17: 186. Google Scholar From the Division of Plastic and Reconstructive Surgery, Sisli Etfal State Hospital, Istanbul, Turkey© 1999 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 162Issue 4October 1999Page: 1445-1446 Advertisement Copyright & Permissions© 1999 by American Urological Association, Inc.KeywordspenislymphangiomascrotumskinMetricsAuthor Information B. SADIKOĞLU More articles by this author İ. KURAN More articles by this author H. ÖZCAN More articles by this author A. GÖZÜ More articles by this author Expand All Advertisement PDF downloadLoading ...