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Differential Diagnosis of Lymphedema
Abstract
Lymphedema causes progressive overgrowth of an extremity because of anomalous development of the lymphatic vasculature or injury to regional lymph nodes. Although lymphedema is a specific disease, the term “lymphedema” often is applied to any enlarged limb regardless of the underlying cause. The differential diagnosis of lymphedema includes: Capillary malformation, CLOVES syndrome, hemihypertrophy, infantile hemangioma, kaposiform hemangioendothelioma, Klippel–Trénaunay syndrome, lipedema, lipofibromatosis, microcystic/macrocystic lymphatic malformation, obesity, Parkes Weber syndrome, systemic diseases (e.g., cardiac, renal, hepatic, rheumatological), trauma, venous malformation, and venous insufficiency. It is important to accurately determine whether a patient has lymphedema because the prognosis and treatment of this condition differs from other potential causes of extremity overgrowth. Lymphoscintigraphy can accurately determine whether a patient has lymphedema. If lymphatic function is normal, then MRI often is useful to diagnose the patient’s condition.
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Categorization of vascular anomalies with overgrowth is evolving rapidly with the aid of massively parallel genomic sequencing; however, accurate clinical diagnosis is still essential. We identified a group of patients with an extensive, diffuse, reticulate capillary malformation (CM) and variable hypertrophy without major complications.
We sought to study a subset of patients with diffuse CM to better define prognosis and management.
Chart review identified 73 patients with diffuse CM who did not fit the criteria for known disorders with CM and/or overgrowth.
Soft-tissue or bony overgrowth did not correlate with location, morphology, or intensity of the vascular stain. Patients required periodic follow-up to monitor for leg length discrepancy. They were found to exhibit normal neurologic development and proportionate overgrowth rather than progressive, disproportionate asymmetry or vascular complications.
This retrospective review was limited to observations documented at clinic visits; these patients require long-term assessment. Further studies are necessary to accurately assess Wilms tumor risk and clinical outcomes in older adults.
We propose the term "diffuse capillary malformation with overgrowth" to designate this extensive reticular vascular staining with proportionate overgrowth. We differentiate diffuse capillary malformation with overgrowth from other disorders with CM and hypertrophy.
There are many causes for a large lower limb in the pediatric age group. These children are often mislabeled as having lymphedema, and incorrect diagnosis can lead to improper treatment. The purpose of this study was to determine the differential diagnosis in pediatric patients referred for lower extremity "lymphedema" and to clarify management.
The authors' Vascular Anomalies Center database was reviewed between 1999 and 2010 for patients referred with a diagnosis of lymphedema of the lower extremity. Records were studied to determine the correct cause for the enlarged extremity. Alternative diagnoses, sex, age of onset, and imaging studies were also analyzed.
A referral diagnosis of lower extremity lymphedema was given to 170 children; however, the condition was confirmed in only 72.9 percent of patients. Forty-six children (27.1 percent) had another disorder: microcystic/macrocystic lymphatic malformation (19.6 percent), noneponymous combined vascular malformation (13.0 percent), capillary malformation (10.9 percent), Klippel-Trenaunay syndrome (10.9 percent), hemihypertrophy (8.7 percent), posttraumatic swelling (8.7 percent), Parkes Weber syndrome (6.5 percent), lipedema (6.5 percent), venous malformation (4.3 percent), rheumatologic disorder (4.3 percent), infantile hemangioma (2.2 percent), kaposiform hemangioendothelioma (2.2 percent), or lipofibromatosis (2.2 percent). Age of onset in children with lymphedema was older than in patients with another diagnosis (p = 0.027).
"Lymphedema" is not a generic term. Approximately one-fourth of pediatric patients with a large lower extremity are misdiagnosed as having lymphedema; the most commonly confused causes are other types of vascular anomalies. History, physical examination, and often radiographic studies are required to differentiate lymphedema from other conditions to ensure the child is managed appropriately.
Venous malformation results from an error in vascular morphogenesis. Although this condition is present at birth, it may not become evident until childhood or adolescence when it has grown large enough to cause a visible deformity or symptoms. This article discusses the types, diagnosis, and the nonoperative and operative management of venous malformations.
Lymphatic malformation results from an error in the embryonic development of the lymphatic system. Clinically, lymphatic malformation is characterized by the size of the malformed channels: microcystic, macrocystic, or combined (microcystic/macrocystic).This article describes the clinical features, diagnosis, and management of lymphatic malformations.
Overgrowth syndromes with complex vascular anomalies pose a challenge for diagnosis and management. The purpose of this descriptive study is to present a cohort of patients with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi syndrome, a distinct clinical phenotype characterized by a complex truncal-lipomatous mass, vascular, acral, and other anomalies. This cohort was ascertained following review of patient data entered into the Vascular Anomalies Center database of the Children's Hospital, Boston over a period of 7 years. Clinical data, imaging findings, and the photographic archive were reviewed. The search identified 18 unrelated patients with a distinct phenotype. Variable portions of the truncal masses observed in these patients were composed of a lymphatic malformation. Capillary malformations and high-flow lesions were commonly encountered. The lipomatous mass infiltrated the adjacent anatomic spaces and was associated with capillary, lymphatic, venous, and arteriovenous vascular malformations. Paraspinal-intraspinal extension was associated with morbid sequelae. Acral deformities included large, wide feet and hands, macrodactyly, and a wide sandal gap. Scoliosis and other musculoskeletal, neurologic, renal, and cutaneous malformations were also encountered. The uniform and highly characteristic features of the truncal lipomatous mass, in combination with vascular, acral, and other anomalies, provide evidence of a distinct nosologic and clinical entity. Morbid sequelae of the truncal involvement in this condition can be deforming and disabling; hence, prompt diagnosis and multidisciplinary care are necessary.
Lymphedema is the chronic, progressive enlargement of tissue due to inadequate lymphatic function. Although lymphedema is a specific condition, patients with a large extremity are often labeled as having "lymphedema," regardless of the underlying cause. The purpose of this study was to characterize referrals to a center to determine if lymphedema should be managed by specialists.
Patients treated in our Lymphedema Program between 2009 and 2013 were reviewed. Diagnosis was determined based on history, physical examination, photographs, and imaging studies. Lymphedema type (primary or secondary), location of swelling, patient age, sex, and previous management were documented. The accuracy of referral diagnosis and the geographic origin of the patients also were analyzed.
Two hundred twenty-five patients were referred with a diagnosis of "lymphedema"; 71% were women and 29% were children. Lymphedema was confirmed in 75% of the cohort: primary (49%) and secondary (51%). Twenty-five percent of patients labeled with "lymphedema" had another condition. Before referral 34% of patients with lymphedema received tests that are nondiagnostic for the disease, and 8% were given a diuretic which does not improve the condition. One third of patients resided outside our local referral area. The average time between onset of lymphedema and referral to our Lymphedema Program was 7.7 years (range, 1-59 years).
Patients presenting to a center with "lymphedema" often have another condition, and may be suboptimally managed before their referral. Patients with suspected lymphedema should be referred to specialists focused on this disease.
Superficial venous disease is a common clinical problem. The concerning disease states of the superficial venous system are venous reflux, varicose veins, and superficial venous thrombosis. Superficial venous reflux can be a significant contributor to chronic venous stasis wounds of the lower extremity, the treatment of which can be costly both in terms of overall health care expenditure and lost working days for affected patients. Although commonly thought of as a benign process, superficial venous thrombosis is associated with several underlying pathologic processes, including malignancy and deep venous thrombosis.
Objective:
To examine the presentation characteristics of patients with Kaposiform hemangioendothelioma (KHE) to describe the spectrum of disease and risk factors for Kasabach-Merritt phenomenon (KMP).
Study design:
A retrospective review of 163 patients referred to the Vascular Anomalies Center at Children's Hospital Boston for KHE between 1991 and 2009 identified 107 patients with sufficient data for inclusion.
Results:
The prevalence of KHE in Massachusetts is ∼0.91 case per 100000 children. KHE manifested in infancy in 93% of cases, with 60% as neonates. Common presenting features included enlarging cutaneous lesion (75%), thrombocytopenia (56%), and musculoskeletal pain or decreased function (23%). Cutaneous KHE favored the extremities, especially overlying joints. In our cohort, 71% developed KMP (11% after initial presentation), and 11% of patients lacked cutaneous findings. Retroperitoneal and intrathoracic lesions, though less common, were complicated by KMP in 85% and 100% of cases, respectively. Compared with superficial lesions, KHE infiltrating into muscle or deeper was 6.3-fold more likely to manifest KMP and 18-fold higher if retroperitoneal or intrathoracic. KHE limited to bone or presenting after infancy did not manifest KMP.
Conclusion:
An enlarging cutaneous lesion is the most common presenting feature of KHE in infancy. Older patients with KHE or those lacking cutaneous manifestations present with musculoskeletal complaints or atypical symptoms. The risk of KMP increases dramatically when tumor infiltrates muscle or when KHE arises in the retroperitoneum or mediastinum.
Lymphedema results from maldevelopment of the lymphatic system (primary) or injury to lymphatic vasculature (secondary). Primary lymphedema is far less common than the secondary condition. The purpose of this study was to determine the clinical features of primary lymphedema in the pediatric age group.
The authors' Vascular Anomalies Center database was reviewed for patients evaluated between 1999 and 2010 with onset of lymphedema before 21 years of age. Cause, sex, age of onset, location, and familial/syndromic association were determined. Morbidity, progression, and treatment were analyzed.
Lymphedema was confirmed in 142 children: 138 cases (97.2 percent) were primary and four (2.8 percent) were secondary. Analysis of the primary cohort showed that 58.7 percent of the patients were female. Age of onset was infancy, 49.2 percent; childhood, 9.5 percent; or adolescence, 41.3 percent. Boys most commonly presented in infancy (68.0 percent), whereas girls usually developed swelling in adolescence (55.3 percent). Lymphedema involved an extremity (81.9 percent), genitalia (4.3 percent), or both (13.8 percent). The lower limb was most commonly affected (91.7 percent), and 52.9 percent had bilateral lower extremity disease. Eleven percent of patients had familial or syndromic lymphedema. Cellulitis occurred in 18.8 percent of children; 13.0 percent required hospitalization. The majority of patients (57.9 percent) had progression of their disease. Treatment was compression garments alone (75.4 percent) or in combination with pneumatic compression (19.6 percent); 13.0 percent had operative intervention.
Pediatric primary lymphedema usually involves the lower extremities. Boys typically are affected at birth, and girls most often present during adolescence. Most patients do not have major morbidity, are successfully managed by compression, and do not require surgical treatment.
A binary classification of vascular anomalies was approved 14 years ago by the International Society for the Study of Vascular Anomalies. The purpose of this study was to determine whether the International Society for the Study of Vascular Anomalies system is being used to categorize anomalies, and whether incorrect nomenclature affects patient care.
The PubMed database was searched for English language publications with the term "hemangioma" in the title/abstract during 2009. Outcome variables were (1) whether accepted nomenclature was used to describe the vascular anomaly and (2) whether or not patients received incorrect treatment. Predictive variables for terminological accuracy were patient age, location of the anomaly, and the primary author's medical specialty.
"Hemangioma" was used incorrectly in 71.3 percent (228 of 320) of publications. Patients whose lesions were mislabeled were more likely to receive improper treatment (20.6 percent) compared with subjects whose lesions were designated using International Society for the Study of Vascular Anomalies terminology (0.0 percent) (p = 0.001). The patients were younger in articles that properly identified hemangioma (4.1 months) compared with articles that used hemangioma to describe another anomaly (36.1 years) (p < 0.0001). Publications focused on integument/soft-tissue lesions were more accurate (57.4 percent) than those in other anatomical areas (86.3 percent) (p < 0.0001). The erroneous use of hemangioma was independent of the authors' discipline: pediatrics (60.0 percent), internal medicine (61.4 percent), surgery (68.9 percent), and obstetrics/gynecology (70.0 percent) (p = 0.68).
Hemangioma continues to be commonly misused to describe any type of vascular anomaly, and terminological imprecision is prevalent among both medical and surgical fields. Inaccurate designation of the vascular anomaly is associated with an increased risk of erroneous management.
Like single-channel-type vascular malformations, combined lesions are categorized as slow-flow and fast-flow lesions. Many of the combined vascular malformations are associated with soft tissue and skeletal hypertrophy. This article discusses the diagnosis, management, and treatment of patients with capillary lymphaticovenous malformation, capillary-arteriovenous malformation, and capillary-arteriovenous fistulas and congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies syndrome.
This article describes the clinical features, diagnosis, and management of arteriovenous malformation, capillary malformation-arteriovenous malformation, and PTEN-associated vascular anomaly.
Vascular tumors of childhood are typically benign. The 4 most common types are infantile hemangioma (IH), congenital hemangioma (CH), kaposiform hemangioendothelioma (KHE), and pyogenic granuloma (PG). Vascular tumors must be differentiated from vascular malformations. Although tumors and malformations may appear as raised, blue, red, or purple lesions, their management differs significantly.
Lipofibromatosis is a slow-growing, childhood soft-tissue neoplasm that is often confused with other conditions. We report a patient with lipofibromatosis causing extremity enlargement at birth. The lesion initially was thought to be a vascular anomaly or lipedema on clinical and MRI examination. When involving the lower extremity, diffuse lipofibromatosis must be differentiated from more common causes of lower limb enlargement in children: lymphatic malformation, lymphedema, or lipedema. Compared with these more frequent conditions, lipofibromatosis usually causes less morbidity. Management of the tumor includes observation or excision. Because complete extirpation of the lesion is difficult, the recurrence rate is high.
Lymphoscintigraphy (LS), performed with technetium 99m-labeled antimony trisulfide colloid (Cadema Medical Products, Inc., Middletown, N.Y.), was used as a noninvasive diagnostic examination to evaluate the lymphatic circulation in 190 extremities of 115 patients. Forty-six patients had primary lymphedema, 48 had secondary lymphedema, and 21 patients had other causes of limb swelling. To determine the value of LS in surgical decision making, preoperative and postoperative LS of 16 patients who underwent surgical repair of the lymphatic abnormality were studied separately. Semiquantitative evaluation of the lymphatic drainage and visual interpretation of the image patterns were reliable to differentiate lymphedema from edemas of other origin (sensitivity: 92%, specificity: 100%). Although certain image patterns were characteristic of either primary or secondary lymphedema, LS could not consistently differentiate between the two types. Episodes of cellulitis in lymphedema clearly delayed lymph transport. LS was helpful in patient selection and follow-up after lymphatic surgery, but it did not prove patency of lymphovenous anastomoses. It was diagnostic in the evaluation of lymphangiectasia and was used to document successful surgical treatment of reflux of chyle. LS is safe and reliable and has no side effects. It should replace contrast lymphangiography in the routine evaluation of the swollen extremity.
Primary lymphedema, a disorder causing persistent swelling in an extremity, is rare in children and adolescents; it affects 1.15/100,000 persons less than age 20 years. It primarily affects girls near menarche. The records of 125 children and adolescents, aged 0 to 20 years, who were examined at the Mayo Clinic were analyzed; 99 of these patients were contacted to obtain follow-up data. The influences of estrogen and inflammation are thought to be important etiologic factors in primary lymphedema. The diagnosis can be made on the basis of a thorough history and physical examination. Lymphangiograms, venograms, and biopsies add nothing to the diagnosis because of the low incidence of tumor in children and adolescents. Conservative treatment is recommended: a Jobst-type stocking, elevation, and proper foot care. Diuretics are not recommended. Careful psychologic counseling, especially in adolescents, is highly recommended.
In a review of 250 cases of lymphedema of the lower extremity, 9 patients were noted to share unique similarities in their history and physical findings. Although these patients had mild swelling in their pretibial areas and were all referred with a diagnosis of lymphedema of the legs, their findings differed significantly from the usual patient with either congenital or acquired lymphedema. Notably, the lower extremity swelling was always bilateral and symmetrical in nature and never involved the feet. Skin changes characteristic of lymphedema were not found, and consistent fat pads were present anterior to the lateral malleoli in each patient. These findings are representative of a clinical entity known as lipedema, which is distinct from lymphedema and for which treatment may be different.
Children with hemihypertrophy are screened for Wilms tumor, because this condition is a risk factor for developing the neoplasm. Patients with Klippel-Trenaunay syndrome (KTS) are often considered potential candidates for Wilms tumor, because they have unilateral overgrowth of the lower limb. In our experience, however, an association between KTS and Wilms tumor has not been observed.
To determine whether KTS and Wilms tumor are associated, we reviewed our institutional experience for patients with both diagnoses and searched the Klippel-Trenaunay literature for patients with Wilms tumor. The National Wilms Tumor Study Group database also was studied to identify patients with KTS. Two-sided exact binomial tests were used to evaluate whether patients with 1 condition had an increased risk for the other. Ninety-five percent confidence intervals for these 2 risks were compared with the general population risks of Wilms tumor (1 in 10 000) and KTS (1 in 47 313).
None of the 115 patients with KTS followed at our institution developed Wilms tumor. One case of Wilms tumor has been reported in 1363 patients with KTS in the literature, giving a confidence interval of (1/57 377) and (1/267). None of the 8614 patients in the National Wilms Tumor Study Group database had KTS, giving a confidence interval of (0, 1/2336). Because the risks of KTS and Wilms tumor in the population fall within these confidence intervals, one cannot conclude that the risks of KTS among Wilms tumor patients or Wilms tumor among KTS patients are any different from the corresponding risks in the general population.
Patients with KTS are not at increased risk for developing Wilms tumor and thus should not undergo routine ultrasonographic screening.
We describe six patients with an uncommon variant of infantile hemangioma that we have termed reticular , occurring in the extremity, which were associated with intractable ulceration, anogenito‐urinary‐sacral anomalies, and sometimes cardiac overload. The extreme end of the spectrum is exemplified by a male neonate who presented with a stained, enlarged, pulsatile lower extremity, and cardiac failure. He also had hepatic hemangiomas and ambiguous genitalia. Progressive soft tissue necrosis and bony destruction necessitated amputation. The histopathologic features differed from those of typical infantile hemangioma: infiltrative (not lobular) and involving fascia, muscle, and bone.
The mid‐spectrum is illustrated by five females with reticular infantile hemangioma of the lower limb, buttock, and perineum. Four of these infants had a ventral‐caudal anomaly, including omphalocele, recto‐vaginal fistula, solitary/duplex kidney, imperforate anus, and tethered cord; one infant also had hepatic hemangiomas. Deep ulcerations healed following corticosteroid therapy; one patient required skin graft for closure of a thigh wound. The minor end of the spectrum is exemplified a patchy lesion in the distal limb.
The reticular variant of infantile hemangioma can be confused with other vascular anomalies in the limb, such as capillary malformation, cutis marmorata telangiectasia congenita, diffuse arteriovenous malformation (Parkes Weber syndrome) and capillary‐lymphatico‐venous malformation (Klippel–Trenaunay syndrome). The macular network‐like appearance of the tumor and coexisting ventral‐caudal structural anomalies is analogous to the association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities association in the craniofacial region.
Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.
Obesity-induced lymphedema: clinical and lymphoscintigraphic features
- A K Greene
- F Grant
- S A Slavin
- R A Maclellan
Diffuse lipofibromatosis of the extremity
- A K Greene
- B Labow
- AK Greene
Vascular Anomalies: Classification, Diagnosis, and Management
- A K Greene
- AK Greene
Concepts and controversies
- R T Ballock
- G L Wiesner
- M T Myers
- RT Ballock
Trenor 3rd CC. Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals
- S E Croteau
- M G Liang
- H P Kozakewich
- A I Alomari
- S J Fishman
- J B Mulliken
- SE Croteau