Acroangiodermatitis (Pseudo-Kaposi’s Sarcoma) Seen in Conjunction with Marfan Syndrome and a Hypercoagulable State: Is There a Link?

 A case study of acroangiodermatitis is presented in conjunction with chronic venous disease, Marfan syndrome, and a hypercoagulable state. A possible link between acroangiodermatitis and Marfan syndrome is explored.

  A 42-year-old black male presented with a chief complaint of long standing painful ulcers caused by varicose veins and recurrent blisters in both lower legs that would heal and then reopen. He stated his father was also afflicted with multiple recurrent episodes of “blisters” and “ulcerations” that appeared similar in nature. The patient’s past medical history included chronic venous insufficiency; recurrent deep vein thrombosis (DVT); past episodes of pulmonary embolism; thrombophlebitis secondary to a hypercoagulable state of unknown origin; orthostatic hypotension; and sickle cell trait. The patient stated that many of these issues began at age 21. Current medications included Coumadin 5 mg/day and baby aspirin 81mg/day. Past surgical history included the placement of a Greenfield filter to further prevent pulmonary emboli in 1992. The patient admitted to an allergy to general anesthesia. A review of the patient’s family history revealed his father had a long history of recurrent “blisters” and multiple episodes of DVT and pulmonary embolism. The patient denied smoking or the use of alcohol or recreational drugs.

  Physical examination revealed an ulcer over the area of right medial malleolus that measured 3.0 cm x 2.0 cm x 0.3 cm. An irregular border surrounded by a 2.0-3.0 mm hyperpigmented rim without periwound erythema was noted. No signs of infection were observed. The wound base was composed of mixed tissue including crust, fibrin, and granulation tissue.

  Additionally, the bilateral distal lower extremities were covered with what appeared to be bullae that were crusted over at the tips (Figure 1). The bullae were forming plaques and nodules and were surrounded by hemosiderin deposits. Varicosities and lipodermatosclerosis were also present, however no edema was noted bilaterally to the distal lower extremity. Skin temperature proximal to the distal lower extremity was warm to cool, and pedal pulses were diminished bilaterally. Capillary refill time was within normal limits. Neurologic exam revealed vibratory and sharp/dull sensations, as well as protective threshold, to be grossly intact bilaterally. Deep tendon reflexes were within normal limits bilaterally. Active and passive range of motion of the ankle joints and pedal joints produced no limitation, crepitus, or pain, and muscle strength was within normal limits bilaterally. A resting tremor was noted when the patient’s feet were placed in eversion. X-ray exams were noncontributory. Further evaluation revealed macrognathia, protuberance of the forehead, sternal malformation, generalized ligamentous laxity, mild scoliosis, and elongated extremities. This, combined with the patient’s history of recurrent DVT, pulmonary emboli, and a family history of similar findings, supported the possibility of a secondary diagnosis of Marfan syndrome, an autosomal dominant hereditary disease caused by a defective fibrillin 1 gene (FBN1) on chromosome 15, which codes for the glycoprotein fibrillin.

  Immunofluorescence studies, useful in the detection of immune complex diseases such as pemphigus, were conducted via 2 perilesional skin punch biopsies on the right leg and transferred in Michel’s transport medium, but were negative. Biopsies of the venous stasis ulcer itself failed to reveal any malignancies, vasculitis, or vasculopathy. Biopsies were also evaluated via polymerase chain reaction (PCR) for HHV-8 consistent with Kaposi’s sarcoma and PCR lab tests were run for possible HIV. Both tests were negative. Extensive blood work, including complete blood count, sedimentation rate, C-reactive protein, prealbumin, protein C, protein S, Factor V Leiden, and antiphospholipid antibody, was also performed but provided little pertinent data. The patient was referred to a dermatopathologist for a second opinion and repeated biopsy. Microscopic description of the biopsy of the bullae revealed dermal nodules composed of spindle-shaped cells arranged in a lobular pattern. There were no slit-like spaces or promontory sign. The vascular spaces aligned back-to-back and were surrounded by chronic infiltrate with siderophages and scattered plasma cells. Based on the biopsy evaluation, the dermatopathologist proffered a diagnosis of acroangiodermatitis, also known as pseudo-Kaposi’s sarcoma.

  Wound care of the venous stasis ulcer was based on the clinical picture and included weekly debridements, applications of topical medications, and 4-layered compression wraps. While the ulcer completely epithelialized over a period of 3-4 weeks, the bullae lesions remained recalcitrant (Figure 2). The pseudo-Kaposi condition was referred to a dermatopathologist for further evaluation and treatment. The patient was advised to follow-up with his general physician for possible Marfan syndrome as well as recommendations to seek vascular consultation for surveillance and evaluation for aortic aneurysm and dissections.

  This case includes a multiplicity of medical conditions that may be functioning in tandem. A review of the literature was undertaken for each of the significant comorbidities to elucidate potential parallels.

  Chronic venous insufficiency. Chronic venous insufficiency (CVI) encompasses a group of venous disorders including varicose veins and chronic venous diseases that are characterized by retrograde blood flow in the lower extremity. Venous blood flow in the lower extremity has 3 components: the superficial, the perforators, and the deep systems. In a competent venous system, the perforators connect the superficial to the deep system via multiple 1-way bicuspid valves located in all 3 systems. These valves open only in the direction of the deep system, which allows effective movement of blood in the direction of the heart and inhibits retrograde flow. In the lower extremity, the movement of flow in the direction of the heart is accomplished primarily through the calf muscle pump function.¹ When functioning in congruence with competent valves, action of the calf pump compresses the deep system increasing venous pressure and forcing cephalic blood flow. The bicuspid valves close when the deep system is drained causing a transient drop in venous pressure to 0-10 mm Hg in the deep system. This transient drop in pressure opens the valves and allows blood to flow from the superficial system.²

  Chronic venous insufficiency occurs when this process fails to work properly for a prolonged period of time. When functioning improperly, the deep system pressure does not transiently drop but remains elevated, causing pressure build up in 1, or all 3, venous systems. This is known as venous hypertension, and it occurs due to 1 of 4 pathophysiologic mechanisms: 1) dysfunction of valves in the superficial and/or communicating veins because of congenital or acquired incompetence, 2) dysfunction of valves in the deep system because of congenital absence, thrombotic damage by thromboembolism, or inherent weakness, 3) deep venous outflow obstruction such as DVT, and 4) muscle dysfunction and calf muscle pump failure from inflammatory conditions of muscles such as fibrosis or neuropathies.2 Furthermore, a history of DVT, obesity, heredity, fixed ankle equinus, and pregnancy can predispose an individual to venous hypertension and subsequent venous leg ulcer (VLU). Therefore, in this case the patient had multiple risk factors for VLU creating additional links to the multifactorial nature of the patient’s disease.

  Patients with CVI usually present with venous hypertension, varicosities, edema to the lower extremity, leg cramps, leg aches, skin tension, and skin tenderness. If left untreated, CVI can lead to hyperpigmentation, lipodermatosclerosis, atrophie blanche, and scarification in the gaiter area of the leg which often culminates in ulceration.^3,4 Acroangiodermatitis shares a similar etiology. Diagnosis is made by clinical presentation, history, and physical exam, and most often includes the completion of a confirmatory test such as a duplex ultrasound.⁴

  Marfan syndrome. Marfan syndrome is an autosomal dominant, hereditary disorder of connective tissue, specifically fibrillin. Clinically, it is defined by the presence of ectopia lentis, aortic root disease, long-limbed body habitus, and a positive family history. More specifically, Marfan syndrome is a defect in the FBN1, which codes for the protein fibrillin 1 and is needed for the structural support of tissues outside the cell. The growth and development of the body are effected particularly in the connective tissues of the aorta, eye, and skin.

  However, fibrillin 1 also binds to transforming growth factor beta (TGF-β), thus inhibiting its deleterious effects on the extracellular matrix (ECM)⁵ which communicates with cells in the general wound population through dynamic reciprocity. Therefore, decreased levels of fibrillin could potentially cause this process to fail, leading to a wound remaining in a stalled/chronic state; it has been postulated that chronic wounds, such as venous leg ulcers, remain “stuck” in the inflammatory phase of wound healing secondary to increased and sustained levels of proinflammatory cytokines and proteases (ie, matrix metalloproteinase [MMP]-2,MMP-8, MMP-9, and serine elastase)⁶ leading to destruction of the ECM. Low levels of growth factors such as TGF-β along with faulty receptor sites further compromise normal wound healing. In venous disease, this phenomena, coupled with excessive production of fibrinogen secondary to edema caused by distention of capillary walls and leakage of macromolecules, causes erythrocyte aggregation⁷ and stagnation of white blood cells, both leading to potential capillary closure and local ischemia.⁸ It has been hypothesized this fibrin cuff theory may be largely responsible for ulcer formation.⁹ This may create a link between Marfan syndrome and venous leg ulcer pathology.

  Furthermore, although hypercoagulability is not generally associated with Marfan syndrome, there have been rare cases of patients with Marfan syndrome and thromboembolism of unknown etiology,¹⁰ suggesting that some patients defy thorough investigation.¹¹ This finding also suggests patients who have Marfan syndrome could be predisposed to hypercoagulability and to further venous insufficiency, potentially providing a link to conditions such as acroangiodermatitis. Additionally, conditions such as aortic aneurysms and dissections (common in Marfan syndrome) could lead to symptoms such as microembolic/embolic showering causing DVTs and pulmonary embolisms that could potentially mimic a hypercoagulable state.

  Acroangiodermatitis/pseudo-Kaposi’s sarcoma. Acroangiodermatitis (pseudo-Kaposi’s sarcoma), coined by Mali et al¹² in 1965, is described as a rare skin disease characterized by the presence of hyperplasia of pre-existing vasculature. The condition is caused by venous hypertension secondary to severe chronic venous stasis or paralysis of the lower extremity, leading to nonfunctional calf muscle pump.¹³ Clinically, the disease is consistent with Kaposi’s sarcoma making the diagnosis somewhat challenging (Figure 3). However, in contrast to Kaposi’s sarcoma, acroangiodermatitis is not characterized by progression of skin changes.¹³Both diseases often present with bilateral violaceous indurated plaques, nodules, or papules with edema noted to the lower extremity (Figure 4). Histological examination includes hyperplastic capillaries with perivascular mononuclear infiltrate and extravasated erythrocytes in both diseases, which provides little help in differentiating the 2 and further complicating the diagnosis. However, there is lack of spindle cells and slit-like vessels which can be seen histologically with Kaposi’s sarcoma.¹⁴ Although both diseases present with vascular proliferation, acroangiodermatitis is a hyperplasia of pre-existing vasculature often showing stasis dermatitis, and Kaposi’s sarcoma is hyperplasia of vasculature that is independent of existing vessels.

  Although the exact etiology of acroangiodermatitis is currently unknown, several theories have been postulated. Most noted is venous hypertension, secondary to chronic venous stasis and insufficiency. This leads to chronic tissue hypoxia from edema caused by capillary distention, inducing fibroblast and vascular proliferation.¹⁵ This process is very similar to the vascular proliferation noted with chronic inflammatory cytokine release in venous disease, providing another potential connection to both CVI and Marfan syndrome. Other theories include vascular malformations such as arterioveous anastomoses of the lower extremities consistent with Klippel-Trenaunay syndrome, as well as iatrogenically induced arteriovenous shunts, often occurring in patients with renal disease on hemodialysis.¹³ Although similar in appearance, vascular malformations are often seen unilaterally compared to venous stasis etiologies.

  Proposed treatment. Once diagnosed, acroangiodermatitis may be treated at several levels of the disease process. First and foremost is the correction of the underlying vascular pathology. Compression stockings, compression pumps, and compression dressings, along with local wound management, are mainstays of treatment for venous stasis. With the presence of underlying arteriovenous shunts, surgical repair by a vascular surgeon may be indicated. Concurrent use of drugs including antimicrobials, topical and oral steroids, and diuretics have also been employed.^15,16

  Although difficult to differentiate clinically, there are diagnostic markers that allow for a definitive diagnosis of acroangiodermatitis vs Kaposi’s sarcoma. Validation of the presence of HHV-8 using PCR or immunohistological methods provides clear distinction from Kaposi’s sarcoma, as do the endothelial cells that line the proliferative vessels, and the spindle-shaped fibroblasts in Kaposi’s sarcoma stain with CD34 antigen, which is absent in acroangiodermatitis. In addition, cellular atypia of the endothelium may be present in late stage Kaposi’s sarcoma, further differentiating the 2 diseases. Lab tests and biopsies should be performed on difficult wounds with idiopathic etiology to aid in ruling in or out differential diagnosis. Although numerous theories have been presented, more research is required to further elucidate the pathophysiology of acroangiodermatitis.

  Although the clinical picture of Marfan syndrome, CVI, and a definitive diagnosis of acroangiodermatis was evident in this patient and his father, current literature on the topic is sparse at best and failed to reveal a definitive connection between the 3 conditions. However, several common elements in the pathophysiology of these diseases may provide insight into its mixed etiology. Chronic inflammation and microangiopathy contribute to varying degrees of skin injury and increased mechanical tissue stresses that often manifest as dermatitis, blisters, lipodermatosclerosis, and ulceration,17 and have been reported in all 3 conditions. Further exploration into the underlying hereditary component of this disease, as well as the possible connection to Marfan syndrome, is needed.

Ryan Vazales is a fourth year student, Barry University School of Podiatric Medicine, Miami Shores, FL. Robert J. Snyder, DPM, MSc, CWS is Director of Clinical Research and Fellowship Program, and Professor, Barry University School of Podiatric Medicine, Miami Shores, FL.

Address correspondence to:
Ryan Vazales
Barry University School of Podiatric Medicine
11300 NE 2nd Avenue
Miami Shore, FL 33161
ryan.vazales@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.