Case Report
Reactive Angioendotheliomatosis Secondary to Perforated Peptic Ulcer Surgery in a Patient with Coronary Artery Disease
Min-Hsin Lin
1, Yu-Ping Hsiao
1, Jen-Jung Cheng
1*1 Department of Dermatology, Chung Shan Medical University Hospital, Taichung, Taiwan
Introduction
Reactive angioendotheliomatosis (RAE) is a rare benign angioproliferative condition of the skin, which mainly arises in patients with underlying systemic diseases or inflammatory conditions.1 RAE usually presents solely in the skin and generally resolves or improves spontaneously after the cessation of occlusion and hypoxia.2 The histological hallmark of RAE is intravascular hyperplasia of endothelial cells with vascular proliferation in the dermis and subcutis.
Based on histologic findings of benign vascular proliferation, the presentation of RAE is similar to that of glomeruloid angioendotheliomatosis, angiopericytomatosis, diffuse dermal angiomatosis, and acroangiodermatitis. It is crucial to differentiate RAE from malignant tumors such as Kaposi’s
sarcoma and angiosarcoma. Herein, we report the first case of RAE after perforated peptic ulcer surgery in Taiwan.
Case presentation
* Correspondence to: Dr. Jen-Jung Cheng
Department of Dermatology, Chung Shan Medical University Hospital.
Address: No.110, Sec.1, Chien-Kuo N. Rd. Taichung City 402, Taiwan.
Tel: +886-4-24739595 ext. 34511
E-mail: [email protected] (J-J Cheng)
Reactive angioendotheliomatosis (RAE) is a rare disease characterized by angioproliferation limited to skin. Patients with coexistent systemic diseases are most vulnerable. Histopathologically, it is marked by hyperplasia of endothelial cells with vascular proliferation but without cytological atypia. Although the pathogenesis is still not completely understood, it has been proposed that immunologic factors and hypoxic stimulus lead to RAE. In what is the first reported case in Taiwan, we describe a 76-year- old female with a history of coronary artery disease who developed RAE after perforated peptic ulcer surgery.
Keywords: Reactive angioendotheliomatosis, RAE, surgery
Figure. 1 (A) Multiple non-tender violaceous nodules and papuloplaques, some with central ulcer and blackish crust; (B) After 6 months no new lesions developed, but hyperpigmentation remained.
A 76-year-old woman with a history of coronary artery disease for which she had been taking regular medication presented with multiple bluish to violaceous papules and nodules on the bilateral lower legs and insteps (Figure 1A), which progressed rapidly two weeks after surgery for a perforated peptic ulcer.
The surgery was performed due to the sudden onset of epigastric pain. Computed tomography showed hollow organ perforation with peritonitis, which was treated with simple closure with omental patch. After the operation, she was fitted with an endotracheal tube with ventilator support due to respiratory dysfunction and pneumonia. Culture of the pus from the abdominal wound revealed Staphylococcus aureus infection.
On the 12th postoperative day, ecchymosis and crust formation on the bilateral lower legs were noted. Physical examination showed multiple non- tender violaceous nodules and papuloplaques.
Some of the lesions had merged, while others had developed central ulceration and blackish crust.
The patient denied any cancer history, use of immunomodulatory medication, trauma history, or body weight loss, as well as any systemic disease except for coronary artery disease. Non- contributory family history was also noted.
Laboratory examination results included normal values for ANCA, cryoglobulin, and antibody levels of HBV and HCV. Coagulation factor survey and autoimmune test were likewise unremarkable.
We performed a skin biopsy on a solitary violaceous papule on her left inner ankle. Hematoxylin and eosin stain revealed multilobular vascular proliferation with intraluminal endothelial proliferation in the dermis and superficial subcutis without endothelial
atypia. Mild inflammatory cell infiltration was present (Figure 2A). There were no features of Kaposi’s sarcoma, such as eosinophilic spindle cell proliferation, slit-like blood vessels, chronic inflammatory cell infiltration involving plasma cells, or promontory sign(s) with jagged vascular space surrounding adnexa. Immunohistologically, the intraluminal proliferative endothelial cells stained with anti-CD31 (Figure 3A) were within pre-existing blood vessels. Occasional mitotic activity and extravasations of red blood cells were noted. Moreover, there was positive HHV-8 staining (Figure 3C) but only focal CD34 staining (Figure 3B).
After 1 month of conservative treatment, the skin lesions improved with residual hyperpigmentation.
No new lesions developed during the following 6 months (Figure 1B). Based on the histopathology and self-limited clinical course, she was diagnosed with RAE. (Figure 1B).
Discussion
In this report, we describe the first case of RAE following surgery in Taiwan. We propose that in this patient RAE is related to major surgery for perforated peptic ulcer, with hemodynamic change causing distal hypoxia. Likewise, the comorbidities of cardiovascular diseases, pneumonia, and peritonitis may have played roles in the development of RAE. RAE has been noted for its similarities in presentation to a wide spectrum of other conditions. Clinically, there Figure. 2 (A) Multinodular vascular proliferation in the
dermis and superficial subcutis (hematoxyline and eosin, H&E, x40); (B) Epithelioid epithelium proliferation without endothelial atypia (hematoxyline and eosin, H&E, x200)
Figure. 3 Immunochemistry: (A) CD31 staining; (B) focal CD34 staining; (C) HHV-8 staining
are multiple bluish-violaceous patches or plaques which are occasionally ulcerative or necrotic.
The distribution of RAE is extensive but mainly occurs on the limbs.3 To the best of our knowledge, the etiology of RAE is mainly due to coexistent diseases that result in occlusion or inflammation in the vascular system (Table 1). RAE after distal irrelevant surgery has not been previously reported.
RAE is characterized by intravascular endothelial proliferation. It is important to be aware of similar pathologic patterns associated with rapidly progressive and fatal malignant tumors such as Kaposi’s sarcoma and angiosarcoma. We provide comparisons of these three conditions in Table 2. Comparing RAE with Kaposi’s sarcoma histopathologically, the former is typically characterized by intravascular hyperplasia of endothelial cells with vascular proliferation in the dermis and subcutis. Fibrin-microthrombi in well- formed capillaries may also characterize RAE.
Meanwhile, prominent spindle cells and slit-like vessels are present in Kaposi’s sarcoma, accompanied by promontory sign, lymphoplasmacytic infiltration,
and eosinophilic granules.4 Positive staining for CD31 and CD34 is consistent in both diseases. However, CD34 is only focally positive in RAE while strongly diffuse in Kaposi’s sarcoma. Moreover, HHV-8 stains positively more often in Kaposi’s sarcoma than in RAE, according to a case series study by McMenamin et al.4 Regarding clinical course, cutaneous lesions spontaneously resolved with conservative treatment in our patient. Such self-limited clinical course is not observed in Kaposi’s sarcoma.
Surgery for perforated peptic ulcer is not complicated and can be done within a short time.
However, septic shock, bowel obstruction, hernia, intra-abdominal abcess, postoperative ileus, and pulmonary complications may occur. In our case, peritonitis and pneumonia were noted, which may have led to systemic inflammation and the precipitation of RAE.
The pathogenesis of RAE is not clearly understood, but immunologic factors and hypoxic stimulus may play a role. Among the many hypotheses proposed, the one that is most convincing is that RAE derives from vessel occlusion and tissue hypoxia that leads to vascular and endothelial proliferative changes. Once hypoxic stimulus stops, abnormal proliferation stops. Furthermore, active bleeding and operation may cause hemodynamic change(s), resulting in distal tissue hypoxia, which may also lead to RAE.
Semeraro et al. revealed that sepsis causes hemostatic problems with thrombocytopenia, hypercoagulable state, formation of thrombin and fibrin, and disseminated intravascular coagulation.5 Salama et al. suggested that immunoglobulin deposition in vessels within the skin may be caused by a generalized hypersensitivity reaction.
Subsequently, formation of thrombi contributes to local hypoxia and angiogenic factors from local cells result in neovascularization.6 In our case, peritonitis and pneumonia brought about systemic inflammation. Indeed, experimental peritonitis-induced sepsis in an animal model has demonstrated alteration in cerebral microcirculation and tissue hypoxia.7 In our case, microcirculation in the limbs may have been altered so as to induce hypoxia, ultimately bringing about RAE.
To sum up, we introduce a patient with coronary Table 1. Etiology and coexistent diseases of RAE
Systemic infection
Mainly subacute bacterial endocarditis Local hypoxia and hemodynamic change
Peripheral vascular disease Valvular cardiac disease Renal disease
Postrenal transplantation Autoimmune disease
Rheumatoid arthritis Cryoglobulinemia
Lymphoproliferative disorder Hepatitis
Cholesterol emboli Arterio-venous shunt Antiphospholipid syndrome Chronic lymphatic leukemia Dermal amyloid angiopathy
Predominant risk group (age/gender /race) Clinical manifestation
Location Pathology Immuno-histochemistry stain Treatment
Kaposi’s sarcoma Most often on the oral mucosa, face (especially the nose), genitalia, and lower extremities
Age: >60 Gender: 3:1, male: female ratio Race: Mediterranean or Central/Eastern European Origin, Middle Eastern, Equatorial Africa
n males Positivity for HHV-8, Ki-67, D2-40, CD31, CD34. CD34 is strongly and diffusely positiv
e Local: radiotherapy, excision,
cryotherapy, laser ablation, intralesional or topica
l Systemic: chemotherapy: pegylated liposomal doxorubicin, vinblastine,
paclitaxel, oral etoposide, vinorelbine, gemcitabine, and immunomodulators 1. Purplish, reddish blue, or brown/black skin lesions (macules, nodules, plaques
)
on the lower extremities 2. Often accompanied by lymphedema Angiogenesis, inflammation, and spindle cell proliferation with diffuse slit like lumen formation
,
eosinophilic globules and some nuclear atypia
Angiosarcoma Most common on scalp and
face, previously treated with radiation therap
y
Age: 65-70 Gender: 2:1 male: female ratio Race: Caucasian male
s
Positivity for vascular markers, such as the ERG transcription factor, CD31, CD34, and Factor VIII antigen Local: radiotherapy, neoadjuvant
chemotherapy Systemic: taxanes (especially paclitaxel), doxorubincin
Blue or purple lesions (macular, nodular, or plaque) with hemorrhage or ulceration Pleomorphic spindle or epithelioid cells, often with bizarre or multinucleated forms; mitoses are evident
RAE Spread throughout the body, but mainly on the limbs
Age: middle age Gender: 1.3:1 male: female ratio Race: non-specific CD31 and focally positive for
CD34 antibody-staining of spindle-shaped, round, or epithelioid cells, HHV-8(+ or -), and other endothelial markers Treatment of the underlying condition/disorder may result in regression of RA
E
Clinical presentation is often dramatic but not distinctive, including multiple erythematous tumors, plaques, macules, and
ulcerated lesions with purpuric change Firmly piling capillaries usually without endothelial atypia, and fibrin microthrombi in well-formed capillaries
Table 2. Differential diagnoses of Kaposi’s sarcoma, Angiosarcoma and RAE
artery disease who developed RAE after perforated peptic ulcer surgery accompanied by peritonitis and pneumonia. This is the first such case reported in Taiwan. Accordingly, physicians should be aware of postoperative and rapidly progressive lesions on the skin, especially in patients with cardiovascular disease. Since the clinical presentation of RAE is often dramatic but not distinctive and RAE shares histologic similarities with other conditions, early differentiation from malignant tumors such as angiosarcoma and Kaposi’s sarcoma is crucial.
References
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4. McMenamin ME, Fletcher CD. Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum.
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