In the current literature and in our practice, GU involvement in male patients primarily refers to bleeding from vascular malformations of the urethra and bladder (1, 4–6, 13, 16, 19, 27, 33, 35, 39, 40, 54–58). Confirmed hematuria of the ureter or kidney has rarely been reported and has not been encountered in our center.

In our previous study (2), avalvulia and reflux of the internal iliac vein (IIV) were identified in patients with KTS with pelvic involvement. The IIV, gluteal veins, and marginal veins comprise a valveless malformed reflux system (2). IIV reflux leads to congestion and focal venous hypertension of the pelvic organs, including the rectum, bladder, prostate, and urethra (2). VM develops slowly with age; therefore, chronic hematuria may manifest when a vein with submucosal reticular phlebectasia ruptures. The rupture of the vesical venous plexus causes painless hematuria. Rupture of the prostatic venous plexus can lead to bleeding from the prostate and urethra. These venous plexuses drain into the IIV through the inferior vesical vein and/or the internal pudendal vein (Figure 1).

Reflux or stagnant flow in a VM can predispose patients to thrombosis and thrombus propagation, which may trigger localized intravascular coagulopathy (LIC) (1, 59, 60). LIC is common in VM and features elevated D-dimer levels, low fibrinogen levels, and variable platelet counts (59, 60). Once the VM ruptures, bleeding rarely resolves spontaneously, but manifests as intermittent or persistent bleeding. The effects of LIC may have an important role in causing localized bleeding and/or thrombosis (59, 60). Anticoagulants such as rivaroxaban and low-molecular-weight heparin can be used to treat this localized coagulopathy (59, 60).

Phlebectasia, VM, or capillary malformation of the scrotum/perineum usually exists in patients with KTS with GU involvement (24, 61). Intrascrotal masses of VM and lymphatic malformation can also exist, usually with little or no clinical significance (24). The pelvis is routinely evaluated in patients with KTS and GU manifestations by using magnetic resonance imaging (MRI) without contrast. If serial T2-weighted axial MRI scans of the pelvis revealed that the IIV had a higher fluid signal than that of the contralateral normal vein, we considered that IIV reflux was documented (2). In patients evaluated by using magnetic resonance venography (MRV), a significantly dilated IIV was considered to indicate IIV reflux (2). MRI can reveal IIV dilation, reflux, plexus VM, and venous incompetence (1, 2).

We do not define malformative veins as dilated veins of > a certain millimeter in diameter. Phlebography is required to confirm MRI findings (2). Computed tomography is not routinely used to evaluate GU involvement in KTS. In our experience with MRI studies and complete phlebography of more than 500 patients with KTS, we defined pelvic VM in terms of venous hemodynamics rather than vein size. Anomalous venous flow includes stagnant flow, centrifugal flow (i.e., reflux), active flow from large veins into smaller tributaries, flow in persistent embryonic veins, venous drainage through extra-anatomic pathways, and flow in spongiform VMs (Figure 2). For example, when using our modified phlebography method or diversion phlebography (2), if free reflux occurred from the external or common iliac vein down into the IIV, continued into the rectal, vesical and/or prostatic venous plexus, and drained through the contralateral IIV, these findings were unified concepts of pelvic venous flow disorder in adult women (53), we considered these as pelvic involvement in KTS (1, 2).

Although the symptoms and venous malformation component can be determined by taking a careful history and performing comprehensive physical, ultrasound, and MRI examinations, complete phlebography is necessary to fully assess the pelvic hemodynamics in these patients and to determine the pathophysiologic component. Complete phlebography is also important and helpful in evaluating possible bleeding sites, identifying the responsible veins, and planning an interventional approach. Imaging of the femoral vein, marginal vein, gluteal veins, common iliac vein, external iliac vein, internal iliac vein, left gonadal vein, left renal vein, and pelvic venous plexus is required.

Bleeding management is initially conservative, and includes LIC management, reducing thrombotic risk and hence the averting of this stage by anticoagulant use, blood transfusions, iron supplements, sirolimus, and stool softeners (1, 4, 62). However, GU VM with clinically significant bleeding usually requires invasive management, including cauterization (4), embolization (12, 13), and surgical excision of the bleeding site (4, 9, 12, 54, 63, 64).

Sclerotherapy has recently become a popular management approach. On account these veins are drainage tributaries of the IIV, and bleeding of these venous plexuses is primarily from IIV reflux, two methods exist to approach these venous plexuses: direct puncture and trans-IIV access (Figure 3) (2). Ethanol-based sclerotherapy is the preferred treatment. Cystoscopic injection of ethanol at the bleeding sites and surgical resection of the bleeding site can also be considered if conservative treatments fail (Figure 3).

Intrascrotal masses of VMs and lymphatic malformations usually have little or no clinical significance, and therefore do not commonly require intervention (24). In rare cases, surgical removal is indicated for prevention of thrombosis in left renal vein or massive lesions after sclerotherapy failure.

Gross bleeding from malformations of the external urethral meatus may be seen in KTS if they are intertwined with engorge capillaries. Bleeding can be managed by the direct injection of bleomycin and topical sirolimus (65). Ethanol can cause scarring and partial necrosis of the glans penis; therefore, caution should be exercised in this condition.

The pathophysiology of GU involvement is more complicated in women than in men with KTS (Figure 1). Men and women can experience hematuria. However, in female patients, dysmenorrhea and menorrhagia can also occur when VM affects the uterus and the vagina (Figure 4) (2, 12, 20, 23, 32, 36, 37, 43, 52, 66). In women with KTS with GU involvement, a valveless IIV system has a broad communication network and provides a large capacitance to accommodate hemodynamic alterations. The left renal hilum, pelvic visceral and parietal veins, and superficial extrapelvic veins serve as venous reservoirs (67). At the pelvic escape points, these reservoirs communicate with the superficial extrapelvic veins in the thighs and the perineum through the pelvic floor. These veins communicate with the left renal hilum through the left ovarian vein (67). Congenital pelvic VMs in KTS result in stagnant pelvic venous flow, hypertension, and congestion (2), which can be transmitted to the adjacent venous plexus, thereby leading to associated symptoms and phlebectasia. The etiologies underlying dysmenorrhea and menorrhagia in patients with KTS with GU involvement are complicated. Our previous study (2) demonstrated that IIV reflux may be associated with GU bleeding, dysmenorrhea, and menorrhagia in female patients with lower extremity KTS. Pelvic pain can also be caused by reflux of the left ovarian vein. In practice, the coexistence of reflux and IIV has been observed in some patients with KTS and dysmenorrhea (Figure 5). Pain relief can be achieved after ablation of reflux (2). In some patients, dysmenorrhea may be exclusively caused by incompetence of the uterine veins (Figure 4). In patients with KTS with dysmenorrhea and/or menorrhagia, the etiologies include IIV reflux, left ovarian vein reflux, uterine VM, or both.

Mechanical venous hypertension may be caused by outflow obstruction of the gravid uterus. Pregnancy may also precipitate and worsen existing pelvic VM because progesterone and estrogen are at extreme physiological levels during pregnancy, which can increase the circulating blood volume and worsen focal venous hypertension (7, 8, 49, 52, 68, 69). Therefore, some patients show symptom progression during pregnancy (68). On account of focal venous hypertension and possible LIC, rupture of the vesical venous plexus, vaginal plexus, and uterine venous plexus causes hematuria, abnormal colporrhagia, and menorrhagia, respectively.

Phlebectasia, VM, or capillary malformation of the external genitalia/perineum usually exist in female patients with KTS with pelvic involvement and often affect the labia (Figure 4) (68, 70, 71). The IIV and vesical, vaginal, and uterine venous plexuses require a full assessment of venous hemodynamics by using MRI and confirmative phlebography. Imaging of the left ovarian vein is also required, in addition to imaging of the femoral vein, marginal vein, gluteal veins, common iliac vein, external iliac vein, and IIVs. Phlebectasia/VM of the external genitalia/perineum can be punctured directly to perform phlebography of the pelvic veins (Figure 4).

If conservative treatment fails, sclerotherapy is the most commonly used treatment strategy. The aforementioned pathophysiology of hematuria and abnormal colporrhagia and menorrhagia and interventional radiological approaches to the pelvic venous plexuses include direct puncture, trans-IIV access, and trans-left ovarian vein access (Figure 5). If phlebectasia/VMs of the external genitalia/perineum are visible and accessible, direct puncture of these veins can be used to perform ethanol-based sclerotherapy (Figure 4). Because the marginal vein often drains into the IIV via the inferior and superior gluteal veins, these veins can also be accessed and used for transcatheter intervention through the marginal vein (Figure 5). We preferred administering sclerotherapy with a combination of ethanol and foam polidocanol. Cystoscopic injection of ethanol at the bleeding sites, cauterization, and surgical resection of the bladder bleeding sites can also be considered. Hysterectomy is rarely required in patients with KTS with uterine involvement.