Kaposiform Lymphangiomatosis in a Male Adolescent: A Clinical Challenge and the Role of Genetics

Abstract

Kaposiform lymphangiomatosis (KLA) is a rare and aggressive generalized lymphatic anomaly (GLA), with distinctive clinical, radiology, morphologic, and genetic features. It does not have a current standard treatment and presents poor overall prognosis. Somatic mutations in the RAS pathway were reported as the likely driver for the majority of patients. We report a case of a 17-year-old male adolescent who was referred to the emergency department due to a severe anemia. Laboratory workup confirmed the anemia and revealed coagulation factor consumption and fibrinolysis. Chest-abdomen-pelvis computed tomography revealed an extensive cervical, mediastinal, abdominal and retroperitoneal “hematoma.” During admission, progressive pancytopenia, and disseminated intravascular coagulation were observed, and the hypothesis of a tumor/neoplastic etiology was considered. A thoracoscopy revealed a moderate hemorrhagic pleural effusion and a mediastinal mass resembling a “hemolymphangiomatosis” malformation, which was biopsied. Histology displayed a lymphatic-venous malformation. The patient was presented at the multidisciplinary Vascular Anomalies Center and, due to the complex vascular anomaly diagnosis, oral sirolimus monotherapy was initiated. Four years later, the patient remains clinically stable, with stability of the lesion’s dimensions and characteristics. A p.Q61R variant in the NRAS gene [NM_002524.4: c.182A>G, p.(Gln61Arg)], with 5% allelic fraction and 1993x coverage was detected. In conjunction with clinical and pathological findings, it allowed KLA final diagnosis. This case reinforces the importance of a high index of clinical suspicion and highlights the need of referring these cases to referral to Vascular Anomalies Centers.

Introduction

Kaposiform lymphangiomatosis (KLA) is a rare generalized lymphatic anomaly (GLA), first described in 2014 by Croteau et al. ¹ Although presenting similar features with a longer-known vascular anomaly, kaposiform hemangioendothelioma (KHE), KLA presents distinctive clinical, radiology, morphologic, and genetic characteristcs.

Typically, most KLA cases present in childhood with hemorrhagic and respiratory symptoms. Occasionally late adolescence or adulthood cases have also been reported.^1,2 It is an aggressive, infiltrative, multifocal, and systemic lymphatic anomaly, without current standard treatment and poor overall prognosis.^1,3,4 Histologically the lesion is characterized by the presence of dilated lymphatic vessels, typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled endothelial cells, positive for D2-40, PROX1, and CD31.^2,5 In the last years, somatic mutations in the RAS pathway were reported as the likely driver for the majority of patients, allowing its use for diagnosis and clinical purposes. ³

We report a case of an extensive mediastinal and retroperitoneal lymphatic anomaly in a 17-year-old male adolescent presenting with severe anemia, thrombocytopenia, and coagulopathy, currently stable under sirolimus treatment, in whom genetics played a crucial role in definitive diagnosis. This case illustrates the difficulties in managing these patients and reinforces the importance of its awareness and prompt referral to a multidisciplinary Vascular Anomalies Center.

Case Report

A 17-year-old male adolescent was referred to the emergency department due to a severe anemia (hemoglobin [Hgb] level of 3.5 g/dL, leukocyte count of 4200/μL, platelet count of 206 000/μL ). During the previous 2 months, he complained from asthenia and adynamia and had been medicated with an antidepressant. He denied any other complaints, such as fever, pain, unintentional weight loss, dyspnea, and respiratory symptoms. Previous bleeding episodes or evident food intake deficits were not reported, nor was there any history of recent infectious or traumatic events. His physical examination showed pallor and tachycardia.

Laboratory workup confirmed severe anemia (Hgb = 3.4 g/dL), associated with iron deficiency, but without hemolysis, elevated inflammatory parameters, or folic acid or vitamin B12 deficits. Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), low fibrinogen, and elevated D-dimer levels, reflecting coagulation factor consumption and fibrinolysis, were present (PT = 14.4 seconds, aPTT = 27.6 seconds, fibrinogen = 86 mg/dL, D-dimer = 10 317 ng/mL). To exclude an underlying hemorrhagic/thrombotic condition, a contrast enhanced thoraco-abdomen-pelvic (TAP) computed tomography (CT) was performed. It revealed an extensive “hematoma” extending from cervical to the mediastinal, abdominal, and retroperitoneal compartments and sternal lytic bony lesions. Echocardiogram was normal, without signs of pericardial effusion. The patient was admitted to intensive care, and additional comprehensive workup was taken.

Due to the patient evolution to pancytopenia (minimum leukocyte and platelet count of 3730/μL and 74 000/μL, respectively) and disseminated intravascular coagulation (DIC), despite multiple red blood cell and fibrinogen transfusions, the hypothesis of a tumor/neoplastic etiology was considered. Bone marrow aspirate’s phenotypic study was non-specific, showing a reactive process with erythropoiesis. A right thoracoscopy was performed, revealing a moderate hemorrhagic pleural effusion and a mediastinal mass resembling a “hemolymphangiomatosis” malformation with associated internal hemorrhage’s signs, which was biopsied. Histology displayed a lymphatic-venous malformation.

The patient was transferred to our hospital and presented at the multidisciplinary group consult on vascular anomalies. Dynamic contrast-enhancing magnetic resonance imaging (MRI) confirmed an extensive cervical, mediastinal, abdominal, and retroperitoneal lesion, with bilateral hilar, pleural, mesenteric, and perirectal involvement, with fluid signal and some foci of late enhancement (Figure 1). Hepatosplenomegaly and minimal abdominopelvic ascites were also present. Intranodal lymphangiography revealed delay in contrast progression and deviation to vascular malformation’s ectatic lymphatic channels at abdominal, thoracic, and cervical levels (Figure 2). Histology second look revealed remarkable presence of dilated lymphatic channels (podoplanin positive), confirming a lymphatic-venous malformative vascular anomaly (Figure 3). Due to the complex vascular anomaly diagnosis and its aggressive clinical course, oral sirolimus monotherapy was initiated, targeting serum trough levels of 10 to 15 ng/mL. During treatment, platelets have remained above 70 000/μL, fibrinogen above 100 mg/dL, and D-dimer levels have remained slightly elevated, around 6000 ng/mL.

Figure 1.

Coronal chest (A) and abdominal (B) T2-weighted MRI images show extensive and infiltrative cervical, mediastinal, abdominal, and retroperitoneal lesion, with bilateral hilar, pleural, mesenteric, and perirectal involvement.

Figure 2.

Thoracic (A), abdominal (B), and pelvic (C) intranodal lymphangiography reveal delay in contrast progression and deviation to vascular malformation’s ectatic lymphatic channels.

Figure 3.

The histologic analyses show remarkable presence of dilated lymphatic channels (podoplanin positive). The immunostain for actin displays the irregularity of the vessel wall, due to the irregular proliferation of the muscular layer.

Four years later, the patient remains clinically stable, without anemia or DIC. On the last two blood samples, platelet count were >100 000/μL and fibrinogen >200 mg/dL. The last MRI showed stability of the lesion’s dimensions and characteristics, without further findings.

Somatic genetic analysis was only recently performed, using a comprehensive NGS panel Oncomine Childhood Cancer Research Assay. We detected a p.Q61R variant in the NRAS gene [NM_002524.4: c.182A>G, p.(Gln61Arg)] with 5% allelic fraction and 1993x coverage. In conjunction with clinical and pathological findings, a diagnosis of KLA was finally established.

Discussion

KLA is a rare lymphatic anomaly, characterized by a distinctive clinical aggressive and progressive clinical course, with unique morphologic features. ¹ Intrathoracic disease, with respiratory distress, dyspnea, and hemorrhagic effusion have been considered hallmarks of KLA. ¹ Our patient was referred to the emergency department with a misdiagnosis of depression and a severe anemia, reflecting intralesional bleeding and a 2-month history of fatigue, asthenia, and adynamia. There was no previous history of worsening respiratory symptoms or evident hemorrhagic symptoms.

Although presenting an extensive and infiltrative disease, with multifocal and systemic involvement, an hemorrhagic pleural effusion, abnormal DIC profile, and deteriorating clinical course, KLA’s suspicion was not raised. Its rarity and non-specific findings may have contributed for its misdiagnosis and delayed definitive diagnosis. In cases of GLA associated with DIC and hemorrhagic effusion, KLA should be considered.^1,2

KLA is often mistaken with a longer-known vascular anomaly, kaposiform hemangioendothelioma (KHE). KLA and KHE present some clinical, imaging, and histological similarities, making its diagnosis even more challenging. Unlike KLA, most KHEs are located in the extremities and have associated cutaneous manifestations. ⁶ Intrathoracic and multifocal cases are very rare. ⁶ As in our patient, KLA may manifest with thrombocytopenia, hypofibrinogenemia, and prolonged PT and/or aPTT, similar to Kasabach-Merritt phenomenon seen in approximately 70% of KHE patients.^1,6 However, the thrombocytopenia in KLA is generally less severe, although there are some previous reports of extremely severe low platelets, similar to KHE.^1,6 Histologically, although both are positive for podoplanin (lymphatic marker D2-40), the spindle endothelial cell component in KHE is primarily solid and rounded, showing defined and confluent vascularized nodules with microthrombi, glomeruloid foci, and fibrin.^1,6 KLA usually presents a sparse with poorly marginated clusters or anastomosing strand/sheets.^1,6 Similarly, the former presents as a unifocal, infiltrative, image-enhancing mass, often associated with stranding of subcutaneous tissues, while the latter presents as a diffuse and multifocal mass, frequently involving the mediastinum and multiple bones. ¹

Although initial investigation enabled a lymphatic-venous malformation diagnosis, final characterization was achieved after the identification of the NRAS p.Q61R variant in the patient’s lesional tissue. This genetic variant is a well-know oncogenic variant of NRAS and was recently implicated in the disease’s pathogenesis when Barclay et al, in 2018, described it in 10 of 11 patients with KLA. ³ Noteworthy, we detected the NRAS p.Q61R variant with an allelic fraction of 5%, which is in agreement with a mosaic condition linked to post-zygotic activating NRAS variants. NRAS is involved in MAPK and PI3K/AKT signaling pathways, which are known to have a role in cell proliferation regulation and in the etiopathogenesis of other vascular anomalies. ³ This variant has not been found in KHE samples, which may provide a useful molecular differentiation between these two entities. ⁶

In our case, the histological alterations usually described in KLA were not present. ⁵ Beyond the presence of abnormally dilated venous and lymphatic channels, no clusters of spindled D2-40 positive cells were identified. Our interpretation was that, probably due to sampling error, our sample did not reveal the peculiar characteristics that allow the morphological diagnosis of KLA, since it is known that the typical foci of kaposiform spindle cells can be ample to sparse and can escape a small biopsy.^2,5

So far, there is no standard treatment for KLA. Multimodal therapy has been discussed, namely surgical procedures (resection, drainage, pleurodesis and ligation of the thoracic duct) and pharmaceutical drugs used in complex vascular anomalies (interferon-alpha, corticosteroids, vincristine). However, the overall prognosis of KLA remains poor, with a 5-year and overall survival rates of 51% and 34%, respectively. ¹

Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), which is a pivotal molecule in regulating cell proliferation and migration through PI3K/AKT pathways.^4,7 Sirolimus has been reported as a well-tolerated alternative approach for complicated vascular anomalies and has recently been studied as a potential option for KLA.^4,7 Previous studies reported health-related quality of life improvement and clinical stabilization, but still without clear impact on overall KLA patients’ mortality.^8,9 Our previous experience with sirolimus in other complex vascular anomalies compelled us to initiate it before trying other options and even without having a definitive diagnosis. Although the most appropriate dosage and duration of treatment still remains an unanswered question, ⁷ our patient was treated with targeting low serum concentration of 10 to 15 ng/mL and long-term monotherapy maintenance. Recent isolated reports have demonstrated promising results with the MEK inhibitor, trametinib, in patients harboring RAS mutation pathway.^10,11

In conclusion, KLA is a rare, little-known entity and may have an atypical presentation, as happened in our case. This case reinforces the importance of a high index of clinical suspicion and highlights the need of referring these cases to referral to Vascular Anomalies Centers.