Tufted angioma with kasabach-merrit syndrome successfully treated with everolimus.

M. CHERRAFI

Introduction:
Kasabach-Merritt syndrome (KMS) is a life-threatening condition. It is defined as the association of a
vascular tumor with thrombocytopenia and a variable degree of CIVD and sometimes anemia. It is
commonly accepted that KMS occurs on two histological types of vascular tumors: kaposiform
hemangioendothelioma (KHE), and less frequently with tufted angioma (TA). The diagnosis is
established by histopathology. Treatment of KMS remains challenging (1). However, mammalian
target of rapamycin (mTOR) inhibitors have shown efficacy in this condition. In 2014, Teruaki Uno
and colleagues reported the first case of KMS treated with a mechanistic target of rapamycin (mTOR)
inhibitor, everolimus (2). The second patient has been reported by Matsumoto in 2016 (3).
In the present study, a patient with KMS arising from tufted angioma was successfully and variously
treated with everolimus. Following therapy with everolimus for 1 year, there has been no evidence of
recurrence during 2 years of follow-up. Currently, the patient is alive and well.

Case report:
A 2-month-21 day’s old infant with no previous history, was admitted to Dermatology department
for a rapidly enlarging tumor located in the left cheek. The clinical examination found an indurated,
reddish and purplish lesion of 5 cm diameter, irregularly shaped, poorly demarcated and showed
signs of swelling and inflammation. Palpation seemed to be painful (Fig. 1). No other cutaneous
lesions were revealed.

Figure 1: Initial aspect of the lesion

Admission laboratory testing indicated a severe drop in platelet count (77000/mm3); an
undetectable fibrinogen level, a very high D-dimer level (>10 000 ng/ml) and anaemia with
haemoglobin down to 7.2 g/dl. Based on thrombocytopenia, consumptive coagulopathy and purpura
associated with a huge vascular tumor, the patient was diagnosed as KMS.
The biopsy found angiomatous lobules of the dermis made up of collapsed capillaries packed against
one another. These lobules were surrounded by a dilated capillary of arciform appearance. This
result allowed us to conclude that a tufted angioma was present.
Regarding therapy: The patient was first treated by oral prednisolone (3mg /kg /day), acetylsalicylic
acid (10mg/kg /day), and ticlopidine (10mg /kg /day). And in view of the non-availability of sirolimus
in our hospital structure; treatment with everolimus (0.1 mg/kg /day) was started. Informed consent
was obtained from the patient's parents prior to treatment. Routine blood parameters, coagulation
function, liver and kidney function, serum lipids were monitored regularly. The steroid was
withdrawn gradually, starting from the onset time of everolimus.
During the following months, patient showed after 1 month significant improvement in hematologic
parameters and a decrease in the size of lesion (figure 2)with a significant reduction in intensity of
color and thickness until almost total disappearance of the vascular mass at the 3rd month (figure 3).
Platelet count increased to 467000/mm3, fibrinogen to 3,2g/l, D-dimer to 398ng/ml after 3 months
of therapy.

Figure 2: Aspect of the lesion after 1 month.

Figure 3: Aspect of the lesion after 3 months.

Figure 4: Aspect of the lesion after 6 months.

The patient was being treated with everolimus, ticlopidine and acetylsalicylic acid for 12 months. At
the time of writing the present study, the patient is still under ticlopidine and acetylsalicylic acid. He
is healthy without evidence of relapse for 1 year after stopping everolimus. The cutaneous
component of the patient’s TA has now resolved as well.
Regarding adverse effects, patient has presented 2 episodes of urinary tract infection well controlled
under antibiotic therapy. We did not note any metabolic disturbance on the biological assessment.
Respiratory symptoms were not noted during the 12 months of everolimus treatment.

Discussion:
Kasabach–Merritt syndrome, first described in 1940(5), is a rare life-threatening complication of
vascular tumors, of unknown prevalence (6). It is defined as the combination of profound
thrombocytopenia and consumptive coagulopathy (low fibrinogen, elevated soluble complexes, very
elevated D-dimers) in infants aged below 6 months with a vascular tumor (6).
KMS is exclusively associated with the vascular tumors kaposiform hemangioendothelioma (KHE)
and tufted angioma (TA), which are rare, benign vascular tumors that typically present in infancy (5).
Both arise from capillary and lymphatic endothelium and are notable for their convoluted vascular
architecture (5). Tufted angioma (TA) is a rare vascular tumor that usually presents as brown, blue, or
dusky red to violaceous infiltrated macules, plaques, or nodules of various sizes (7). Only a limited
number of TA cases associated with KMP have been reported (7.8). Although the onset of TA has also
been reported in adults, most cases occur during infancy and early childhood, especially within the
first year of life without sex predominance (7.9)
The development and progression of vascular tumors with KMS is extremely dangerous, resulting in a
mortality rate of 12–30% and making treatment extremely difficult (4, 10).
The pathophysiology is not established. The hypothesis is one of the platelet trapping by abnormally
proliferating endothelium, leading to platelet activation and fibrinogen consumption (11, 5),
The management of KMS is challenging due to its rarity and the lack of well‑established systematic
treatment strategies (12). Several treatment regimens for KMS have been proposed with variable
efficiency. Including (6, 7, 9, 13): corticosteroid, vincristine, IFN, chemotherapy, radiation, laser,
propranolol and platelet aggregation inhibitors, possibly in combination (acetylsalicylic acid,
ticlopidine). Surgical resection is possible. Furthermore, once KMP develops, surgery is inadvisable
given the hemodynamic risks (6.5). Arterial embolization may be offered in certain circumstances but
it carries the risk of necrosis of local structures (5). Transfused platelets may become trapped in the
tumor and lead to further abnormal coagulation, worsening KMP (5).
MTOR inhibitors:
MTOR is a multifunctional kinase complex that plays a pivotal role in cell growth and metabolism
(14). Rapamycin (sirolimus) is an mTOR inhibitor that is a serine/threonine kinase. It was isolated
from a Streptomyces species from the soil of the Easter Island (Rapa Nui) (15, 18). Rapamycin is a
macrolide with antifungal and immunosuppressive properties (19). Rapalogs bind to the FK506-
binding protein-12 (FKBP12). This complex inhibits the mammalian target of rapamycin (mTOR), a
protein kinase that regulates cell growth, proliferation, and survival and is frequently deregulated in
cancer (15). Sirolimus is an important therapeutic option that has been increasingly used in the last
few years. It affects cell growth and angiogenesis; it is also a powerful immunosuppressor and an
antitumoral drug (13).
In recent years, several studies, most of which were case reports or case series, have reported the
application of inhibitors of the mammalian target of rapamycin (mTOR) for the treatment of vascular
tumors with KMS with good results. Boccara et al. (13) reported a sirolimus cohort of 5 cases with
KMS; they were treated with sirolimus (0-1 mg/kg / day, once daily) as a second-line treatment after
antiplatelet therapy or corticosteroids and vincristine. Platelet count normalized in 10 days to
2-5 months (average 45- 4 days). In four of the five patients, D-dimer levels normalized within 6
months.
Adams et al (14) reported a prospective clinical trial for 60 cases of vascular anomalies treated with
sirolimus, including 10 patients with kaposiform hemangioendothelioma or tufted angioma. A
response rate of 100% after 6 months or 1 year of sirolimus therapy, and impressive disease
outcome was seen in patients with KHE and KMS, particularly in their hematologic response.

Everolimus:
Everolimus is an inhibitor of the mTOR system, an immunosuppressive drug derived from sirolimus.
In addition to being a potent immunosuppressive agent, everolimus is currently being investigated as
an anticancer agent based on its potential to act directly on the tumor by inhibiting tumor cell
growth and proliferation and indirectly by inhibiting angiogenesis.
In vitro everolimus reduces expression of HIF1 and VEGF, suggesting that everolimus may also act as
an anti-angiogenic agent (15). This anti-angiogenic activity of everolimus was confirmed in vivo. Mice
with primary and metastatic tumors treated with everolimus showed a significant reduction in blood
vessel density, when compared to controls (15, 16).
In a dose-escalation study of everolimus in 92 patients with advanced cancer patients, everolimus
was rapidly absorbed after oral administration, with a median time to peak blood levels of 1–2h after
administration (15, 17).The terminal half-life was 30 h. High-fat meals alter the absorption.
Everolimus is metabolized and excreted into the feces >80% (15).

The main adverse events reported with everolimus in clinical studies were (15): stomatitis, non-
infectious pneumonitis, infections, and renal failure. In addition, hyperglycemia, hyperlipidemia,
anemia, neutropenia, and thrombocytopenia.
2 cases have reported the application of inhibitors everolimus for the treatment of
hemangioendothelioma kaposiform with KMS with good results. In 2014,

Uno (2) has reported the first case of successful Treatment of Kaposiform
Hemangioendothelioma with everolimus. He described an eight-year-old male with KHE in the
right femur that was resistant to prednisolone, vincristine and propranolol. At the dosage of
0.1mg/kg/day, the size of the tumor was objectively reduced with the associated symptoms
improving significantly. The patient tolerated everolimus well with the anticipated side effects
manageable: self-limiting stomatitis, erythematous skin rash, a sense of worthlessness and
moderate hyperlipidemia, without discontinuing or reducing the dose.

In 2016, Matsumoto (3) describe the case of a 3-month-old girl with KHE complicated by KMS
who responded dramatically to treatment with everolimus at 0.2 mg/kg/d. After 4 weeks of
everolimus treatment, the drug was discontinued because of dyslipidemia. , 2 weeks later, FDP and
D-dimer levels were elevated again, so everolimus was restarted. Everolimus was discontinued after
5 weeks of treatment. The tumor continued to decrease in size until it was no longer palpable. The
patient’s platelet count returned to normal, and her coagulopathy resolved. We observed no adverse
drug reactions other than reversible dyslipidemia. The patient has had hematologic remission with
ongoing propranolol treatment in 8 months of follow-up; repeat magnetic resonance imaging
demonstrated dramatic tumor shrinkage.
In our case, the initial therapy of platelet aggregation inhibitors and prednisone was combined with
everolimus to obtain a regression of the KMS. Long-term therapy with everolimus has shown to be
effective in controlling the disease without side effects.

Conclusion
Vascular tumors complicated by Kasabach–Merritt syndrome are rare but deserve to be widely
known because they mandate rapid medical management. Our experience suggests that the
usefulness of everolimus in KHE also holds true in tufted angioma. Everolimus may be recommended
as an early treatment of severe KMS instead of steroids or vincristine. Future studies are needed to
validate this approach and define the best duration of treatment.
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