Case 2 -
Children's Hospital of Wisconsin
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A newborn baby, 3150 gm, was delivered via cesarean section at 38 weeks of gestation to a 24-year old mother with lupus. A prenatal ultrasound had shown a large neck mass, which at birth was purple colored and firm. A biopsy of the mass was obtained on day of life 7.
This case is an example of Kaposiform Hemangioendothelioma (KHE), first discussed under this name in
the literature by Zukerberg et al. . This histologically and clinically distinctive vascular
lesion, most commonly seen in infancy and childhood, is strikingly associated with Kasabach-Merritt
phenomenon (KMP), a life-threatening bleeding diathesis. The case originally described in 1940 by
Kasabach and Merritt  as a "giant capillary hemangioma" in a 2-month old with
thrombocytopenia, was almost certainly a case of KHE, rather than a common infantile hemangioma.
KMP is characterized by profound thrombocytopenia due to platelet trapping in the tumor, and sometimes
is accompanied by microangiopathic hemolytic anemia and secondary consumption of coagulation factors. It
is distinct from the consumptive coagulopathy that may develop in large venous or lymphatic malformations
of KHE present in early childhood, especially in the first two years of
life, and are occasionally detected prenatally
as in this case. A minority of cases may
present in adults, nearly all without KMP
The lesions range from superficial locally
infiltrative stains and plaques to deeply seated bulky masses. The latter may occur in soft tissue of
the extremities, trunk, or the head and neck, or may be diagnosed as large body cavity or retroperitoneal
masses, often followed by a complicated course with KMP and adverse outcome. Skin manifestations include
purpura and ecchymoses. MRI usually demonstrates a diffusely enhancing, T2 hyperintense lesion with
ill-defined margins that cross tissue planes. Untreated tumors do not regress .
Characteristic pathologic findings
At low power, the tumor shows irregular, ill-defined nodular growth, either in a freely infiltrative
pattern, or with variable stromal response, including dense fibrosis. The slit-like lumina, formed by
the plump spindled endothelial cells contain erythrocytes, reminiscent of Kaposi sarcoma. Mitotic
activity is typically low, but may be focally moderate. In addition to platelet-rich microthrombi –
highlighted by CD31 or CD61 immunostaining – extravasated red cells and hemosiderin granules are often
present, as are intracytoplasmic erythrocyte fragments and hyaline globules.
- Infiltrative, ill-defined, frequently coalescing nodules of
spindled endothelial fascicles admix with nodular epithelioid nests and areas of more typical capillary
- Spindled endothelial cells
- are moderately plump, with eosinophilic to clear
cytoplasm and bland nuclei.
- form elongated slit-like lumina containing
- curve around epithelioid nests rich in pericytes
surrounding platelet-rich microthrombi.
- Dilated crescentic lymphatic vessels surround and intermingle with
nodules, most prominently at margins of the lesion.
- By immunohistochemical stain, the spindled cells are positive for
CD31 and CD34, variably weakly positive for vWF, and strongly positive for the lymphothelial markers
podoplanin (D2-40) and LYVE-1.
the spindled endothelial cells are positive for the
panendothelial marker CD31 (and variably von Willebrand's factor), as well as for CD34, and the
lymphothelial markers podoplanin (D2-40) and LYVE-1. All endothelial cells comprising KHE, whether
spindled or more normal in configuration, are completely negative for infantile hemangioma markers such
as GLUT1 and LeY antigen. Pericytes can be highlighted by SMA staining.
Three entities enter the histologic differential considerations: (1) tufted angioma (TA), to which
KHE is very closely related and with which it shares an overlapping clinical and pathologic spectrum, (2)
infantile hemangioma, which was a historic player in the past nosologic confusion, and (3) Kaposi sarcoma
TA is classically described as poorly demarcated lesions in the in the dermis and subcutis, consisting
of multiple discrete cannonball-like lobules of vascular proliferations that are peripherally surrounded
by thin-walled vascular vessels. The pinpoint-like capillary lumina occasionally contain fibrin and
platelet microthrombi. Endothelial cells focally may appear spindled at the periphery of lobules, but
this is never a prominent feature. By immunohistochemistry, endothelial cells are focally positive for
podoplanin (D2-40) and LYVE1.
Given their additional histologic and immunohistochemical overlap, it's been suggested that TA may be
a superficial mild form of KHE. They both occur equally in both genders and in young children. Areas of
classical TA histology are often seen in skin overlying deeper zones more typical of KHE.
Major clinical differences between KHE and infantile hemangioma (IH)
female predominance and universal lack of KMP in the latter, typically different physical appearance, and
the lack of spontaneous involution (i.e. without treatment) for the former. In small biopsies,
histological distinction can be assured by immunohistochemical stains, as both KHE and TA are negative
for GLUT1 and other infantile hemangioma-associated endothelial markers, and are positive for lymphatic
endothelial markers. In contrast, infantile hemangioma capillaries are GLUT-1 positive and negative for
lymphatic endothelial markers.
KHE shares some histological features with its namesake, Kaposi sarcoma (KS)
imparted mostly by fascicles of spindle cells forming slit-like vascular lumina with luminal
erythrocytes, extravasation of erythrocytes, remnants of red cells, and a similar mixed lymphatic blood
vascular immunophenotype. However, KHE lacks KS' characteristic lymphoplasmacytic background infiltrate,
and does not form glomeruloid bodies. Since the identification of HHV8 as the causative agent of KS,
either PCR or immunostain for the HHV8 latent nuclear antigen-1 (LNA1) may be utilized and is a
confirmatory test for KS. In the literature, all KHE cases tested for HHV8 has been reported as negative
for this virus.
KHE has been termed a hemangioendothelioma, rather than a "hemangioma", to reflect early uncertainty
regarding possible borderline malignant behavior, since regional lymph node metastases have been reported
in two cases . However, accumulated evidence suggests that true metastasis is unlikely in
KHE . Multifocal development along a regional lymphatic chain or in separate regions has
been proposed as an alternative explanation for the above phenomenon. No distant metastases have been
The reported 10-12% mortality rate associated with KHE is secondary to KMP or to local effects
The life-threatening thrombocytopenia of KMP is due to platelet entrapment by the
tumor. Platelet transfusions have sometimes paradoxically worsened the coagulopathy. Platelet
activation and release of angiogenic factors, such as platelet-derived growth factor, may stimulate
vascular proliferation in KHE. It's been hypothesized that a self-sustaining cycle of platelet trapping
and tumor growth may be significant factors in development of full-blown KMP .
Most cases of KHE that present without KMP are diagnosed in later childhood and in adults. This form
is indistinguishable from KHE with KMP histologically, immunophenotypically and radiologically. It's
been hypothesized that that the generally small size of these lesions without KMP may be a contributing
(but not a defining) factor.
Wide local excision, when possible, is curative. Medical treatment
when KMP is associated with KHE and when the lesion is not resectable. No single regimen has yielded
consistent results either in terms of tumor size reduction or mitigation/correction of
thromobocytopenia. Vincristine has emerged as a preferred treatment of choice. Efficacy of interferon
alfa-2a and -2b has been reported, but has fallen out of favor due to risk of permanent spastic
paraplegia when administered in infancy. Corticosteroid monotherapy is not effective. Treatment of
small lesions without KMP is controversial.
Kaposiform hemangioendothelioma (KHE) is a vascular tumor primarily of early childhood, and
occasionally it is detected prenatally. On the skin, lesions often appear as red to violaceous
ill-defined plaques, but may present as large infiltrative masses, especially in the viscera. On MRI
they appear as diffuse enhancing, T2 hyperintense lesions with ill-defined margins.
Histologically, they are composed of infiltrative, ill-defined, frequently coalescing lobules of
spindled endothelial cell fascicles. The moderately plump spindle cells form elongated slit-like lumina
that contain erythrocytes and frequently remnants of erythrocytes. Nodular pericyte-rich epithelioid
nests, with pinpoint vascular lumina, often surround platelet-rich microthrombi. Dilated lymphatic
vessels surround and intermingle with nodules, most prominently at the margins of lesions. The spindled
endothelial cells strongly co-express markers for blood vascular endothelium (CD31 and CD34) and
lymphatic endothelium (podoplanin and LYVE-1). They are negative for infantile hemangioma markers such
KHE and tufted angioma (TA) account for the vast majority of so-called "KMP", caused by selective
platelet trapping within these tumors, causing life-threatening thrombocytopenia. Clinically and
histologically KHE is closely and perhaps fundamentally related to TA. The majority of tumors arise in
the superficial or deep soft tissues of the extremities and trunk; however, large and/or non-resectable
tumors of the retroperitoneum and mediastinum may pose further risk of fatality. Although KHE has been
categorized as a borderline lesion, in part on the basis of two reported cases with metastasis to
regional lymph nodes, accumulated evidence suggests that true metastasis is unlikely in KHE. Untreated
cases do not regress.
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