—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 2 - Kaposiform Hemangioendothelioma

Sara Szabo
Children's Hospital of Wisconsin
Milwaukee, WI





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Clinical History:
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.


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CD31


Introduction:
This case is an example of Kaposiform Hemangioendothelioma (KHE), first discussed under this name in the literature by Zukerberg et al. [1]. 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 [2] 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.

Pathologic Features:
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 [3].

Most cases [4, 5, 6, 7] of KHE present in early childhood, especially in the first two years of life, and are occasionally detected prenatally [8, 9], as in this case. A minority of cases may present in adults, nearly all without KMP [10, 11]. 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 [9].

Characteristic pathologic findings [4, 5, 6, 7, 9]:
  1. Infiltrative, ill-defined, frequently coalescing nodules of spindled endothelial fascicles admix with nodular epithelioid nests and areas of more typical capillary formation.

  2. Spindled endothelial cells
    • are moderately plump, with eosinophilic to clear cytoplasm and bland nuclei.

    • form elongated slit-like lumina containing erythrocytes.

    • curve around epithelioid nests rich in pericytes surrounding platelet-rich microthrombi.
  3. Dilated crescentic lymphatic vessels surround and intermingle with nodules, most prominently at margins of the lesion.

  4. 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.
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.

By immunohistochemistry [7, 12], 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.

Differential Diagnosis:
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 (KS).

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) [4, 5, 7, 13, 14] include 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) [15, 16], 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.

Final Diagnosis:
Kaposiform Hemangioendothelioma

Discussion:
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 [1]. However, accumulated evidence suggests that true metastasis is unlikely in KHE [7]. 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 reported.

The reported 10-12% mortality rate associated with KHE is secondary to KMP or to local effects [3, 17, 18]. 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 [7].

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 [9, 17, 18] is warranted 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.

Conclusions:
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 as GLUT1.

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.

References:
  1. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993;17:321-8.

  2. Kasabach HH MK. Capillary hemangioma with extensive purpura. Am J Dis Child . 1940;59:1063–70.

  3. Cohen MM Jr. Vascular update: morphogenesis, tumors, malformations, and molecular dimensions. Am J Med Genet A . 2006 Oct 1;140(19):2013-38. Review.

  4. Enjolras O, Wassef M, Mazoyer E et al. Infants with Kasabach-Merritt syndrome do not have "true" hemangiomas. J Pediatr. 1997;130:631-40.

  5. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg. 1997;100:1377-86.

  6. Lyons LL, North PE, Mac-Moune Lai F, Stoler MH, Folpe AL, Weiss SW. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol. 2004;28:559-68.

  7. North PE, Waner M, Buckmiller L, James CA, Mihm MC, Jr. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol. 2006;15:303-17.

  8. Walsh MA, Carcao M, Pope E, Lee KJ. Kaposiform hemangioendothelioma presenting prenatally with a pericardial effusion. J Pediatr Hematol Oncol. 2008 Oct;30(10):761-3.

  9. Enjolras O, Mulliken JB, Wassef M et al. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol. 2000;42:225-35.

  10. Gruman A, Liang MG, Mulliken JB et al. Kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon. J Am Acad Dermatol. 2005;52:616-22.

  11. Vetter-Kauczok CS, Strobel P, Brocker EB, Becker JC. Kaposiform hemangioendothelioma with distant lymphangiomatosis without an association to Kasabach-Merritt-Syndrome in a female adult! Vasc Health Risk Manag. 2008;4:263-6.

  12. Debelenko LV, Perez-Atayde AR, Mulliken JB, Liang MG, Archibald TH, Kozakewich HP. D2-40 immunohistochemical analysis of pediatric vascular tumors reveals positivity in kaposiform hemangioendothelioma. Mod Pathol. 2005;18:1454-60.

  13. North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000 Jan;31(1):11-22.

  14. North PE, Mihm MC Jr. Histopathological diagnosis of infantile hemangiomas and vascular malformations. Facial Plast Surg Clin North Am. 2001 Nov;9(4):505-24. Review.

  15. Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol. 2008;3:31.

  16. Cheuk W, Wong KO, Wong CS, Dinkel JE, Ben-Dor D, Chan JK. Immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin Pathol. 2004;121:335-42.

  17. Haisley-Royster C, Enjolras O, Frieden IJ, Garzon M, Lee M, Oranje A, de Laat PC, Madern GC, Gonzalez F, Frangoul H, Le Moine P, Prose NS, Adams DM.. Kasabach-Merritt phenomenon: a retrospective study of treatment with vincristine. J Pediatr Hematol Oncol. 2002 Aug-Sep;24(6):459-62.

  18. Adams DM, Wentzel MS. The role of the hematologist/oncologist in the care of patients with vascular anomalies. Pediatr Clin North Am. 2008 Apr;55(2):339-55.