Hemangioendothelioma

We describe the case of a 31-week fetus who died in utero with an invasive retroperitoneal kaposiform hemangioendothelioma. This rare vascular neoplasm usually presents as a localized violaceous skin lesion in infants and behaves in a benign fashion; however, kaposiform hemangioendothelioma may present as an invasive neoplasm of the chest or abdominal cavity, where it can lead to the Kasabach-Merritt syndrome, which consists of thrombocytopenia, consumptive coagulopathy, and microangiopathic anemia in association with a vascular anomaly. The case we describe is unique in that the tumor presented in utero and led to intrauterine nonimmune fetal hydrops. Kaposiform hemangioendothelioma has been described in utero; however, to our knowledge, intrauterine fetal death as a direct consequence has not been reported previously in the literature.

(Arch Pathol Lab Med. 2004;128:678-681)

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm of infants and children. Although cutaneous forms usually follow a benign clinical course, thoracic and retroperitoneal neoplasms may be complicated by Kasabach-Merritt syndrome and/or invasion of vital organs. We describe a case of retroperitoneal KHE presenting in a fetus at 31 weeks' gestation, which was complicated by invasion and hemorrhage and led to intrauterine fetal death.

REPORT OF A case

A 29-year-old woman presented at 31 weeks' gestation complaining of cessation of fetal movement. Two weeks earlier, the patient had suffered an upper respiratory tract viral infection. The pregnancy was otherwise uneventful, and results of clinical evaluation and ancillary tests had been normal. Years earlier, the woman had a normal pregnancy and delivery.

On physical examination, the fundal height was 37 cm with no other significant findings. Vital signs were normal, and there were no significant laboratory abnormalities. An ultrasound scan revealed a diffusely edematous, viable fetus with prominence of the soft tissues of the left lower abdomen, left proximal lower extremity, and the labia of the external genitalia. During the next 24 hours, the fetus died in utero and vaginal delivery was induced. The placenta was bulky and pale with increased weight (1000 g), and microscopic examination showed hydropic changes within the placental villi.

PATHOLOGIC FINDINGS

An edematous, extensively macerated, stillborn, female fetus was delivered with physical parameters of weight, length, chest, and head circumference within the normal limits for a gestational age of 31 weeks. The external examination was remarkable for violaceous discoloration and thickening of the skin of the left lower abdomen, left flank, labia, and proximal extremities (Figure 1). En bloc evisceration revealed hepatomegaly; hemorrhagic tissue fragments adherent to the posterior aspect of the peritoneum, descending colon, and left kidney (Figure 2); and an extensive, ill-defined, left retroperitoneal hemorrhagic mass.

The mass was composed of hemorrhagic indurated tissue, which occupied the entire left retroperitoneum, extending from the posterior inferior aspect of the left kidney to the inferior aspect of the psoas muscle. The violaceous appearance of the skin was due to extension of the neoplasm into the subcutaneous tissues of the left flank, inguinal region, vulva, and left proximal extremity. Microscopically, nodules and sheets of homogeneous spindle cells with rare mitoses invaded the perirenal and retroperitoneal fat, the psoas muscle, and the subcutaneous tissue (Figure 3). The spindle cells formed slitlike spaces variably filled with blood, merging with areas forming rounded capillary-like spaces. Immunohistochemical stains for vascular markers (CD31 and CD34) decorated the neoplastic spindle cells (Figure 4). There were extravasated red blood cells, many of which were nucleated, among the spindle cells, producing a histologie picture similar to Kaposi sarcoma (Figure 5). Collections of hematopoietic precursors were also identified within the neoplasm. Dilated capillaries engorged with blood were seen interspersed throughout and at the periphery of the neoplasm (Figure 6). There was invasion of the epineurium of retroperitoneal nerves, but no direct invasion of retroperitoneal or inguinal lymph nodes by the tumor. An immunohistochemical stain for smooth muscle actin demonstrated scattered positive cells throughout the neoplasm, while stains for GLUT-1 and human herpesvirus 8 were negative. Based on these findings, a diagnosis of KHE was made.

COMMENT

Kaposiform hemangioendothelioma is a rare vascular neoplasm that occurs mainly in newborns and infants, although cases have been reported in adults.1'3 The case reported here is unique in that the neoplasm was identified in utero and caused death by hemorrhage. Whether the hemorrhage was a consequence of the Kasabach-Merritt syndrome is uncertain, because there was no laboratory evidence of thrombocytopenia and no platelet or fibrin thrombi were seen within the neoplasm. However, the extent of the neoplasm and its hemorrhagic nature can explain nonimmune fetal hydrops.

Kaposiform hemangioendothelioma has been categorized as a vascular neoplasm of intermediate malignancy by the World Health Organization and by Enzinger and Weiss because of its locally infiltrative growth pattern and low-grade histomorphologic features.4,5 The biologic potential of KHE is determined by (a) the potential development of Kasabach-Merritt syndrome, which is characterized by consumption coagulopathy due to platelet trapping and activation of the coagulation cascade within the neoplasm with resultant hemorrhage,6 and (b) local invasion of vital organs in the abdominal and chest cavities. Kasabach-Merritt syndrome occurs with extensive neoplasms involving the mediastinum and retroperitoneum and is unusual in tumors limited to the skin and subcutaneous tissue.

Before the 1990s, KHE had been described in the literature under a variety of different names, most of them in descriptive case reports from as early as 1979.7a Undoubtedly, there had been earlier reported and likely unreported cases of spindle cell neoplasms in infants with features of KHE, which were unrecognized as such. In fact, Sarkar et aP suggested that the neoplasm described by Kasabach and Merritt in 1940 was actually a KHE, based on the morphologic description and clinical features. They also suggested that Kasabach-Merritt syndrome is unique to KHE.

Kaposiform hemangioendothelioma presents in infants and children as violaceous plaques of the skin and subcutaneous tissue. The location of skin lesions is highly variable and may include the extremities, trunk, and head and neck. Tumors may also present as fleshy to hemorrhagic masses involving the mediastinum and retroperitoneum, where they may become large, potentially producing the Kasabach-Merritt syndrome, and may invade vital structures, such as the liver and intestines. For these reasons, the location of KHE has the most significant impact on the biologic behavior and clinical outcome.

The histomorphologic features include nodules or solid sheets of cytologically bland, monomorphic spindle cells forming slitlike spaces with extravasation of red blood cells, hence the descriptor kaposiform. Although absent in this case, fibrin thrombi and hemosiderin may be present within the slitlike spaces. The spindle cell component may be accompanied by larger, open, capillary-like structures reminiscent of capillary hemangiomas, as seen in the present case. The so-called glomeruloid nests of rounded epithelioid cells sometimes seen in KHE1 were not present in this case. Kaposiform hemangioendothelioma is also reported to be associated with lymphangiomas and lymphangiomatosis, neither of which was identified in the present case.1

Immunohistochemical staining confirms the vascular differentiation of KHE, with CD31 and CD34 decorating most neoplastic cells. Vascular endothelial growth factor receptor-3 (VEGFR-3), a marker of lymphatic vascular differentiation, has been demonstrated in KHE; however, this antibody was unavailable for evaluation.10 Focal smooth muscle differentiation is usually present among scattered spindle cells between vascular spaces (as in the present case). Ultrastructural findings are reported to be consistent with the endothelial differentiation of KHE.1

The differential diagnosis of KHE includes Kaposi sarcoma, which is exceedingly rare in infants and uncommon in children, save for the African lymphadenopathic form. Even in pediatrie patients with acquired immunodeficiency syndrome, Kaposi sarcoma is rarely encountered. Clinically, the multiplicity of lesions and the location of Kaposi sarcoma, most often involving mucosal surfaces and skin, are in contrast to KHE. Histomorphologically, Kaposi sarcoma displays a solid pattern of growth, as opposed to the typical nodular pattern of KHE, and is often accompanied by an inflammatory infiltrate composed of lymphocytes and plasma cells, which is usually lacking in KHE. Furthermore, KHE shows no association with human herpesvirus 8, unlike Kaposi sarcoma.11

Capillary hemangiomas are a group of vascular neoplasms that must be differentiated from KHE because of their nodular growth pattern and other histomorphologic features. A subtype of capillary hemangioma, the juvenile hemangioma, is a benign vascular neoplasm of infancy, which proliferates rapidly and involutes over several years. The proliferative phase is characterized by well-defined masses of plump endothelial cells with round Iumina, as opposed to the spindle cell proliferation and slitlike spaces of KHE. Brisk mitotic activity may be sseen in the proliferative phase of juvenile hemangioma, while mitoses are rare in KHE. In the involutional phase of juvenile hemangioma, the capillary proliferation is replaced by loose fibroadipose tissue. A distinguishing immunohistochemical feature of juvenile hemangioma is reactivity for the highly specific erythrocyte glucose transport protein GLUT-1, which stains the neoplastic cells during the proliferative and involutional stages of the disease.12

Spindle cell hemangioendothelioma is a benign vascular neoplasm with bland spindle areas with slitlike spaces in between thin-walled cavernous vessels, bearing morphologic resemblance to KHE. A distinct feature found within the spindle cell areas is the presence of epithelioid neoplastic cells with vacuolization. Furthermore, spindle cell hemangioendotheliomas are neoplasms of young adults; most reported cases occur in the upper extremities, especially the hands. Another vascular neoplasm of adults, acquired tufted hemangioma, is histologically indistinguishable from KHE and is considered by some to be a limited adult form of this tumor.4,13 Acquired tufted hemangioma is usually confined to the skin and has been described in association with Kasabach-Merritt syndrome.14

To date, the therapeutic options for KHE have been limited by a lack of experience due to the relative rarity of this neoplasm. Several case reports have described positive patient outcomes with multimodality and chemotherapeutic regimens; however, the overall mortality remains high for retroperitoneal and mediastinal neoplasms.15

In conclusion, we describe an unusual in utero presentation of a retroperitoneal KHE associated with nonimmune fetal hydrops.

References

1. Zukerberg LR, Nickoloff B), Weiss SW. Kaposit'orm hemangioendothelioma of infancy and childhood: an aggressive neoplasm associated with KasabachMerritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993;17:321-328.

2. Mentzel T, Mazzoleni C, Deitos AP, Fletcher CDM. Kaposiform hemangioendothelioma in adults: clinicopathologic and immunohistochemical analysis of three cases. Am J Clin Pathol. 1997;108:450-455.

3. Cooper JG, Edwards SL, Holmes ID. Kaposiform hemangioendothelioma: case report and review of the literature. Br l Plast Surg. 2002;55:163-165.

4. Weiss SW, Goldblum JR, ed. Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St Louis, Mo: Mosby; 2001.

5. Fletcher CDM, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002. World Health Organization Classification of Tumors; vol 5.

6. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura: report of a case. Am J Dis Child. 1940:59:1063-1070.

7. Pearl GS, Mathews WH. Congenital retroperitoneal hemangioendothelioma with Kasabach-Merritt syndrome. South Med J. 1979;9:239-240.

8. Niedt GW, Greco MA, Blanc WA, Knowles DM. Hemangioma with Kaposi's sarcoma-like features. Pediatr Pathol. 1989:9:567-575.

9. 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;100:1377-1386.

10. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor-3 (VEGFR-3): a marker for vascular tumors with presumed lymphatic differentiation, including Kaposi's sarcoma, kaposiform and Dabska-type hemangioendothelioma, and a subset of angiosarcomas. Mod Pathol. 2000:13:180-185.

11. Nickoloff BJ, Foreman KE. Etiology and pathogenesis of Kaposi's sarcoma. Recent Results Cancer Res. 2002;160:332-342.

12. North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangioma. Hum Pathol. 2000; 31:11-22.

13. Lyons LL, North PE, Stoler MH, Folpe AL, Weiss SW. Kaposiform hemangioendothelioma (KH) is histologically, immunohistochemically and biologically distinct from common (juvenile) hemangioma (JH): a bi-institutional analysis of 33 cases [abstract]. Mod Pathol. 2003;16:16A.

14. Alvarez-Mendoza A, Lourdes TS, Ridaura-Sanz C, et al. Histopathology of vascular lesions found in Kasabach-Merritt syndrome: review based on 13 cases. Pediatr Dev Pathol. 2000;3:556-560.

15. Blei F, Karp N, Rofsky N, Rosen R, Greco MA. Successful multimodal therapy for kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon: case report and review of the literature. Pediatr Hematol Oncol. 1998:15:295-305.

Antonio E. Martinez, MD; Morton J. Robinson, MD; John B. Alexis, MB,ChB

Accepted for publication February 5, 2004.

From the Arkadi M. Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FIa.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Antonio E. Martinez, MD, Arkadi M. Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Rd, Blum Bldg, Room 201, Miami Beach, FL 33140 (e-mail: amartin2@msmc.com).

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