Clonal X-chromosome inactivation suggests that splenic cord capillary hemangioma is a true neoplasm and not a subtype of splenic hamartoma

Abstract

Splenic hamartoma is a rare tumor-like lesion composed of structurally disorganized red pulp elements. It has been hypothesized that two other splenic lesions, cord capillary hemangioma and myoid angioendothelioma, may fall within the spectrum of splenic hamartoma, simply representing morphological variants. In this study, we compared the vascular and stromal composition of cord capillary hemangioma and myoid angioendothelioma with those of classical hamartoma. In addition, we assessed the clonal vs polyclonal nature of the lesions in nine female cases by performing clonality analysis for X-chromosome inactivation at the human androgen receptor locus (HUMARA) on laser-assisted microdissected samples. In 15 of 17 cases, increased reticulin and/or collagen content was observed. The classical hamartoma cases showed a vasculature predominantly composed of CD8 þ CD31 þ CD34À splenic sinuses, whereas cases of cord capillary hemangioma and myoid angioendothelioma contained many CD8À CD31 þ CD34 þ cord capillaries, but very little CD8 þ vasculature. All cases lacked expression of D2-40 and Epstein Barr virus-encoded RNA. All cases showed a proliferation index of r5% by Ki-67. Cases of classical hamartoma lacked significant perisinusoidal expression of collagen IV and low-affinity nerve growth factor receptor. Both markers were variably expressed in the other lesions. Increased CD163-positive histiocytes were found in four cases (three cord capillary hemangiomas and one myoid angioendothelioma). HUMARA analysis was informative in all nine tested cases, of which three cases showed a non-random X-chromosome inactivation pattern, indicating clonality. All three clonal cases were cord capillary hemangiomas. Our study has shown that in spite of considerable morphologic heterogeneity and overlapping features, classical hamartoma and cord capillary hemangioma and myoid angioendothelioma are different in terms of their vascular and stromal composition. Clonality analysis supports a true neoplastic origin for the cord capillary hemangioma. A larger study using additional immunohistochemical and molecular studies is necessary to further evaluate the biological significance of the current findings.

A case of cord capillary hemangioma of the spleen: A recently proven true neoplasm

“…However, the morphological and immunohistochemical characteristics of our case match those of CCH. The benign nature of CCH in this case was supported by the lack of nuclear atypia and the low proliferation index (<5%), consistent with the observation by Chiu et al …”

“…5 Meanwhile, in 2011, Chiu et al performed clonality analysis of CCH, the results of which supported the true neoplastic nature of CCH, which was different from a hamartoma. 6 CCH is composed of vessels predominantly expressing CD34 and CD31, but not CD8, which is consistent with the expression by capillaries. Few splenic sinuses expressing CD8 and CD31, but not CD34, may exist in CCH.…”

“…Meanwhile, in 2011, Chiu et al . performed clonality analysis of CCH, the results of which supported the true neoplastic nature of CCH, which was different from a hamartoma …”

“…Before Chiu et al . presented seven cases of CCH in 2011, there had been three reported cases of CCH . When strictly defined according to the relative proportion of the types of constituent vessels, there have only been 8 documented cases of CCH to date …”

CD105 expression in oral capillary hemangiomas and cavernous hemangiomas

“…Capillary hemangioma is classified as a true tumor by the International Society for the Study of Vascular Anomalies (ISSVA) (2; http://issva.org/ content.aspx?page_id=0&club_id=298433&module_ id=152904) but is classified as a pyogenic granuloma (lobular capillary hemangioma) in the World Health Organization (WHO) classification of skin tumors (3). Chiu et al reported that capillary hemangiomas exhibit clonal X-chromosome inactivation and should thus be considered true neoplasms (4). In contrast, cavernous hemangioma is considered a venous malformation by the ISSVA and WHO (2,3).…”