Retiform hemangioendothelioma: a case series and review of the literature

According to the 5th edition of World Health Organization (WHO) classification of tumors of soft tissue and bone, vascular tumors are classified as benign, intermediate and malignant. The intermediate category is further divided into those with locally aggressive behavior and those which rarely metastasize. Retiform Hemangioendothelioma (RH) is a rare vascular neoplasm which belongs to the rarely metastasizing subgroup of intermediate category [1]. It commonly involves the skin and subcutaneous tissue of the lower extremities in patients over a wide age range. However, children and young adults are commonly affected. Uncommon sites of involvement include head and neck region, trunk, penis and pleura [2, 3]. Microscopically, the tumor is composed of arborizing vascular spaces which resemble the normal rete testis on low power, as the name implies. The vascular spaces are lined by single layer of endothelial cells with prominent hobnail nuclei projecting into the lumen. Most cases show local recurrence. Distant metastasis is extremely rare. Two of the earliest cases have reported to have metastasized to lymph nodes [2, 4]; while, metastasis to liver has only been reported in a single case [5]. We herein describe the clinicopathological and histological features of 3 cases of RH with thorough review of literature which will help us in establishing correct diagnosis and understanding the behavior of this rare tumor.

The Surgical Pathology database of the Department of Pathology and Laboratory Medicine at Aga Khan University Hospital (AKUH), was searched for cases reported as RH. Glass slides of all 3 cases were retrieved and reviewed, including the Hematoxylin & Eosin (H & E) stained slides as well as those of immunohistochemical (IHC) analysis. The clinical and follow-up data were obtained from medical records and by telephonic conversation. Radiological findings were also analyzed when available. 1 patient was lost to follow-up.

Three cases of RH have been reported from 1st June 2015 to 31st March 2020 at our department. Of these, 2 were females and 1 male. The age range was 18–50 years. Histologically, none of these cases showed features like nuclear atypia, spindle cell proliferation forming slit like spaces or more than rare mitotic figures that would suggest a diagnosis of angiosarcoma or Kaposi Sarcoma (KS).

RH was first reported in 1994 by Calonje et al. who described it as a rare vascular tumor affecting patients over a wide age range without gender predilection [2]. The 5th edition of WHO classification of tumors of soft tissue and bone (2020) describes RH as a tumor affecting mostly younger population [1]. In contrast to WHO and similar to the earliest reported series, our cases showed a wide range of ages, from a teenager to a middle aged patient. Although, the most common site of involvement described in the literature is lower extremities [1, 2], several rare sites have also been reported, such as the pleura, mediastinum, head and neck region and spleen and so on [3, 5‐7]. This diversity is apparent in our series with 2 of the cases arising at unusual paces that is the scalp and the mediastinum.

RH may present as multiple enhancing tumor nodules as reported in the earliest of descriptions of this entity [8], the same was observed in one of our patients, who presented with symptoms of cough and shortness of breath due to widespread mediastinal involvement. The other 2 cases had solitary tumors.

The cutaneous vascular tumors present mostly as indurated plaques [1], including hemangiomas, angiolymphoid hyperplasia with eosinophilia, kaposiform hemandioendothelioma, angiosarcoma and RH. One of our cases presented in a similar manner, with a lesion on the skin of scalp, while another one showed a variation on this theme. This latter patient had a hard growth on the toe, despite the tumor growing in the dermis and subcutis microscopically.

The first of our cases had an atypical presentation with shortness of breath. Such a presentation has only been described in the literature in a single case of RH involving the pleura [3]. The symptoms resulted from mass effect rather than direct involvement of the vital structures.

RH can be commonly seen as a component of a complex vascular lesion, admixed with other components of intermediate category of vascular tumors. The most common of these being the papillary intralymphatic angioendothelioma (Dabska tumor). Composite hemangioendotheliomas, may also harbor areas morphologically indistinguishable from RH. These two entities belong to the most important differential diagnoses of RH and must be considered before making a final diagnosis of RH. Though Dabska tumor itself is an extremely rare entity, composite hemangioendotheliomas are slightly more common than RH and Dabska tumor as described in the WHO 2020 [1]. Histologically, Dabska tumor exhibits intravascular papillary proliferations lined by single layer of cells, with hobnailing of nuclei (Fig. 3e, f). The intraluminal papillae have hyalinized cores. Similar papillary structures may be seen in RH, as seen in 3rd case of our series. Anne-Fore Albertini et.al reported an unusual case of RH in a 6-year-old female, which showed areas of Dabska tumor. This tumor had developed at the site of a treated lymphangioma [9]. Some authors still believe these two entities to be closely related to each other and a definite distinction between the two may not be possible in all cases. However, presence of branching, interconnected vascular channels is a useful diagnostic clue and intraluminal proliferation with papillary architecture of Dabska tumor is completely absent in most cases of RH. Extravasation of red blood cells and lymphocytic infiltration in the background is more common in Dabska tumor. In addition, areas of lymphangioma at the periphery are seen in Dabska tumor [10]. IHC usually provides little help in distinction between these two tumors as both of these share positivity for vascular markers including CD31, CD34, ERG and Claudin-5. Podoplanin (D2-40), a marker of lymphatic lineage, is more frequently expressed in Dabska tumor than RH [1]. D2-40 was not performed on any of the cases described in this series.

It is also important to differentiate RH from more aggressive vascular tumors such as angiosarcoma, which may also show areas with hobnail endothelial cells, particularly in a small biopsy specimen (Fig. 3a, b). By definition, angiosarcoma shows nuclear atypia and mitoses in the endothelial cells, which is not seen in RH. KS should also be considered in the differential diagnosis of RH as both of these tumors occur in the dermis and subcutaneous tissue.

KS is usually considered in a patient who is immunocompromised, but this piece of information may not be available in every case. Characteristic histological features of KS include atypical spindle cell proliferation with intervening slit-like vascular spaces (Fig. 3c, d). Few cases of KS may show hobnail nuclei and retiform pattern of vascular channels. However, neither spindle cell proliferation nor slit-like spaces are observed in RH. IHC stain for Human Herpes Virus 8 (HHV8) may also be helpful in difficult cases as KS is positive and RH is negative for HHV8 immunostaining [11].

All three cases of this series showed characteristic morphological and IHC features of RH. Any other patterns to render a diagnosis of composite hemangioendothelioma were not seen, nor were there any features of malignancy.

RH demonstrates locally aggressive behavior as recurrence is reported in 60% cases. These recurrences are multiple and develop over many years. In addition, there is no evidence to suggest that deep seated tumors fare worse than their superficial counterparts. In contrast, Dabska tumor shows a lower comparative recurrence rate of about 40% [10]. Metastasis to lymph nodes is seen in very few cases and distant metastasis has been observed in a single case [5]. KS and angiosarcoma exhibit malignant potential. KS can metastasize to lymph nodes and distant organs, albeit to a lesser extent than a conventional angiosarcoma, which is notorious for its aggressive behavior and a dismal outcome in most cases, despite aggressive treatment.

KS is known to be associated with HHV8, which mostly affects individuals with a compromised immunity, specifically patients with low T-cell counts. The virus promotes neo-angiogenesis along with tampering with the DNA of the infected cell. The result is an uncontrolled proliferation of phenotypically as well as genotypically modified endothelial cells [12].

In contrast, angiosarcomas exhibit epigenetic and oncogenic mutation patterns along with UV damage signatures, as described in a recent study [13]. The availability of more advanced molecular techniques has enabled researchers to find specific genetic mutations that can serves as targets for therapies, as are commonly available for some of the epithelial tumors. The author came across a recent paper, in which the role of Endoglin (CD105) mutations has been studied in angiosarcomas [14]. Endoglin has been found to act as a coreceptor for TGF-Beta signaling pathway and has been found on malignant endothelial cells of angiosarcoma. Manipulation of this particular gene may act as a novel therapeutic target for angiosarcomas. Although, its role in other vascular tumors has not yet been described.

The molecular defects seen in some cases of RH include rearrangements and fusions of YAP1 and MAML2 genes, also seen in cases of composite hemangioendotheliomas. This finding supports the debate about these two entities representing a morphological spectrum in a single tumor type [15].

RH is traditionally treated by complete surgical resection with negative margins. In cases of cutaneous involvement, this may be achieved by Mohs micrographic surgery [16]. For unresectable tumors and tumors with multifocal presentation, some chemotherapeutic agents have been described in the literature, like low doses of Cisplatin along with radiation therapy [17].

RH is a rare tumor of intermediate biological behavior. It should always be considered in the differential diagnoses while evaluating small biopsies showing vascular proliferation in dermis, particularly those with a hobnail pattern of endothelial cells. It may occur as a component of a composite hemangioendothelioma, which makes it necessary to examine different areas of a large resection specimen with care, the latter being more important in order to completely rule out a possibility of an angiosarcoma or a KS, which may harbor areas morphologically similar to RH.