Are You Confident of the Diagnosis?
Intravascular papillary endothelial hyperplasia (IPEH) is an unusual benign vascular lesion comprising approximately 2% of vascular tumors of the skin and subcutaneous tissue.
Three different types of IPEH have been reported, and in 1993, Pins et al calculated the incidence of each type following a comprehensive literature review. The “pure” form (55.8%) arises de novo in a dilated vascular space with no causative comorbidity. The ”mixed” form (39.9%) is found superimposed over a preexisting vascular anomaly. These associated anomalies may include arteriovenous malformations, hemangiomas, pyogenic granulomas, and chronic illnesses such as paroxysmal nocturnal hemoglobinuria, which is associated with venous thrombosis.
The “extravascular” form (4.3%) is associated primarily with trauma-induced hematoma formation, which acts as a template for endothelial proliferation.
Characteristic findings on physical examination
Although the most common sites of IPEH are the head, neck, fingers and trunk, these tumors may occur in any blood vessel. Less frequently, IPEH has been documented in the upper respiratory tract, skeletal muscle, urogenital systems, renal and hepatic systems, and rarely, in the gastrointestinal tract. For skin and subcutaneous IPEH, the common site is the face, followed by the hands, fingers, neck, chest, leg, thigh, axilla and groin (Figure 1).
Typical locations for oral IPEH are the lower lip (47.4%), tongue (15.8%), upper lip (15.8%), buccal mucosa (12.3%), and mandibular vestibule (8.8%).
IPEH is slightly more frequent in females with a ratio of 1.7:1. The age of patients varies from a few months to more than 80 years but is more common during their sixth decade of life.
The lesions generally grow slowly but can be of variable clinical duration (days to years) with a variable history of antecedent trauma; the lesions may be tender or painless.
The typical signs and symptoms are nonspecific and depend primarily on the anatomic location of the lesion. For example, when this pathology occurs in the gastrointestinal tract, patients may have vomiting, melena, pharyngitis, anemia, hematochezia, abdominal pain and upper gastrointestinal bleeding. When the lesion is located intracranially, it may present with different symptoms such as headache, visual field deficits and facial nerve paresis.
Clinically, it is almost impossible to diagnose IPEH just by inspecting a lesion. The usual clinical appearance of IPEH is a firm or tender nodule or mass with slight elevation, sharp demarcation and slow growth; there is a red or blue color in the overlying skin or mucous membrane (Figure 2).
The lesions have been clinically mistaken for the following: hemangioma, angiosarcoma, hematoma, mucocele, thrombosed vein, phlebectasia, lymphangioma, Kaposi sarcoma, traumatic fibroma, granuloma, salivary gland tumor, nevus, epidermoid cyst, lipoma, granuloma pyogenicum, wart, glomus tumor and facial lymph gland.
There are no definitive or specific radiographic appearances for IPEH. Computed tomography (CT), magnetic resonance imaging (MRI), and angiographic patterns of IPEH can mimic other benign and malignant processes such as pyogenic granuloma, Kaposi’s sarcoma, hemangioma, bacillary angiomatosis, and papular angioplasia.
The CT scan findings of IPEH often present as either homogenous or nonhomogenous and either a contrast-enhancing or nonenhancing lesion. This is related to the varying amounts of parenchymal tissue and anastomotic, stagnant, or low-flow vascular channels. Gray scale duplex scans or angiograms should reveal the mass. Color duplex scans may be able to define an internal “net” of microvessels within the lesion.
Areas of microcalcification have been noted in IPEH lesions. Phleboliths, however, are also common in patients with hemangiomas. Likewise, calcification can occur in hematomas and tumors and can follow the necrosis of soft tissues. Moreover, on angiography, IPEH can manifest as either a vascular or avascular mass. MRI is usually the best initial diagnostic test for vascular malformations, and further investigations are usually not necessary in low-flow lesions. CT, MRI, and angiographic patterns of IPEH can all simulate other benign (eg, hemangioma) and malignant (eg, angiosarcoma) conditions.
When a Masson’s tumor causes bone erosion as a result of pressure effects, its radiologic features can be even more suggestive of malignancy. Therefore, while radiologic investigations can contribute to management, they are not sufficiently characteristic alone to make a diagnosis of IPEH.
Because of a lack of specific clinical characteristics, the final diagnosis must be made only after a biopsy and microscopic examination.
An accurate diagnosis of IPEH is challenging because it is difficult to differentiate IPEH from neoplastic and vascular lesions solely based on clinical findings. Furthermore, the histopathology of IPEH resembles an angiosarcoma, and therefore, the differentiation between these two lesions is very important because the treatment approach for benign versus malignant disease is quite different.
Regardless, the primary concern when forming a clinicopathologic diagnosis is the differentiation of IPEH from an angiosarcoma.
Given that the confusion with angiosarcomas occurs primarily because of the unique factors of IPEH, which include their ability to outgrow the confines of the vascular lumen and rupture the vessel, similar to an invasive angiosarcoma, a helpful differentiating characteristic is its intravascular location because angiosarcomas are almost never confined to a single vascular lumen. IPEH also differs from angiosarcoma in that the endothelial cells lack evidence of necrosis, marked pleomorphism, significant mitotic activity, or solid sheet formation.
The clinical presentation of a cutaneous angiosarcoma (large and extensive lesion that usually presents with smaller outlying nodules, necrosis and ulceration, which commonly affects the elderly) and gross characteristics (noncircumscribed and infiltrating mass) are findings that help to differentiate it from IPEH. An evaluation by an expert surgical pathologist or referral center should be performed if there is any doubt regarding the diagnosis prior to beginning antineoplastic therapy.
HISTOPATOLOGIC DIFFERENTIAL DIAGNOSIS
Histologically, IPEH is characterized by a papillary proliferation of endothelial cells forming vascular channels, and it is commonly associated with a thrombus (Figure 3).
Histologic differentiation of oral cases includes hemangioma, mucocele, intravenous pyogenic granuloma, Kaposi sarcoma, spindle cell hemangioendothelioma, malignant endovascular papillary angioendothelioma (Dabska’s tumor), and intravascular endothelioma.
An intravenous atypical vascular proliferation may be present, but most often the diagnosis is supported by the findings of a solid and not a papillary endothelial proliferation, no close association to a thrombus and an extension into and beyond the vessel wall.
IPEH may be clinically and histopathologically mistaken for an angiosarcoma. Among these diagnoses, the most important is angiosarcoma owing to great microscopic similarity. Nonetheless there are important histologic distinctions between the two lesions. In IPEH:
The proliferative process is entirely confined to an intravascular space,
Most of the papillary structures are associated with thrombi,
The papillae consist of fibrohyalinized tissue that is covered by no more than two endothelial cell layers,
The endothelial cells may be hyperchromatic, but extreme nuclear atypia and frequent mitotic figures are absent,
Tissue necrosis is absent,
Invasion of the surrounding tissue is absent.
An intraoral pyogenic granuloma is mostly found in the gingiva, but it can also affect the lips, buccal mucosa, and tongue. This lesion is characterized by a pedunculated mass with a smooth, verrucous surface that may become hemorrhagic. Endothelial cells are prominent features in both pyogenic granuloma and IPEH, but in the latter, no surrounding vascular wall is evident.
Clinically, Kaposi sarcoma can be detected in the oral cavity, palate, or tongue as a reddish-brown or blue, flat, vascular lesion that can mimic IPEH. Histopathologically, characteristic features of Kaposi sarcoma include anastomosing slit-like vessels with a fascicular pattern of spindle-shaped cells, capillary proliferation, hemosiderin pigment deposition, and plasma-cell infiltration.
Hemangiomas can be differentiated from IPEH by their lack of endothelial proliferation, unless they are secondarily traumatized. Endovascular papillary angioendotheliomas are histologically similar to IPEH, but they can be differentiated by their more columnar endothelial cells and a lymphatic component. Mucoceles may resemble IPEH clinically when they present as a bluish raised mass on the lower lip, floor of the mouth, or tongue. However, these lesions are easily distinguished microscopically; they are observed to be a cavity consisting of fibrous connective tissue and fibroblasts containing eosinophilic coagulum.
In the immunohistochemical examination of IPEH, some authors have described that IPEH is closely related to organizing thrombi using antibodies to factor VIII-related antigen, ferritin, and vimentin.
The immunoprofile of IPEH demonstrates that the majority of endothelial cells are positive for CD34. CD34 has been reported to be an optimal panendothelial marker that stains not only “newly forming” vessels, but also normal ones trapped within tumor tissue. In addition, staining for CD34 is positive in normal blood vessel walls with a high sensitivity and is also specifically positive in well-differentiated, mature blood vessels.
Yonezawa et al described that the examination of CD31 in the endothelial cells of a lesion revealed that the mass was of blood vessel origin and that the endothelial cells were proliferating on the inner vessel wall. After performing an examination for factor VIII-related antigen and alpha-smooth muscle antibody (SMA). Yonezawa et al concluded that the tumor was of blood vessel origin with a thrombus and a thin layer of smooth muscle cells around the endothelial cells.
Some authors studied IPEH immunohistochemically and compared it to organizing thrombi. The results showed a similar progression of the immunophenotype of the endothelial cells in both entities: they are initially positive for a histiocytic marker, ferritin, then acquire vimentin positivity and only display factor VIII-related antigen in mature lesions. This also suggested that IPEH is closely related to organizing thrombi and is probably a peculiar form of it.
Makos et al demonstrated the endothelial nature of cells by a positive result with the special immunohistochemical stain ULEX-Europaeus Agglutinin (UEA-1). These cells are relatively immature because of a negative reaction for human hematopoietic progenitor cell antigen CD34.
The basement membranes of the vessels have been shown to be positive for collagen type IV and laminin. Both laminin and collagen IV are the major constituents of the basement membrane, separating the endothelial tissue from underlying connective tissue. Some vessels presented pericytes as revealed by immunohistochemistry for SMA. The hyalinized areas in the stroma were positive for collagen type I, and all cells in the stroma were positive for vimentin, which is an antibody of mesenchymal origin cells in normal or neoplastic tissue.
CD105 (endoglin) is a 180-kD homodimeric membrane glycoprotein expressed by the proliferation of human endothelial cells and is inducible with hypoxia. These characteristics make CD105 a very important marker of newly forming vessels that is not expressed in preexisting blood vessels. Soares et al demonstrated that the proliferation of endothelial cells was negative for CD105, suggesting that IPEH is an old reactive process, different from what occurs in a pyogenic granuloma where the cells are all CD105 positive.
Although an H&E section is sufficient for the diagnoses of IPEH confined to a dilated vessel, as in the current cases, CD105 immunohistochemistry (IHC) could be helpful in determining the extravascular locations of an IPEH lesion, thereby differentiating it from angiosarcoma due to the fact that this molecule is overexpressed in angiosarcoma-associated endothelial cells.
This distinctive histologic appearance is sufficient for a definitive diagnosis. Immunohistochemical confirmation may be required only if the endothelial origin of the lesion is in question. In such cases, endothelial cell markers such as the von Willebrand factor, CD 31, factor XIIIa, and CD 43 may be used, which would highlight the endothelial lining around the papillary tufts. The characteristic architecture is sufficient to differentiate it from a thrombus, which lacks the papillary anatomy and proliferation of endothelial cells noted in IPEH
Who is at Risk for Developing this Disease?
IPEH is an unusual benign vascular lesion comprising approximately 2% of skin and subcutaneous tissue vascular tumors. IPEH suggests a preexisting vascular lesion such as a hemangioma, aneurysm, arteriovenous malformation, lymphangioma, pyogenic granuloma, or hematoma; even an unusual thrombus organization or trauma can be possible risk factors for the development of this lesion.
Demographically, females appear slightly more susceptible to IPEH than males in a ratio of 1.2-2:1; this suggests that a hormonal factor may exist.
What is the Cause of the Disease?
The precise pathogenesis of IPEH lesions remains elusive. In 1923, Masson proposed that the lesion represented a true neoplasm with secondary thrombosis.
However, other authors have demonstrated that the growth pattern of IPEH suggests a benign reactive process consisting of endothelial cells organizing and proliferating around a thrombosis in the setting of venous stasis. On a cellular level, IPEH closely resembles granulation tissue, which further supports the theory that this process is reparative. The endothelial cells appear to originate, in their earliest formation, with a histiocytic phenotype before transformation into an endothelial phenotype, further lending support to the prevailing theory.
The pathogenesis of the lesion has been suggested to be a benign reactive process, possibly related to trauma, which justifies the presence of these lesions on the lip and tongue, as these are areas commonly affected by trauma. The lesions occur as a result of chronic stimulation with the lesion growing slowly due to vascular proliferation arising at the site of the trauma.
A possible hormonal role has been suggested due to the female predominance, and local angiogenic growth factors may contribute to endothelial proliferation.
Levere et al demonstrated elevated levels of basic fibroblast growth factor (bFGF) in cases of IPEH compared with non-IPEH organizing thrombi. They proposed that the release of bFGF from macrophages recruited to the lesion triggers the proliferation of endothelial cells, which in turn release more bFGF, resulting in a vicious cycle.
A pathophysiologic explanation for the distinct papillary architecture of IPEH is currently lacking. It seems likely that turbulence, fluctuating intravascular pressure, and physiologic clot retraction could fragment a thrombus and that endothelialization of repeatedly injured surface fragments leads to the formation of papillae.
Systemic Implications and Complications
Systemic implications and/or complications have not been reported.
Treatment consists of complete resection of the tumor, including ample margins, to avoid recurrence. Based on the limited nature of this benign lesion, a 2mm excision margin is adequate where borders are evident, but larger margins may be required. It is important to add that there is no consensus regarding the margins of resection. However, because tumor size is generally small, direct closure is usually possible after excision.
Optimal Therapeutic Approach for this Disease
The appropriate treatment for IPEH is conservative surgical excision. The removed segment of vessel or excised mass should be sent for pathologic examination. Pathologists should be asked to examine the lesion microscopically.
Surgical resection is curative for IPEH in its pure form, and no recurrence of this lesion has been reported after surgical resection with clear margins. Recurrence rates in various skin cases have been documented at a range of 7% to 10% for mixed and extravascular lesions.
Unusual Clinical Scenarios to Consider in Patient Management
Invariably, the prognosis appears to be excellent with the exception of patients with intracranial lesions, which can be fatal. Recurrence is extremely rare and is thought to occur only when the underlying vascular lesion is not completely excised.
What is the Evidence?
Pins, MR, Rosenthal, DI, Springfield, DS, Rosenberg, AE. “Florid extravascular papillary endothelial hyperplasia (Masson’s pseudoangiosarcoma) presenting as a soft-tissue sarcoma”. Arch Pathol Lab Med. vol. 117. 1993. pp. 259-63. (Reports a case of extravascular papillary endothelial hyperplasia that extensively involved a large, traumatic, deep soft-tissue hematoma in a 19-year-old man and clinically presented as a soft-tissue sarcoma. This work reviewed the characteristics of 314 cases of papillary endothelial hyperplasia reported in the literature and identified 13 likely cases of the rare extravascular form.)
Tosios, K, Koutlas, IG, Papanikolaou, SI. “Intravascular papillary hyperplasia of the oral soft tissues: report of 18 cases and review of the literature”. J Oral Maxillofacial Surg. vol. 52. 1994. pp. 1263-8. (The authors report the clinicopathologic features of 18 examples of IPEH of the oral soft tissues and lips and review such features of 55 previously reported oral cases. The differential diagnosis and possible histogenesis of the lesion are discussed.)
Soares, AB, Altemani, A, Furuse, C, Demasi, AP, Gati, C, Nunes, N. “Intravascular papillary endothelial hyperplasia: report of 2 cases and immunohistochemical study”. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. vol. 106. 2008. pp. 708-11. (An excellent report of two cases with review of the clinical, histologic, and immunohistochemical characteristics of this lesion.)
Yonezawa, H, Hiraki, A, Iyama, K, Shinohara, M. “Intravascular papillary endothelial hyperplasia associated with venous pool arising in the lower lip: A case report”. Int J Dent. vol. 2009. 2009. pp. 940686(In this report, an adult female was diagnosed as having mimicked hemangioma arising in the lower lip by clinical finding and MRI, and the lesion was excised completely. The lesion was examined by histopathologic and immunohistochemical methods.)
Makos, CP, Nikolaidou, AJ. “Intravascular papillary endothelial hyperplasia (Masson’s tumor) of the oral mucosa. Presentation of two cases and review”. Oral Oncol EXTRA. vol. 40. 2004. pp. 59-62. (This is a presentation of two cases of oral IPEH that describe perfectly this clinical localization and a great discussion of these features is provided.)
Kim, D, Israel, H, Friedman, M, Kuhel, W, Langevin, CJ, Plansky, T. “Intravascular papillary endothelial hyperplasia manifesting as a submandibular mass: an unusual presentation in an uncommon location”. J Oral Maxillofac Surg. vol. 65. 2007. pp. 786-90. (This case report shows an unusual presentation of intravascular papillary endothelial hyperplasia; the authors discuss the clinical features.)
Güvenç, MG, Dereköylü, L, Korkut, N, Oz, F, Oz, B. “Intravascular papillary endothelial hyperplasia (Masson lesion) of the hypopharynx and larynx”. Ear Nose Throat J. vol. 87. 2008. pp. 700-1. (This interesting case report clinical and histopathologic features, differential diagnosis, and treatment. The lesion was excised entirely via a lateral pharyngotomy approach.)
Pantanowitz, L, Muc, R, Spanger, M, Sonnendecker, H, McIntossh, WA. “Intravascular papillary endothelial hyperplasia (Masson 's tumor) manifesting as a lateral neck mass”. Ear Nose Throat J. vol. 79. 2000. pp. 806(This work discusses the management of this lesion, with emphasis on radiologic and histologic assessment and the differential diagnosis.)
Steffe, CH, Iskandar, SS. “Intravascular papillary endothelial hyperplasia in a thrombosed renal allograft vein”. Hum Pathol. vol. 27. 1996. pp. 986-99. (This article presents the first report of IPEH in an allograft vessel, in association with a thrombus of clinically discernable age, to be strong evidence supporting the hypothesis that IPEH represents an uncommon morphology of organizing thrombus. The authors discuss the immunohistochemical features of this lesion. Immunohistochemical stains for factor VIII, CD34, and in particular CD31, however, confirmed the nature of both the papillary and solid areas of the proliferation as vascular endothelium.)
Levere, SM, Barsky, SH, Meals, RA. “Intravascular papillary endothelial hyperplasia: a neoplastic “actor” representing an exaggerated attempt at recanalization mediated by basic fibroblast growth factor”. J Hand Surg. vol. 19. 1994. pp. 559-64. (A comprehensive review of the pathogenesis of this lesion. This excellent work suggests that the pathogenesis of IPEH involves an autocrine loop of endothelial basic fibroblast growth factor secretion stimulating endothelial cell proliferation.)
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