Clinical and pathological differences between the pyogenic granuloma and lobular capillary hemangioma in the oral cavity: a scoping review

Introduction

The pyogenic granuloma (PG) was first described in 1943 [1]. Since then, it is being referred to as a red colored, smooth, or lobulated exophytic lesion on a pedunculated or sometimes sessile base, with a tendency to bleed easily [2]. The term “pyogenic granuloma” is a misnomer, for the lesion is neither “pyogenic” (pus forming) nor is it a “granuloma” (an organized collection of inflammatory cells of the monocyte family). Therefore, the term “lobular capillary hemangioma” (LCH) was introduced in 1980 as the underlying histological equivalent [3]. Over the years, the meaning of this term has changed significantly, from a reactive hyperplastic mucosal lesion, granulation tissue, to a benign vascular tumor, which contributes to the confusion in the literature. In 2003, Toida et al. brought some clarity by stating that there are in fact two types of the lesion: the LCH and the non-LCH, each with distinct clinical, histological, and pathophysiological features [4]. However, since the disconnection of these two types, few attentions has been given to it in later research. Discrepancy exists even in the major classifications, where in the WHO 2017 classification of head and neck tumors, the PG and LCH are considered synonyms and are classified as hemangiomas, and in the ISSVA classification (International Society for the Study of Vascular Anomalies, 2018) both lesions are classified as benign tumors. Of course, this adds to the confusion. Despite the limited number of articles on this specific topic, we attempted to offer an overview of any evidence on clinical and pathological differences between the two lesions in the oral cavity, based on a scoping review of the available literature.

Material and methods

A literature search was performed in the Medline database using the search terms presented in Table 1, revealing 342 usable articles, excluding non-English articles and articles published before 2001. The articles were screened by title and abstract on relevance. Inclusion criteria were English language and full text availability provided by the KU Leuven. Further exclusion criteria were irrelevant descriptions of the lesion, individual case reports, and reviews. After this selection, 15 relevant studies remained (Figure 1). Areas of interest were formulated (cfr. subheadings) and data was obtained from the articles (Table 2).

Results

Where possible, the articles were classified according to the type of lesion studied, PG and/or LCH, based on histological descriptions provided. In the following sections, areas of interest are covered to enable distinct description and differential diagnosis of both pathological entities (PG and LCH).

Definition and synonyms

A variety of synonyms are used for PG, such as LCH, granuloma pyogenicum, granuloma telangiectaticum, angiogranuloma, epulis gravidarum, and pregnancy tumor (the latter two when occurring in the gingiva during pregnancy). This spectrum of synonyms creates confusion and for this reason, we will only be using the two terms best known: the PG and LCH.

Clinical features

Pyogenic granuloma

PG is an exophytic, erythematous mass arising from the mucous membranes of the oral cavity (Figure 2). Its surface can be smooth or lobulated, and sometimes ulcerated [2, 5-8]. The most frequent appearance of the lesion is a solitary painless lesion, which tends to bleed upon touching [2, 5, 7]. The lesion is fast growing and develops between 3 to 5 months [2, 5-7]. Other symptoms reported are a burning sensation, halitosis, mobility of associated teeth, bone loss, lip biting, submandibular lymphadenopathy, and occasional pain [7]. The mass is more often pedunculated than sessile [2, 6-9]. The lesion is primarily located on the anterior maxillary gingiva. Other areas affected can be the other gingival sites, lips, tongue, buccal mucosa, and palate [2, 5-9]. The size of the lesion varies between 0.3 to 6 cm in diameter, with a mean of 1.1 to 1.5 cm [2, 6, 9].
PG can occur at any age, with a peak incidence between 10 and 40 years. There is a clear gender predilection with a strong female predominance of 69 to 79% [2, 5-7, 9]. They account for 20 to 30% of all reactive hyperplastic lesions presenting in the oral cavity, 40 to 60% of all gingival lesions, and 3 to 7% of all lesions of the oral cavity [10, 11]. The incidence rate calculated in one study was 3.2% [2]. Caucasians are more frequently affected than Africans [2]. More than 4 out of 5 patients (85%) report a known precipitating factor, allowing a distinction from the LCH [9].
Over 8% of all PGs are found in pregnant women [7, 12]. The occurrence is related to pregnancy duration, with the most PGs’ seen in the third trimester. Women under 25 years of age most commonly develop PG in the first trimester, whereas in an older age group, they develop mostly in the third trimester of pregnancy [6].

Lobular capillary hemangioma

Like the PG, the oral LCH is also a red to brown colored papule, lobulated or smooth surfaced. Ulceration occurs in more than 88% of cases [4]. It is also a fast-growing lesion, with a size ranging from 0.2 to 1.5 cm and a mean diameter of 0.8 cm, making it slightly smaller than the PG [4, 9]. In the oral cavity, it is located mostly on the maxillary gingiva, followed by the tongue, labial mucosa, buccal mucosa, mandibular gingiva, and palate [4, 9]. As in PG, bleeding is a common clinical manifestation [4]. The lesion is more often sessile than pedunculated [4, 9].
The lesion can also occur at any age, but the peak incidence of the LCH is in the 6th and 7th decade of life, which makes this lesion more common in an elderly population than does the PG [4, 9]. There is also a female predominance, but less marked than with the PG, with the percentage of female patients ranging from 57 to 65% of cases [4, 9]. In only 20 to 29% of cases was a known precipitating factor present (e.g., overhanging edges of restauration or biting), in contrast to 85% of PG cases [9]. This contributes to the hypothesis that the pathogenetic mechanism of both lesions are different. An overview of the clinical differences between the PG and LCH is provided in Table 3.
While PG and pregnancy may be related, LCH may show some association with vascular malformations. Indeed, 16% of LCHs’ are associated with arteriovenous malformations [13]. Again, a distinct pathogenetic mechanism is hereby suggested.

Histology

Pyogenic granuloma

The reactive PG can be divided into two distinct areas, such as an ulcerative area, sometimes with bacterial colonization [7], and a central area (Figure 3). The central area consists of small radially organized capillary proliferations resembling granulation tissue, although some authors also report a lobular arrangement [2, 8, 14]. It is comprised of both small vessels with tiny lumina and large thin walled vessels with larger lumina, lined by flat endothelium [7, 9, 15]. The stroma is edematous and richly permeated by a mixed chronic and acute inflammatory infiltrate [2, 3, 7-9, 16]. Sometimes the stroma takes on a myxoid appearance [3, 7]. In chronic lesions, foci of abundant collagen and fibrosis can be seen in the stroma, with reduced vascularity of the area [2, 3, 7, 9, 15, 16]. A great number of mast cells may be present in this fibrous region [17].
The ulcerative area of the PG consists of a superficial layer of fibrin with entrapped neutrophils. Below that, there are vessels of various sizes and various proportions of cells, composing the vascular walls. The stroma is edematous, with a mixed inflammatory infiltrate. Mean vessel diameter is around 19 µm, which is markedly larger than in the underlying area [4, 9].

Lobular capillary hemangioma

The central, or lobular, area of an LCH, consists of characteristic lobular proliferations of microvasculature forming tiny lumina [4, 9, 18]. The vessels are uniform in size and contain a similar proportion of cells forming the vascular wall, which is mostly composed of ovoid to spindle-shaped cells (Figure 3) [4, 12]. A variable number of mitotic figures can be found throughout this region [9]. The stroma is edematous, with occasionally a lymphocytic infiltrate in a superficial lobule [12]. Extensive necrosis can sometimes be seen throughout the lesion [19]. Mean vessel diameter of the lobular area is around 9 microns [4]. The ulcerative area of the LCH is identical to PG.

Pathogenesis

Because both lesions have distinct clinical and histological appearances, the pathogenic mechanisms are likely to be different. PGs’ have an obvious predilection for (pregnant) women and have a marked inflammatory infiltrate, factors, which underlie its pathogenesis. In contrast, no inflammatory infiltrate or provoking factors are seen in LCH, suggesting that its development is rather spontaneous. However, the pathogenic mechanisms are likely to overlap between both lesions.

Pyogenic granuloma

In the PG, the major predisposing factors are female gender and pregnancy, and the primary precipitating factors are chronic low-grade irritation or minor injury. The high levels of estrogen and progesterone in (pregnant) women also contribute to the formation of the PG. An extensive review of pathogenic mechanisms can be found in a paper by Kamar et al. [20]. In conclusion, they all contribute to the characteristic histological appearance of this lesion: increased vascular permeability induced by estrogen leads to stromal edema, penetration of bacteria aids the formation of a mixed inflammatory infiltrate potentiated by estrogen, the effects of VEGF (vascular endothelial growth factor) and HIF-1α (hypoxia-inducible factor-1α) are increased proliferation and migration of vascular endothelial cells, and pericytes and mast cells in the inflammatory infiltrate lead to fibrosis in chronic lesions. During this maturation, progressive fibrous replacement may lead to the development of a fibrous epulis or fibroepithelial polyp. The percentage of fibrous epulis (and fibroepithelial polyps) that develop from pre-existing PG is unknown.
Interestingly, ‘estrogen-receptors’ have not been demonstrated in PG (or LCH) [21, 22]. However, as described above, estrogen is likely to play a role in the pathogenesis. In the same study, ‘progesterone-receptors’ have been found in only 43% of the lesions.

Lobular capillary hemangioma

The pathogenesis of LCH and PG as separate lesions has not yet been presented in the literature. We propose that bone marrow stem cells, induced by an unknown stimulus, differentiate into endothelial cells, pericytes, and ovoid cells. The newly formed ovoid cells play a central role in the further development of the lesion. First, they interact with the pericytes to modulate neovascularization [23]. Secondly, the ovoid cells express the tie-2 receptor, a transmembrane tyrosine-kinase receptor for angiopoietine-1 (ang-1) and angiopoietine-2 (ang-2). In general, ang-1 (agonist) stabilizes the angiogenic process and ang-2 (antagonist), induces neovascularization or angiogenesis. Ang-2 induces overexpression of the wt-1 protein (Wilms’ tumor-1 protein) in the cytoplasm of ovoid cell [24]. This causes proliferation of the vascular smooth muscle cells, endothelial cells, and ovoid cells giving rise to the lesion [25].
Finally, LCHs are known to arise from vascular malformations, such as port-wine stains or arteriovenous malformations, which suggests that these malformations provide a favorable environment for LCHs to develop in. The tissues in and around vascular malformations are thought to be in a constant hypoxic state, due to ineffective delivery of oxygen through the malformed vasculature. This hypoxia, like in the development of the PG, induces the angiogenic factors VEGF and HIF-1α, and thus neovascularization [26].

Differential diagnosis

The differential diagnosis for PG and LCH is briefly discussed. The lesions mentioned may resemble PG and LCH microscopically, and therefore are to be considered during the establishment of a final diagnosis (Figure 4).
Two immunohistochemical stains are used to identify the nature of the lesion that is presented. D2-40 (podoplanin) differentiates between lesions from lymphatic origin (positive stain) and non-lymphatic origin (negative stain), and glut-1 (glucose transporter-1) discriminates between hemangiomas (positive stain), PG, and LCH (negative stain):
• Fibroma [7], described as a fibrous epulis if present on the gingiva, and a fibroepithelial polyp if located on the lining of the oral mucosa. Several most likely represent end stage of a PG, with fibrous replacement of the vascular core.
• Granulation tissue formation is common and a non- specific reaction to the tissue damage [4].
• Peripheral ossifying fibromas are located only on the gingiva and resemble fibrous epulis clinically but are distinguished microscopically by the active deposition of bone in the core of the lesion. How­ever, osteopontin is also expressed in some PG, so that its histopathology may mimic that of the periphe­ral ossifying fibroma [16].
• Peripheral giant cell granulomas [7] are located in the gingiva and represent the peripheral variant of the central type, which is situated in the jawbone.
• Kaposi Sarcoma, tumor stage [15, 27]. Bundles of spindle cells and pseudo-vascular blood-filled spaces are seen. However, there is an invasive rather than a lobular growth pattern. The lesion stains positive for 
HHV-8 (human herpes virus-8) and D2-40, and negative for vWF (von Willebrand factor) and SMA (smooth muscle actin).
• Hemangiomas [7, 14] present as adult or juvenile types [4] and may be associated with inflammation, which complicates the differential diagnosis [28]. Capillary hemangiomas contain capillary-sized endothelial lined vessels and cavernous hemangiomas larger thin walled blood vessel spaces.
• Tufted angioma and Kaposiform hemangioendothelioma [29] are lesions on a spectrum from less aggressive (tufted angioma) to very aggressive (Kaposiform hemangioendothelioma). Lobules are D2-40 negative.
• Hemangiopericytoma (also known as a solitary fibrous tumor) consists of CD34 positive cells forming stag-horn shaped blood vessels in a typical reticulin fiber network.
• Angiofibroma is a rare nasopharyngeal tumor often associated with excessive nose bleeding.
• Angiosarcoma shows a high mitotic index and atypia, but an invasive growth pattern rather than an exophytic growth pattern, such as PG and LCH.
• Bacillary angiomatosis [30] is caused by an infection with Bartonella henselae, and is characterized by a lobular proliferation of endothelial cells resembling a PG with endothelial atypia, neutrophils with leukocytoclasis, and stainable bacteria.

Treatment

For PG, surgical excision (shaving excision and cautery) under local anesthesia, together with removal of local irritants is the standard therapy [2, 6, 7]. Excision down to the periosteum minimizes the risk of recurrence [2]. Recurrence rates vary from 8 to 15% and can occur up to 5 years after surgery, with maxillary lesions and lesions in female patients recurring more frequently [2, 7]. Specific treatment options for LCHs have been less exploited, but as for PG, surgical excision is the most performed.
Many other treatment options have been explored, mainly for cutaneous or conjunctival PG. A brief overview is given below.
• Monoethanolamide oleate is known to induce damage to the vascular endothelium resulting in thrombus formation. In one study, this caused regression of all PG [31].
• Alitretinoin gel 0.1% is an FDA-approved treatment for localized Kaposi sarcoma, and in one study, it has been proven effective in the treatment of PG, possibly due to some histologic similarities [32].
• Low-dose plaque brachytherapy has been reported effective in the treatment of a chronically recurring conjunctival PG [33].
• Imiquimod 5% cream provides a 75 to 99% size reduction of PG, but with possible systemic side-effects (fever, nausea, diarrhea). This regression results from the anti-angiogenic and apoptotic effects of imiquimod [34].
• FSH (follicle stimulating hormone) antagonists are hypothesized to prevent recurrence after primary treatment [35].
• Timolol and other beta-adrenergic blockers have been used to treat infantile hemangiomas as well as some PG (only about 50% of PGs express β-adrenergic receptors). Initial effects are due to vasoconstriction, but significant regression takes more than 6 weeks. β-blockage is believed to inhibit angiogenic factors, and some patients show continuation of regression even after they stop the therapy. This suggests that even a short regimen of beta-blocking agents can induce apoptosis and regression of the lesion [36].
• Injection of absolute 99.5% ethanol resulted in regression of all PG without scarring. Ethanol dehydrates the lesion and causes cell necrosis, resulting in thrombosis and ischemia of the lesion [37].

Conclusions

Based on a scoping review of the available literature, we found several clinical and histological differences between the PG and the LCH. Compared to the LCH, the PG occurs more in the middle-aged range, has a clearer predilection for (pregnant) females, and has more frequently a known triggering factor in the history. Histologically, PGs appear mostly as radially organized capillaries (while LCHs have a lobular pattern), have a mixed inflammatory infiltrate (compared to the occasional lymphocytic infiltrate in LCHs), and can undergo fibrosing transformation when chronic, which is not seen in LCHs.
When first described, the PG was considered a form of exuberant granulation tissue. Later, some lesions were found to show a lobular pattern of capillary proliferation, giving rise to the term “lobular capillary hemangioma” as the underlying histological presence of the lesion. After that, there was mixed use of the names for both the granulation tissue-like PG and the vascular neoplasm-like LCH. The latest WHO classification of head and neck tumors (2017) states that both lesions reside under term “pyogenic granuloma”, with LCH used as a synonym, and both being considered hemangiomas. In contrast, the International Society for the Study of Vascular Anomalies (ISSVA) in their latest classifications (2018) states that both lesions are synonyms and are considered benign vascular tumors. However, given the clinical behavior of the PG (reactive lesion to microtrauma, stops growing at certain size, thus not being a tumor strictu sensu), classifying this under the term “tumors” may lead to even more confusion. We propose that both lesions again to be considered as distinct for two reasons. First, there are the proposed differences in clinical features, histology, and etiopathogenesis. Second, disconnecting the two lesions makes interpretation of the existing literature much easier.
The limitation of this study is that it is a review of articles, which not all make a clear distinction between the PG and the LCH. Also, histological descriptions were often compact, so misclassification of the lesions cannot be ruled out. Because of this, statistical analysis of the data was impossible, nor would it have been conclusive. However, because of the large number of patients in the included articles, some broad perspectives have become clear, which can and need to be addressed in future research.

Conflict of interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.