Defining the Vascular Anomalies in Maffucci Syndrome: A Systematic Review

Abstract

Background:

Maffucci syndrome (MS) is a rare disorder characterized by enchondromas and vascular anomalies (VAs). However, the nomenclature used to define MS in the literature is variable. The purpose of this review is to evaluate definitions of MS and characterize VAs reported in patients with MS, in relation to International Society for the Study of Vascular Anomalies (ISSVA) definitions.

Methods:

MEDLINE and Embase were searched for articles that discussed MS. Articles were analyzed for VAs identified in the disease definition. Case reports of MS were analyzed for VAs diagnosed in their patients.

Results:

Since 1950, 265 articles have defined MS. Disease definitions have varied widely. Over half of the articles identified “hemangioma” nonspecifically as the defining VA, whereas only 2 recognized the ISSVA definition of MS as “enchondromas with venous malformations ± spindle-cell hemangiomas (SCHs).” Of 220 patients in 183 primary reports, only 36 (16%) patients had a VA diagnosis consistent with a specific ISSVA diagnostic label. Only 9 (4%) patients were reported to have venous malformations per the 2018 ISSVA definition of MS, whereas 23 (11%) were reported to have SCHs in the absence of venous malformations.

Conclusions:

The definition of MS remains inconsistent due to the use of ambiguous and outdated nomenclature for classifying VAs. This makes it difficult to identify the true constellation of VAs present in the disease. Clinicians and researchers should adhere to modern nomenclature when discussing VAs. Given multiple histologically confirmed SCHs in the absence of venous malformations, it seems that either lesion may be diagnostic for MS.

Takeaways

Question: How are vascular anomalies (VA) defined in Maffucci syndrome (MS), and do they conform to the International Society for the Study of Vascular Anomalies definitions?

Findings: After conducting a systematic review, 220 patients with MS were analyzed. Only 36 (16%) patients had a VA diagnosis consistent with a specific International Society for the Study of Vascular Anomalies diagnostic label. Diagnosed VAs often varied in the type and specificity of lesions despite using the same nomenclature.

Meaning: The definition of MS remains inconsistent due to the use of ambiguous and outdated nomenclature for classifying VAs, impacting diagnosis and treatment.

INTRODUCTION

In 1881, Italian physician Angelo Maffucci first described a case of “multiple enchondroma and angioma,” a condition which later came to be known as Maffucci syndrome (MS).¹ Today, MS is recognized as a rare genetic syndrome characterized by multiple enchondromas alongside vascular anomalies. It has been estimated to affect less than 1 in 100,000 people.^2,3 However, there is significant heterogeneity in the constellation of vascular anomalies that define the disease in the literature. In early descriptions, the vascular anomalies in MS were often identified as “hemangiomas.” Throughout most of the 20th century, “hemangioma” was used inconsistently to refer to various vascular anomalies with differing etiologies and natural histories.⁴ Evolution in histopathologic understanding and diagnostic methods has led to more precise classification of vascular anomalies. Today, the International Society for the Study of Vascular Anomalies (ISSVA) system is widely recognized as the standard for classifying vascular anomalies.⁵ This system divides vascular anomalies into 2 groups: vascular tumors, which are characterized by abnormal proliferation of vascular endothelial cells, and vascular malformations, which are structural vascular anomalies without abnormal proliferation.⁶

It is now recognized that many of the vascular anomalies identified as “hemangiomas” in early reports of MS are unlikely to represent true vascular tumors.^7–10 The 2018 ISSVA classification identifies the vascular anomalies that define MS as venous malformations, with or without spindle-cell hemangiomas (SCHs).⁵ Despite this, some articles discussing MS continue to identify hemangiomas as the defining vascular anomaly, whereas others specify other lesions. Furthermore, recent case reports of MS describe a heterogeneous array of vascular lesions diagnosed in patients, some of which deviate from both the ISSVA definition and the “hemangioma” definition of the disease.^11,12 A comprehensive evaluation of the vascular lesions present in MS is therefore needed to better understand the spectrum of vascular anomalies that may be present in the disease. Vascular lesions in MS may become malignant in as many as 8.5% of cases, and it is therefore important to distinguish MS from Ollier disease, which is characterized by enchondromas without accompanying vascular anomalies.^3,13 Vascular anomalies in MS commonly cause pain, disfigurement, and functional limitation. Accurate diagnosis is critical to informing their treatment, as not all vascular anomalies are treated using the same modalities. There is at least 1 report of a patient diagnosed with MS undergoing treatment for “recurrent hemangiomas” using propranolol, a medication generally reserved for the treatment of infantile hemangiomas.¹⁴

The purpose of this review is to (1) evaluate how MS is defined in the literature with respect to its vascular component, (2) characterize the vascular anomalies reported in patient reports of MS and the modalities used to diagnose them, and (3) assess the degree of conformity to the ISSVA definition of MS.

METHODS

We conducted a systematic review of articles discussing MS. We performed a search of Ovid MEDLINE(1946 to September 4, 2024) and Embase (1974 to September 4, 2024), using the keyword “Maffucci*” without language restrictions. Titles and abstracts were manually screened for inclusion by 2 reviewers (E.F., T.Z.). Articles were eligible for inclusion if the title or abstract mentioned MS. There were no restrictions on the type of study.

Analysis of Disease Definitions

The first part of the analysis aimed to evaluate the variation in how MS has been defined with respect to its vascular lesions, and how this has changed over time. Articles were included if they stated a definition of MS that specified its vascular anomalies. If an article’s full text was not accessible but its abstract provided a definition of MS, it was included in this analysis. Discrepancies between reviewers were resolved through consensus. Each article’s definition of MS was extracted verbatim and then tabulated based on the type of vascular anomaly used to define the disease. Publication dates were extracted to assess trends in definitions over time.

Analysis of Reported Vascular Anomalies

The second part of the analysis aimed to evaluate the types of vascular anomalies reported in primary reports of patients with MS. Articles were included in the analysis of reported vascular anomalies if (1) they included a primary report of at least 1 patient with MS in which the patient’s vascular anomaly that was diagnostic for MS was reported. Articles whose full text was unavailable and non–peer-reviewed conference/meeting abstracts were excluded. The term used to identify the vascular anomaly, the descriptive characteristics of the vascular anomaly, and the methods used to diagnose the lesion were recorded. Articles were screened for the presence of phleboliths in the diagnosed vascular lesions, based on the reported text, as well as in accompanying radiographic images. Phleboliths are suggestive of either venous malformations or SCHs. The types of vascular anomalies diagnosed were tabulated, and publication dates were extracted to assess trends.

Comparison to ISSVA Classification for Vascular Anomalies

Both the definition of MS and the diagnosis of the vascular anomaly in patients were compared with the 2018 ISSVA Classification for Vascular Anomalies, which defines MS as enchondromas and venous malformations, with or without SCHs present.

RESULTS

A total of 265 articles were included in the analysis of disease definitions. Of these, 183 studies were primary reports of patients with MS that described a diagnosed vascular lesion. Figure 1 contains a flow diagram of the screening process.

Fig. 1.

PRISMA flow diagram of study screening process. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Definitions of MS

A total of 265 articles, published between 1950 and 2024, provided a definition for MS. All definitions included enchondromas as a requirement for diagnosis. More than half (n = 151, 57.0%) defined the disease as “enchondromas with hemangiomas.” Individually, the most commonly cited vascular anomalies were hemangiomas (n = 190, 71.7%), followed by lymphangiomas (n = 33, 13%), cavernous hemangiomas (n = 27, 10%), venous malformations (n = 20, 8%), and SCHs (n = 19, 7%). Thirty articles (11%) provided ambiguous definitions, which included nonspecific (eg, “vascular lesions,” “vascular anomalies,” “vessel tumors”) or nonstandard (eg, “hemangiomatous malformations”) terms, or those that do not refer to vascular anomalies (eg, “vascular hamartoma”). Sixty-four articles (18%) identified more than 1 type of lesion as being a component of MS, with the most common being “hemangiomas or lymphangiomas” (n = 20). Only 2 articles provided the definition “venous malformations ± SCHs,” consistent with that of the 2018 ISSVA classification.^15,16 Table 1 provides a full list of vascular anomalies specified in definitions of MS.

Table 1.

Vascular Anomalies Cited in Definitions of MS

A total of 51 articles were published at least 1 year after the 2018 ISSVA classification for vascular anomalies was established. Of these, more than half (n = 26, 51%) defined MS as “enchondromas with hemangiomas.” Additionally, 9 articles (18%) provided nonspecific definitions (eg, “vascular lesions,” “vascular anomalies”) and 6 (12%) defined MS as “hemangiomas and/or lymphangiomas.” Only 4 articles (8%) cited venous malformations, and 6 articles (12%) cited SCHs among the vascular anomalies that define MS. Only 1 study published in 2019 or later provided a definition consistent with the 2018 ISSVA classification.¹⁶

Diagnosed Vascular Anomalies in Case Reports of MS

There were a total of 220 patients diagnosed with MS across 183 primary case reports published between 1950 and 2024. Figure 2 demonstrates the proportions of commonly reported diagnostic labels of vascular anomalies over time. Only 36 (16%) patients had a vascular lesion diagnosis that was consistent with a specific ISSVA diagnostic label. There were 15 (7%) patients who were reported to have more than 1 type of vascular anomaly. The most commonly reported vascular anomaly was “hemangioma” in 109 (49.5%) patients. Of these, 41 patients had no reported diagnostic methods, and 25 had phleboliths. “Cavernous hemangiomas” were reported in 46 (21%) patients, of whom 27 had phleboliths. SCHs were reported in 28 (12%) patients. “Lymphangiomas” or “lymphangiectasis” were reported in 14 (5%) patients, including 5 in whom “lymphangiomas” were reported as the sole vascular anomaly. Only 9 (4%) patients were reported to have venous malformations, consistent with the 2018 ISSVA definition of MS, of whom 1 patient had both venous malformations and SCHs. Moreover, 23 (11%) patients were diagnosed with SCHs in the absence of venous malformations. There were 18 (8%) patients in whom the reported vascular anomaly diagnoses were ambiguous. Ambiguous diagnoses included nonspecific terms (eg, “vascular anomalies”) or other nonstandard terms (eg, “hemangiomatous malformations”). See Table 2 for a complete full list of vascular lesion diagnostic labels.

Fig. 2.

Proportions of common vascular anomaly diagnostic labels in MS case reports over time.

Table 2.

Diagnostic Labels of Vascular Anomalies Reported in Primary Case Reports of MS

A total of 33 primary case reports reporting on 35 patients were published at least 1 year after the 2018 ISSVA classification for vascular anomalies. Of these patients, the reported vascular anomaly diagnoses included “hemangioma” (17 patients), SCH (5 patients), “cavernous hemangioma” (4 patients), “lymphangioma” (2 patients), and “hobnail hemangioma” (1 patient), a type of hemangioma that is included in the ISSVA classification. Furthermore, only 1 (2.8%) patient was reported to have venous malformations. None of these 5 patients who were diagnosed with SCH were reported to have accompanying venous malformations in accordance with the ISSVA definition of MS. Six patients were given ambiguous vascular anomaly diagnoses, including “mixed SCH and cavernous hemangioma” (3 patients), “vascular malformations” (2 patients), and “angioma” (1 patient).

Diagnostic Modalities of Vascular Anomalies in Patient Reports

Of the 220 patients diagnosed with MS, the diagnostic modalities used to evaluate the vascular anomalies were reported for 177 patients. Diagnostic modalities included histology (92 patients, 42%), radiograph (55 patients, 25%), clinical examination (38 patients, 17%), magnetic resonance imaging (15 patients, 7%), computed tomography (14 patients, 6%), Doppler ultrasound (12 patients, 6%), angiography (6 patients, 8%), and venography (2 patients, 1%).

DISCUSSION

Our review found a lack of consensus in the literature regarding the definition of MS and its associated vascular anomalies. The majority of studies, including those published after the 2018 ISSVA classification update, defined MS as involving “hemangiomas,” with some providing general definitions and others specifying additional types of vascular anomalies. Furthermore, diagnosed vascular anomalies reported in MS case reports varied in the type and specificity of lesions, with many reported as “hemangiomas” with no further histological specification.

The significant heterogeneity in disease definitions and diagnosed vascular anomalies in MS can be attributed, in part, to historical ambiguity in nomenclature. In their landmark 1982 article, Mulliken and Glowacki⁴ highlighted this pervasive issue, stating: “the management of cutaneous vascular lesions is hampered by a bewildering nomenclature that has evolved from ignorance of pathophysiology.” They proposed a system for classifying vascular anomalies based on their endothelial characteristics and natural histories, which was formalized and refined in the 1996 ISSVA classification.¹⁷ The broad classification of vascular anomalies as either vascular tumors or vascular malformations is used today, with vascular tumors exhibiting abnormal proliferation and vascular malformations exhibiting structural abnormality in the absence of neoplasia.⁵

The term “hemangioma” was historically used as a generic term for vascular anomalies of all types.⁴ Today, “hemangioma” formally refers to a number of benign neoplastic vascular lesions.⁵ Despite this evolution in terminology, a 2011 review by Hassanein et al⁸ found that as many as 71% of studies mislabeled vascular anomalies as hemangiomas. Our review was consistent with these findings, with half of the diagnosed vascular anomalies, even in reports published within the last 5 years, labeled simply as “hemangioma.”

The term “hemangioma” is often insufficient as a diagnostic label for vascular anomalies in MS due to its lack of specificity. Under the ISSVA classification, hemangioma refers to a class of lesions with varying natural histories. The most common type of hemangioma is the infantile (“strawberry”) hemangioma, which appears within weeks of birth, undergoes rapid proliferation in the first few months of life, then involutes spontaneously.¹⁸ Nearly all infantile hemangiomas are involute completely by 10 years of age.¹⁹ As such, they are almost never present in adulthood and are therefore unlikely to be vascular anomalies characteristic of MS. In contrast, SCHs, which are characteristic of MS, typically present in adulthood and do not spontaneously regress.²⁰ Different hemangiomas will vary in their response to treatment modalities. Whereas infantile hemangiomas generally respond to treatment with oral propranolol, a nonselective β-blocker, there is no evidence for the use of propranolol in the treatment of SCHs. Instead, surgical excision is considered the standard, with recent reports of sirolimus (rapamycin) showing mixed success.^21–25 The correct identification of vascular anomalies is essential to their treatment. The 2011 review by Hassanein et al⁸ found that up to 20% of patients whose lesions were mislabeled received improper treatment.

“Cavernous hemangioma” was the second most frequent diagnostic label for vascular anomalies in our review. Historically, “cavernous hemangioma” was used to describe lesions characterized by dilated (“cavernous”) vascular spaces. It became recognized that many lesions previously reported as “hemangiomas” or “cavernous hemangiomas” in MS most likely represent venous malformations due to their tendency to be present at birth, grow commensurate with a child’s body, and fail to spontaneously involute.^7–10 The term “cavernous hemangioma” is still sometimes used interchangeably to refer to venous malformations; however, this nomenclature is inaccurate, as venous malformations are not vascular tumors. “Cavernous hemangioma” is not a formally recognized histopathologic entity and should be avoided when labeling vascular anomalies to prevent diagnostic confusion.

The classification of vascular anomalies in MS became further complicated by the relatively recent discovery of SCHs in 1986. SCHs are a type of true vascular tumor and share clinical, histological, and radiological features with venous malformations, making them prone to misdiagnosis as the latter.^26,27 SCHs tend to become noticeable in adulthood and are composed of solid regions of spindle cells and dilated vascular spaces that resemble venous malformations.^28,29 Although sometimes said to be pathognomonic for venous malformations, calcified thrombi (phleboliths) may also be present in SCHs.^28,30–32 This was the case in 47% of reported SCHs in the current review. These overlapping features make it likely that some lesions described as “hemangiomas” or “cavernous hemangiomas” before the discovery of SCHs represent SCHs rather than venous malformations.²⁰ Although the 2018 ISSVA classification lists MS as the association of “venous malformations ± SCHs,” our review identified several patients who were diagnosed with histologically confirmed SCHs in the absence of reported venous malformations.⁵ Furthermore, both enchondromas and SCHs in MS have been found to harbor somatic mutations in genes coding for isocitrate dehydrogenase, specifically IDH1 and IDH2.^33,34 Such an association has not been established in venous malformations.³⁵ These findings prompt consideration of whether the presence of venous malformations should be required to diagnose MS, whether SCHs are more representative of the disease, or whether either lesion may appear alone in the disease.

Our review yielded several other diagnostic labels that merit discussion. SCHs were initially thought to be a form of low-grade angiosarcomas and were called “hemangioendotheliomas” before subsequent analyses reclassified them as benign vascular tumors due to their lack of metastasis.^5,20,36 Despite this, the term “hemangioendothelioma” appeared in several reports, including some recent ones. The term “capillary hemangioma” was used to describe lesions in 2 patients. This ambiguous term has been used to refer to superficial infantile hemangiomas, capillary malformations (“port-wine stains”), and pyogenic granuloma (“pyogenic capillary hemangioma”).^5,8 “Lymphangiomas” and “lymphangiectasias,” now labeled “lymphatic malformations” under the ISSVA classification, were reported in 14 patients.⁵ The earliest report of such a lesion occurring in MS was in 1958, and the first reporting of a “lymphangioma” as the sole vascular anomaly was in 1970.^37,38 In total, “lymphangioma” was included in the disease definition in 33 articles. It is unclear whether these lymphatic malformations were misdiagnosed and instead represent vascular lesions consistent with more common definitions of MS.

To date, there remains no established consensus as to the definition of MS, even among recognized health authorities. Although the 2018 ISSVA classification defines MS as enchondromas plus venous malformations with or without SCHs, other bodies such as the World Health Organization and the Genetics and Rare Diseases Information Center continue to list hemangioma as the defining vascular anomaly.^5,39,40 Additionally, some reports of MS identified patients with other vascular lesions, such as lymphangiomas, in the absence of venous malformations or SCHs.^41,42 Until there is consistent use of nomenclature to describe vascular anomalies occurring in MS, the true constellation of lesions that make up the disease cannot be well defined.

Genetic testing may play an important role in clarifying diagnosis and guiding treatment for patients with MS. Recent studies have demonstrated that most Ollier disease and MS cases are driven by somatic mosaic mutations in IDH1/IDH2, leading to abnormal cartilage proliferation and vascular maturation.³⁴ These mutations are often present in vascular anomalies seen in MS, specifically SCHs.^34,43 Although not all vascular anomalies in MS will harbor IDH1/IDH2 mutations, testing lesional material in patients with enchondromas and vascular anomalies can help rule in MS as a diagnosis^.34,43,44 Future routine use of genetic testing to identify IDH1/IDH2 may help distinguish MS from conventional vascular malformations (eg, infantile hemangiomas), avoid inappropriate treatment, and support surveillance for malignant transformation. Moreover, testing may also clarify the spectrum of lesions that can appear in MS.

This review was limited by the lack of availability of older case reports of MS, many of which are not accessible online. Furthermore, a detailed assessment of the diagnostic accuracy of reported vascular lesion diagnoses was outside the scope of this review. However, such an evaluation may improve clarity regarding the range of vascular anomalies present in MS.

CONCLUSIONS

The definition of MS demonstrates a significant lack of concordance in the literature, owing to continued use of inappropriate, imprecise, and outdated nomenclature for classifying vascular anomalies. The same is true of diagnostic labels used to identify vascular anomalies in patient reports of MS. Terms such as “hemangioma” and “cavernous hemangioma” continue to be used inappropriately to label vascular anomalies in MS, even in recent years. This makes it difficult to identify the true constellation of vascular anomalies present in the disease. We recommend that clinicians and researchers adhere to nomenclature consistent with the current ISSVA classification to identify vascular anomalies. A consensus meeting should be considered to address the ongoing discrepancies in the use of vascular anomaly nomenclature. Based on our findings, the ISSVA definition of MS may not be representative of the vascular anomalies present in the disease. MS may be characterized primarily by SCHs rather than venous malformations, or either lesion may be diagnostic for the disease.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.