A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum

Abstract

Xanthoma disseminatum (XD) is a rare normolipidemic mucocutaneous xanthomatosis within the spectrum of cutaneous non-Langerhans histiocytosis. Managing XD poses substantial challenges, with limited available data. This study aims to comprehensively evaluate existing literature on clinical features of XD and treatment outcomes. A systematic search of MEDLINE, Embase, and PubMed was performed, using “xanthoma disseminatum” and “Montgomery syndrome” as search terms, without restrictions. Screening was performed in duplicate by 2 reviewers. One hundred fifty-one studies met the inclusion criteria, yielding 166 cases of XD (106 females, 60 males), mean age at diagnosis 35.3 years (range: 9 months-87 years). XD typically presented as yellow-to-brown coalescing papules/plaques and nodules. Distribution affects mainly the face (n = 116/166), flexures (n = 45/166), trunk (n = 65/166), and genitalia/inguinal areas (n = 63/166). Most cases (99.4%; n = 165/166) exhibited extracutaneous manifestations, including the pituitary gland and the oropharynx. Treatment options rendered low complete response rates (CRRs). Treatments with reported outcomes included surgical resection (n = 17/99), systemic steroids (n = 40/99), immunosuppressants/immunomodulators (n = 73/99), energy-based devices (n = 7/99), lipid-lowering agents (n = 24/99), cryotherapy (n = 6/99), lasers (n = 10/99), topical steroids (n = 6/99), oral retinoids (n = 2/99), and radiotherapy (n = 5/99), with CCRs of 23.5% (n = 4/17), 5.0% (n = 2/40), 9.6% (n = 7/73), 14.3% (n = 1/7), 4.2% (n = 1/24), 16.7% (n = 1/6), 10.0% (n = 1/10), 0% (n = 0/6), 0% (n = 0/2), and 0% (n = 0/5), respectively. The most promising therapy is cladribine, with the highest CRR of 27.1% (n = 6/22) and the lowest no response rate (9.1%; n = 2/22) of all reported treatments. This review confirms the high prevalence of systemic manifestations in XD. Treatment options vary widely; thus, further research is needed to establish management strategies for this challenging condition.

Introduction

Xanthoma disseminatum (XD) is a rare normolipidemic mucocutaneous xanthomatosis within the spectrum of cutaneous non-Langerhans histiocytosis. It is characterized histologically by the proliferation of histiocytic cells accompanied by deposition of lipids in the dermis. ¹

Clinically, the disease manifests initially as the eruption of symmetrically distributed red-brown cutaneous papules that eventually coalesce to form plaques of yellow-brown colour which primarily affect the face, flexures, and trunk. ² Although the most common manifestation of the disease is cutaneous, it has been reported that 40% to 60% of cases also have mucosal involvement, mainly of the upper respiratory and gastrointestinal (GI) tract. ¹ The classical symptom triad of the disease described in the literature consists of cutaneous xanthoma, mucosal xanthoma, and diabetes insipidus (DI). ³

Even though literature reviews often describe the natural history of this condition as benign, the involvement of some critical organ systems (ie, central nervous system and lower respiratory tract) can be severe and lead to increased morbidity and mortality. ⁴ It has been suggested that there are 3 clinical variants of XD according to their evolution; a self-healing form characterized by spontaneous healing, a persistent form (most common type) with persistent mucocutaneous lesions, and a progressive form affecting multiple organs and causing dysfunction. ²

Numerous treatments such as a low-fat diet, surgical excision, lipid-lowering therapy, glucocorticoids, chemotherapy agents, cryotherapy, and others have been suggested in the literature with varying degrees of success.

Thus, managing XD poses substantial challenges, with limited available data. This study aims to comprehensively evaluate existing literature on clinical features of XD and treatment outcomes.

Material and Methods

A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and registered with PROSPERO (#CRD42023451543). A systematic search of MEDLINE, Embase, and PubMed was performed using “xanthoma disseminatum,” and “Montgomery syndrome” as search terms, with no restrictions. Title and abstract screening were performed in duplicate by 2 reviewers using Covidence online systematic review software. Data extraction was completed using a predetermined extraction form.

Clinical features reported in each study were classified into the subcategories of location, morphology, size, colour, symptoms, pituitary gland involvement, corneal involvement, and other systemic involvement. We also reported on the safety and outcomes of available treatments. Outcomes from each study were coded into 3 categories: complete response (CR), partial response (PR), and no response (NR).

Results

Demographics

The majority of included studies consisted of case reports with some case series. A total of 151 studies met inclusion criteria, yielding 166 cases including 106 females and 60 males. The mean age at onset of XD symptoms was 31.5 years (range: 2 months-85 years) and the mean age at diagnosis of XD was 35.3 years (range: 9 months-87 years). Most patients were Caucasian (18.7%; n = 31/166), closely followed by Asian patients (17.5%; n = 29/166), along with a minority of Black (3.6%; n = 166), Hispanic (1.2%; n = 2/166), Arabic/Middle Eastern (0.6%; n = 1/166), and unspecified ethnicity patients (58.4%; n = 97/166; Supplemental Table S1).

Clinical Features

The primary morphology of the lesions was described in all cases. The most reported colours were yellow (58.4%; n = 91/166), brown (52.4%; n = 87/166), and red (31.9%; n = 53/166), with 81 cases presenting as a combination of these colours. Other colours, such as orange (10.8%; n = 18/166), pink (6.0%; n = 10/166), purple (3.0%; n = 5/166) were also reported. Skin-coloured lesions were found in 2.4% of cases (n = 4/166), hyperpigmented (4.8%; n = 8/166) and hypopigmented (1.81%; n = 3/166) lesions were also described.

XD lesions appeared primarily as papules (72.2%; n = 120/166) with nodules (27.7%; n = 45/166) and plaques (25.3%; n = 42/166) being the most common secondary presentations, with cases appearing with a combination of all 3 aforementioned morphologies. Scars were noted in 2.4% of patients (n = 4/166) and ulcers were described in 1.2% of cases (n = 2/166). Other terms used to describe XD presentation in singular cases included verrucous tumours or tumour-like lesions (1.8%; n = 3/166), pedunculated (1.8%; n = 3/166), maculopapular (1.2%; n = 2/166), macular (1.2%; n = 2/166), frank anetoderma (1.2% n = 2/166), among several others descriptors. Coalescing and evolving lesion features were noted in 25.6% (n = 43/166) and 12.0% (n = 20/166), respectively. The average maximal and minimal size of lesions were 6.7 ± 19.8 mm and 0.9 ± 1.4 mm, respectively. While not often described, lesions were mostly firm (5.4%; n = 9/166), soft/smooth (2.4% n = 4/166), or shiny (3.6%; n = 6/166). Nine patients had pruriginous lesions, 1 patient had painful lesions, and 18 patients had asymptomatic cutaneous lesions, with the remaining cases not disclosing this information.

The location of XD lesions varied greatly across cases. Cutaneous manifestations were reported in 154 cases. Facial involvement was described in 70% of cases (n = 116/166), which affected the periorbital area (48%; n = 80/166), the perioral area (17%; n = 29/166), and the forehead (7%; n = 11/166). Lesions of the neck (46%; n = 77/166), axillae (55%; n = 91/166) and upper extremities (30%; n = 49/166), inguinal and genital area (38%; n = 63/166), flexural areas (27%; n = 45/166), and lower extremities (23%; n = 39/166) were all described in a significant number of cases. Of note, 99.4% of cases (n = 165/166) reported extracutaneous manifestations of XD. Oropharyngeal lesions affected 36.7% of patients (n = 61/166) with involvement of the oral cavity being described in 67.2% of oropharyngeal cases (n = 41/61) and 15.1% (n = 25/166) of all XD patients. Corneal and conjunctival lesions were present in 12.7% (n = 21/166) patients. Skeletal affections were also described in 6.6% of cases (n = 11/166). Most important, central nervous system (CNS) involvement was reported in a quarter of patients (24.6%; n = 41/166) with pituitary gland involvement occurring in 17.5% of XD cases (n = 29/166). Notably, 38 patients were diagnosed at some point with DI, which is a condition linked to XD involvement of the pituitary gland. A younger mean age of diagnosis (25 years, range: 20 months-70 years) and age of symptom onset (28 years, range: 2 months-40 years) was noted for patients with XD and DI.

Among the 7 cases without cutaneous involvement, XD lesions were found to affect multiple systems, including oropharyngeal, respiratory tract, GI tract, spine, and cornea.

Many cases identified singular additional manifestations and locations of XD. XD infiltration of the GI tract led to the following clinical findings: hepatomegaly, liver cysts, sigmoid diverticulitis as well as reports of XD lesions located on the fundus, antrum, liver, and peritoneal and mesenteric surfaces. One patient noted dyschezia due to anorectal involvement of XD. Involvement of bladder and kidneys, leading to renal insufficiency was noted in 1 case. Endocrine manifestations included adrenal glands infiltration. XD presented in joints causing rhizarthrosis, coxalgia, and polyarthrosis. Several ear, nose, and throat (ENT) manifestations occurred which led to hoarseness of voice, dyspnea and dysphagia, rhinorrhea, hyposmia, deafness, hyperaeration, stridor, obstruction of maxillary sinuses, and dimming of frontal sinuses. The CNS was often involved in patients with XD with manifestations such as blindness or blurred vision, optic atrophy, hemifacial paralysis, and spine involvement. Respiratory lesions were reported in the lungs and mediastinum due to infiltration, which was linked to dyspnea. Single cases of ectropion and pelvic involvement were also reported.

A number of other manifestations were reported along with XD symptoms without confirmation of association with XD: splenomegaly to macrocytic anemia and thrombocytopenia, b-cell lymphoblastic acute leukemia, hypothyroidism, weight gain and loss, growth retardation, hypothyroidism, growth retardation, and amenorrhea (Supplemental Table S2).

Treatment Outcomes

In total, 99 patients received treatment, with 10 patients experiencing spontaneous resolution before or following a failed treatment attempt. Our data indicate that cases of spontaneous resolution do not showcase any distinct or recognizable features that would render supportive therapeutical management instead of curative therapy. The most frequently reported treatment modality was immunomodulators (75.8%; n = 75/99), followed by systemic steroids (45.5%; n = 45/99), lipid-lowering agents (26.3%; n = 26/99), surgical resection (23.2%; n = 23/99), lasers (12.1%; n = 12/99), other energy-based devices (9.1%; n = 9/99), cryotherapy and topical corticosteroids (both 6%; n = 6/99), radiotherapy (5%; n = 5/99), and oral retinoids (2%; n = 2/99), with an average follow-up period of 28.1 ± 31.1 months. DI treatment was reported in 17 patients.

In general, complete response rates (CRR) were infrequently achieved. The highest CRR was reported with surgical resection (23.5%; n = 4/17), when excluding the 6 patients with undisclosed treatment outcomes. The partial response rate (PRR) was 41.2% (n = 7/17) and the no response rate (NRR) was 35.3% (n = 6/17).

Two patients had undisclosed outcomes following immunomodulatory therapy. A CRR was achieved in 9.6% (n = 7/73), a PRR of 47.9% (n = 35/73), and a NRR of 41.1% (n = 30/73). Of note, only one case of immunomodulatory therapy was administered topically, specifically tacrolimus which led to PR, with the remaining treatments being systemic immunomodulators.

As for systemic steroids, treatment outcomes were undisclosed in 5 cases, bringing the total number of available results to 40 patients. The CRR was 5% (n = 2/40), while the PRR and NRR were both 47.5 % (n = 19/40).

Two patients treated with lipid-lowering agents had undisclosed results. CRR of 4.2% (n = 1/24) was achieved by lipid-lowering agents, with a PRR of 54.2% (n = 13/24), and a NRR of 42.7% (n = 10/24).

Patients treated with lasers reached a complete resolution in 10% of cases (n = 1/10). PR was achieved in 30% (n = 3/10), and NR in 60% (n = 6/10). Interestingly, the patient’s lipid profile was not an indicator of efficacy of lipid-lowering therapies and dietary restrictions. While the only patient achieving complete resolution of XD with lipid-lowering agents had hyperlipidemia of unspecified subtype, among patients with PRs, only 4 had at least 1 abnormal lipid value. These values included elevated lipoprotein (a), mild elevation of triglycerides, low high-density lipoprotein (HDL), decreased pre-beta-lipoprotein, and the remaining patients with partial clearance of XD lesions were normolipidemic. As for cases with NR to such treatments, 1 patient had type IIB hyperlipidemia, 2 patients had unspecified lipid status, and the remaining were normolipidemic.

Undisclosed outcomes were noted in 2 patients treated with energy-based devices. CRRs were achieved in 1 patient (14.3%; n = 1/7), with a PRR of 57.1% (n = 4/7) and a NRR of 28.6% (n = 2/7). As for DI treatment, 4 patients had undisclosed results. The CRR was 23.1% (n = 3/13), while a PRR was achieved in 53.8% (n = 7/13) of patients and NRR was 30.8% (n = 4/13). A subanalysis on energy-based devices was performed (not shown) and no device seemed to perform better than the other.

Interestingly, 1 treatment of the chemotherapy category, cladribine (2-chlorodeoxyadenosine), was used to treat 22 patients, of which 6 patients had successful complete resolutions (27.3%; n = 6/22), a PRR of 63.6% (n = 14/22), and a NRR of 9.1% (n = 2/22). As such, this treatment has the highest CRR along with the lowest NRR of all treatments (Supplemental Table S3).

Discussion

XD is a rare non-Langerhans cell histiocytosis of unknown etiology presenting with a variety and increasingly debilitating symptoms. The condition progresses over time and spontaneously resolves in only a minority of cases, thus highlighting the importance of adequate treatment strategies. Unfortunately, due to the sparsity of cases, no clear consensus or guidelines have been established to treat symptoms of XD and slow disease progression. This systematic review highlights the significant multisystemic involvement of this condition and the wide variety of treatment approaches which have shown overall modest success. In fact, most patients do not respond to treatment and either remain stable or continue to progress in their disease.

The morphology of XD varies significantly according to the progression of the condition, but the most common presentation includes yellow and red-to-brown papulonodules which tend to coalesce into plaques and progress over time. The most widely recognized manifestation to XD is the involvement of the pituitary gland which occurs in approximately 40% of cases and often leads to the development of DI, but the disease is often well manageable by vasopressin treatment. ⁴ In our study, lesions of the pituitary gland were confirmed with imaging in 11% of patients and DI was diagnosed in 22.9% of patients (n = 38/166). Interestingly, the mean age of patients diagnosed with XD and DI was 25 years, which is 10 years younger than the mean age of XD diagnosis of 35.3 years. Therefore, the difference in DI incidence cannot be explained by the older age of patients with DI, as our patients with DI were younger than all included patients. This age difference may be due to earlier diagnosis of XD as symptoms of DI may be more concerning and lead to more thorough investigation in younger patients than the papulonodular initial cutaneous presentation of XD.

Of note, due to the rarity of the disease, the age of onset of XD remains debated. Some studies suggest that most cases of XD arise between the ages of 5 to 25, ⁵ although there have been reported cases of the disease in individuals older than 40 years. ² Our results include XD diagnosis in children younger than 1 year and patients of 74 years old but remains centred around younger patients. Interestingly, DI was diagnosed in 28 males and only 9 females, even though our systematic review includes 106 females and 60 males, indicating a potential prevalence of XD-associated DI for male patients. This finding does not align with the known prevalence of DI which has been established to affect male and females in similar proportions. ⁶

While DI remains an important comorbidity to consider in XD, lesions can appear almost anywhere and can lead to significant quality of life burden. In fact, our results have found that over 99.4% of patients had extracutaneous involvement. A common difficult manifestation is corneal and conjunctival involvement, which may lead to vision loss, has been reported in 13% of patients. Lesions in the inguinal and genital area were often reported (38%; n = 63/166) and careful physical examination of these areas may be required to remove xanthomas before they become discomforting. Lesions of the CNS often include the pituitary gland but can also be found in other areas of the cerebral cortex, the spine, and cerebellum. Appropriate imaging to rule out CNS involvement may be considered in patients with atypical neurological symptoms.

Treatment of XD remains difficult and complex for multisystemic involvement. Depending on the extent of extracutaneous XD involvement, dermatologists may benefit from collaboration with endocrinologists, neurologists, radiologists, ophthalmologists, and oncologists to better address and mitigate the multiorgan impairment caused by XD infiltration. The most striking finding is the superiority of cladribine compared to other immunomodulatory agents in the treatment of XD, as suggested by our results. In fact, cladribine was categorized under the immunomodulator group, thus 6 out of the 7 patients who achieved complete resolution under immunomodulators received cladribine. Considering the wide array of reported immunomodulatory therapies used to treat XD (imatinib mesylate, methotrexate, vesepid, etoposide, tacrolimus, azathioprine, anti-interferon-gamma, cyclophosphamide, vincristine, chlorambucil), there are promising data for cladribine in the treatment of XD. As for XD resection, it remains a good treatment option for disease limited to a surgically accessible location and should be considered in select cases and could even be used as an adjuvant to cladribine. While individual case reports and series have hypothesized that cladribine may be of significant aid in XD treatment and management, to our knowledge, no literature review has reached this conclusion.^7-9

DI treatment remains underreported, but seemingly efficacious when discussed in included studies. Radiotherapy was often used for intracranial XD lesions and did not lead to complete resolutions, but it had significant NRR. While no adverse events of radiotherapy were reported in included XD studies, it is important to discuss the known risk-to-benefit ratio of this procedure before exposing the patient to its potential side effects. ¹⁰

Systemic corticosteroids and lipid-lowering agents both have low CRR and high NRR. Of note, recent human monoclonal antibodies lipid-lowering agents such as PCK9 inhibitors (evolocumab, alirocumab) have shown great efficacy in familial hypercholesterolemia, but they have not been used in any of our included studies and their efficacy has not yet been assessed for XD. ¹¹ Furthermore, regarding lipid-lowering agents, our findings highlight the poor correlation of lipid status and response to lipid-lowering therapies. Health care providers often prescribed lipid-lowering therapies following histopathological characteristics of XD lesions indicating lipid deposits (ie, foamy cells, Touton-like giant cells) despite normolipidemic status, rendering varying therapeutic outcomes. More research is needed to understand the most efficacious management for patients with XD according to laboratory and histopathological findings.

Destructive modalities such as lasers, cryotherapy, and other energy-based devices had similar CRRs; however, the small sample size of patients treated with cryotherapy and other energy-based devices makes it difficult to interpret the efficacy of these treatments.

This review has several limitations. The categorization of treatment outcomes as NR, PR, and CR does not include the mild or excellent subcategories of PRs to treatment which may be satisfactory to some patients. In fact, the PR category is heterogenous and include various responses levels (mild, moderate, strong, excellent) and grouping them all into PR leads to a loss of information. In cases treated with combination therapies, assessing the effectiveness of individual treatment modalities was difficult and is an important limitation of this review. Furthermore, heterogenicity in patient populations, treatment interventions, and outcome measures of included studies may affect the generalizability of our results. The lack of high-level evidence from randomized control studies and small sample sizes affectes the quality of our results. Differences in treatment dosing and duration contribute to the heterogeneity of our results. Included studies may also include bias, with positive results being more frequently published, potentially increasing PR and CR treatment responses in comparison to studies with NR. Finally, the differences between the efficacy of different treatment sequences for XD have not been explored.

Conclusion

This systematic review presents the main clinical features and treatment outcomes to a rare difficult-to-treat normolipidemic non-Langerhans cell histiocytosis with significant and often debilitating extracutaneous manifestations. Cutaneous lesions most commonly appear as yellow, red-to-brown coalescing papulonodules which may appear on the face, trunk, neck, and inguinal areas flexures and be associated with oropharyngeal manifestations and DI, especially in male patients. Therapy is often unsatisfactory and requires multiple courses of treatment. The best treatment results were found with surgical resection, cladribine, and often required DI treatment. More research is needed to understand risk factors and the best treatment sequence to assure efficacious and reliable outcomes for patients living with this challenging condition.

Supplemental Material

sj-docx-1-cms-10.1177_12034754241274356 – Supplemental material for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum

Supplemental material, sj-docx-1-cms-10.1177_12034754241274356 for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum by Lorena Alexandra Mija, Catherine Keying Zhu and Ilya Mukovozov in Journal of Cutaneous Medicine and Surgery

Supplemental Material

sj-docx-2-cms-10.1177_12034754241274356 – Supplemental material for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum

Supplemental material, sj-docx-2-cms-10.1177_12034754241274356 for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum by Lorena Alexandra Mija, Catherine Keying Zhu and Ilya Mukovozov in Journal of Cutaneous Medicine and Surgery

Supplemental Material

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Supplemental material, sj-docx-3-cms-10.1177_12034754241274356 for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum by Lorena Alexandra Mija, Catherine Keying Zhu and Ilya Mukovozov in Journal of Cutaneous Medicine and Surgery

Supplemental Material

sj-docx-4-cms-10.1177_12034754241274356 – Supplemental material for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum

Supplemental material, sj-docx-4-cms-10.1177_12034754241274356 for A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum by Lorena Alexandra Mija, Catherine Keying Zhu and Ilya Mukovozov in Journal of Cutaneous Medicine and Surgery