Abstract

Background: Lhermitte–Duclos disease (LDD) is a rare tumor, with only about 300 reported cases. It often shows comorbidity with Cowden syndrome (CS); however, it can occur by itself. Radiologically, the “tiger-stripe” appearance is considered pathognomonic. Surgical resection remains the mainstay of treatment. This report aims to describe the clinical and radiological characteristics of LDD and its relationship with CS according to age group.

Methods: PubMed electronic databases were searched in August 2022. The search terms included “Lhermitte– Duclos disease” and “dysplastic gangliocytoma,” which yielded 297 and 103 research articles, respectively. The articles were collected and reviewed by three researchers.

Results: Out of 400 identified articles, we analyzed 302 reported cases. The mean age at presentation was 33.6 ± 16 years; 171 patients (56.6%) were female, and 123 (40.7%) were male. The most commonly reported symptom was headache (174 patients, 57.6%), followed by ataxia (109, 36.1%). In addition, 99 cases (32.8%) were associated with CS, and 60 (19.9%) had a confirmed phosphatase and tensin homolog (PTEN) mutation. A tiger-stripe appearance was observed in 208 cases (58.7%); surgical resection was performed in 64.2% of the cases. Mortality and recurrence rates were 4.3% and 8.6%, respectively. No statistically significant difference was found between adult- and pediatric-onset LDD for the association with CS (P = 0.128).

Conclusion: Our findings suggest that adult and pediatric LDD have major commonalities; however, further prospective studies are warranted.

Keywords: Cowden syndrome, Disease onset, Lhermitte–Duclos disease, Phosphatase and tensin homolog

INTRODUCTION

Lhermitte–Duclos disease (LDD) or dysplastic gangliocytoma of the cerebellum is a benign, rare, hamartomatous lesion characterized by a slow and progressive abnormal growth in the cerebellum.[ 28 ] In general, the clinical features of this benign entity are directly related to the anatomical location of the lesion in the posterior fossa. Lesions in the posterior fossa usually cause clinical symptoms related to the mass effect on the cerebellum and ventricular system, including headaches, hydrocephalus, visual disturbances, and cerebellar signs and symptoms. Although LDD is not considered malignant, its clinical presentation is not always benign or straightforward.[ 30 ]

Given the association between LDD and Cowden syndrome (CS), numerous non-neurological signs and symptoms suggest the existence of such a lesion. LDD was introduced in 1920 by Lhermitte and Duclos,[ 25 ] who described the case of a 36-year-old man with a 10-month history of occipital headache and left-sided hearing impairment. The patient suddenly developed vertigo, recurrent falls, and gait ataxia. Subsequently, the patient became confused and disoriented, eventually succumbing to coma and death.[ 25 ]

Surgical intervention for LDD was described in 1937 by Christensen, who reported a patient with LDD who underwent surgery and was discharged from the hospital without complaints.[ 5 ] Since then, an increasing number of cases have been reported, demonstrating the lesion’s rarity and complexity. However, the nature of the lesion has no established consensus. Lhermitte and Duclos suggested that it might be a congenital malformation and a neoplasm of ganglion cells; contrastingly, other studies have suggested that it might be a blastoma, hamartoma, or hyperplasia of normal tissue.[ 29 ]

The epidemiology of LDD remains unclear, with over 300 cases being reported worldwide. Most cases occur between the 2^nd and 4^th decades, with no apparent sex predominance.[ 29 ] The epidemiology of LDD is usually described from the perspective of its association with CS. Although the frequency of comorbid LDD and CS remains unclear, frequencies of 1.8%, 6%, and 15% have been reported.[ 31 ] The lesion usually develops in the infratentorial region, having an insidious onset with a good overall prognosis.[ 12 , 22 ]

The histopathological characteristics of LDD include the absence of the Purkinje cell layer; increased thickness of the molecular cell layer, which yields axon over-myelinization; hypertrophy of the granular cell layer; replacement of the granular cell layer with dysplastic cortical neurons; and atrophy of cerebellar white matter.[ 12 ] Notably, LDD is radiographically characterized by increased myelinization and vacuolization of axons associated with the tumor. Accordingly, magnetic resonance imaging (MRI) can visualize a characteristic layered pattern.[ 1 ] The lesion is usually hypointense on T1-weighted imaging (T1WI) and produces alternating high- and low-intensity levels on T2-weighted imaging (T2WI), producing the characteristic “tiger-stripe” pattern.[ 49 ] Although this pattern is highly specific, it has been observed in other lesions.

The management of LDD is usually simple, with surgical resection reserved for symptomatic patients; cerebrospinal fluid (CSF) diversion is performed in patients who develop signs and symptoms of increased intracranial pressure. Systemic chemotherapeutic agents are not prescribed. Although other modalities have been used, including molecularly targeted therapies, evidence remains insufficient.[ 20 ]

CS is a rare, autosomal dominant, multisystem clinical entity characterized by malignant and hamartomatous lesions developing across the body, particularly in the breast, endometrium, and thyroid. CS is caused by a germline mutation in the phosphatase and tensin homolog (PTEN) gene, a tumor suppressor gene found on human chromosome 10q23.[ 31 ] This phosphatase regulates signal transduction in the phosphatidylinositol 3-kinase/PTEN/ AKT pathway, which regulates essential cellular processes, including growth, cell migration, and apoptosis.[ 14 ] The estimated prevalence of CS ranges between 1 in 200,000 and 1 in 250,000. CS appears to have a female predominance, which can be attributed to including breast and uterine lesions. Further, most cases occur among Caucasians. The age at diagnosis of CS is 13–65 years. However, these data were reported before the consortium criteria for CS diagnosis were developed.[ 13 ] The main diagnostic criteria, as reported by Pilarski,[ 33 ] include breast cancer, endometrial cancer, thyroid cancer, gastrointestinal hamartoma, macrocephaly, macular pigmentation of the glans of the penis, multiple mucocutaneous lesions, and adult LDD. Minor criteria include autism spectrum disorder, mental retardation, colon cancer, lipoma, renal cell carcinoma, and several other lesions.[ 33 ] The management of CS usually involves tumor screening and prevention.

Although >300 cases of LDD have been reported, research remains insufficient. Specifically, the proportion of cases that recur after surgical resection, the mortality rate of the lesion, and the number of cases associated with CS and PTEN mutations, especially in the pediatric population, remain unclear. This systematic review aimed to describe the clinical characteristics of LDD and its radiological appearance with different conventional MRI sequences. In addition, we aimed to assess the association of adult and pediatric LDD with CS and PTEN mutations, reported surgical and medical management protocols, and the recurrence and mortality rates of LDD.

MATERIALS AND METHODS

Study objectives

The primary study objective was to review the clinical characteristics, radiological appearance, genetic associations, and outcomes in reported cases of LDD. In addition, we aimed to evaluate differences between adult- and pediatric-onset LDD regarding their association with CS.

Search methods

We queried the PubMed database using the search terms “Lhermitte–Duclos disease” and “dysplastic gangliocytoma,” yielding 297 and 103 articles, respectively. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Inclusion and exclusion criteria

We did not include the first report of LDD by Lhermitte and Duclos[ 25 ] since it was absent from PubMed. We included all published studies from 1956 to August 2022 that reported at least one case of LDD and at least one of the following data: age, sex, clinical presentation, radiological presentation, CS status, PTEN mutations, management options, and clinical outcomes. CS was diagnosed based on the opinion of the authors of each case report. For cases published before the international consortium of CS criteria for diagnosis or before the discovery of the association between LDD and CS (n = 11 cases), the diagnosis of CS was confirmed by the authors of the current article using the international consortium of CS criteria for diagnosis and features reported by the original authors.

Selection of studies

The eligibility of identified articles was independently evaluated by three authors (AA, TA, and ZA) through an initial screening of the title and abstract, followed by a full-text review. We included all studies that reported relevant information regarding the predetermined set of variables. The study excluded articles lacking the given variables, non-human cases, non-English articles, LDD-mimicking cases, and reviews that did not report a new case. In addition, we excluded all cases in which data could not be retrieved. Disagreements were resolved by agreement of at least two of the three reviewers [ Figure 1 ].

Figure 1:

Flowchart of the search process. n: Sample size, LDD: Lhermitte-Duclos disease

Data collection

We extracted the following data from the original articles: demographic data, clinical presentation, CS status, presence of PTEN mutations, radiological presentation, management protocol, recurrence, and mortality.

RESULTS

We extracted 302 reported cases from the 400 identified articles. Demographic, clinical, and radiological data were collected from original articles. Descriptive analyses were performed using IBM SPSS Statistics for Windows version 25. Fisher’s exact test was performed to assess differences between adult- and child-onset LDD related to CS, recurrence, and mortality rates.

Demographics

At presentation, the mean age (± standard deviation) was 33.6 ± 16 years, ranging between 3 days and 77 years. We divided patients into two groups based on their age; specifically, patients aged <18 years and >18 years were included in the pediatric (47 patients, 15.6%) and adult (247 patients, 81.8%) groups, respectively, with only eight patients (2.6%) having data missing for age. For sex distribution, female patients (171, 56.6%) outnumbered male patients (123, 40.7%) [ Table 1 ].

CS and PTEN mutation

LDD was associated with CS in 99 patients (32.8%) and not associated in 42 (13.9%); 161 patients (53.3%) lacked data. Moreover, LDD was associated with PTEN mutations in 60 cases (19.9%) and not associated and 42 (13.9%); 161 cases (53.3%) lacked relevant information [ Table 1 ].

Table 1:

Demographic characteristics, Cowden syndrome, and PTEN mutation status (n=302)

Clinical presentation

Regarding the clinical presentation of LDD, the most common symptom was headache (“occipital” or “global;” n = 174, 57.6%), followed by ataxia (n = 109, 36.1%); cerebellar signs, including dysmetria and dysdiadochokinesia (n = 68, 22.5%); papilledema (n = 61, 20.2%); visual disturbances (n = 51, 16.9%); dizziness (n = 40, 13.2%); nausea (n = 36, 11.9%); vomiting (n = 35, 11.6%); diplopia and strabismus, usually involving eye abduction secondary to abducens cranial nerve palsy and elevated intracranial pressure (n = 29, 9.6%); nystagmus (n = 24, 7.9%); vertigo (n = 22, 7.3%); and altered mental status (n = 16, 5.3%). Several cases did not mention the patient’s clinical presentation; 13 cases (4.3%) reported them incidentally [ Table 2 ].

Table 2:

Clinical presentation of 302 cases (n=302)

Radiological presentation

Among the 302 cases, only 208 reported radiological findings; the reported lesions were usually unilateral. The right cerebellar hemisphere (n = 81, 39%) was more affected than the left (n = 75, 36.1%). Only 12 patients (5.7%) presented with bilateral lesions; 4 (1.9%) had midline lesions involving only the vermis. The lesion site was not described in 36 cases (17.3%). Enhancement patterns (usually mild) were present in 31 patients (14.9%) and absent in 82 (39.4%); 95 (45.7%) cases lacked relevant information.

Regarding the characteristic findings of LDD, a classic tiger-stripe appearance was described in only 122 cases (58.7%). The mass effect on adjacent structures was present in 75 cases (36%) and absent in 1 case (0.5%); the other cases lacked relevant data (63.5%). Tonsillar herniation was reported in 43 cases (20.7%); similar results were found for hydrocephalus, with 59 patients (28.4%) presenting radiological signs of increased intracranial pressure. Six reports denied any apparent hydrocephalus; 143 reports had no relevant data.

Signal intensity of LDD in conventional MRI

Regarding intensity, the lesion had a low signal on T1WI in 99 cases (47.6%), a mixture of low and isointensity in 5 cases (7.2%), and a solely isointense pattern in 2 cases (1%). No relevant data were available regarding T1WI in 92 cases (44.2%). On T2WI, isointensity was reported in only 1 patient (0.5%). In most cases (n = 118, 56.7%), the lesion appeared hyperintense. Mixed intensities were reported in two different presentations: mixed isointensity and hyperintensity (n = 11, 5.3%) and mixed hypo- and hyper-intensity (n = 1, 0.5%) [ Table 3 ].

Table 3:

Radiological characteristics of LDD (n=208)

Management of LDD

Conservative management was performed in 14 patients (4.6%), with many refusing treatment. Conservative management included using analgesics, antiemetics, and radiological monitoring (MRI). The type of management was not described for 94 patients (31.1%). Surgical intervention was performed in 194 patients (64.2%). Non-surgical interventions were also reported: 2 patients (0.7%) received chemotherapy and 1 (0.3%) received radiotherapy. CSF diversion was established in 48 patients (15.9%), with the most common method being ventriculoperitoneal shunting (n = 35, 11.6%), followed by external ventricular draining (n = 9, 3%) and ventriculoatrial shunting (n = 1, 0.3%). The CSF diversion method was not specified in 3 cases (1%).

The extent of resection was defined in three different categories. Specifically, gross-total resection (GTR), subtotal resection (STR), and partial resection were indicated by resection of ~100%, 50–100%, and <50% of the lesion, respectively. GTR, STR, and partial resection were reported in 46 (15.2%), 59 (19.5%), and 23 (7.6%) patients, respectively [ Table 4 ].

Postoperative course

Favorable and unfavorable outcomes were reported in 157 (52%) and 4 (1.3%) cases, respectively; the remaining cases had no data regarding the postoperative course. The complication rate was 9.6% (29 patients). Recurrence was observed in 26 patients (8.6%), among whom 11 were associated with CS. Recurrence was not observed in 80 patients (26.5%); 196 cases (64.9%) lacked information regarding recurrence. Death was reported in only 13 patients (4.3%); the remaining cases denied death (n = 91, 30.1%) or had no data regarding death (n = 198, 65.6%) [ Table 4 ].

Table 4:

Management and postoperative course (n=302)

The most common complications were persistent cerebellar symptoms (n = 8, 2.65%), followed by seizures (n = 5, 1.66%) and cerebellar mutism and respiratory difficulty (n = 3, 1%). Hydrocephalus, shunt infection, and ventriculitis were observed in 2 patients (0.7%) each. Other rare complications included encephalomalacia, diabetes insipidus, global cerebral ischemia, vision deterioration, and hypotension [ Table 5 ]. Among the reported deaths, the causes were aspiration pneumonia (n = 2), metastatic breast cancer (n = 2), myocardial infarction (n = 2), intestinal obstruction (n = 1), intratumoral hemorrhage (n = 1), respiratory failure (n = 1), and sigmoid stenosis (n = 1); three patients did not have a caused determined [ Table 6 ].

Table 5:

Complications (n=302)

Table 6:

Cause of death (n=302)

LDD and age-related association with CS

No significant differences were found between adult- and pediatric-onset LDD for association with CS, mortality rate, and lesion recurrence, with P = 0.128, 0.728, and 0.426, respectively [ Table 7 ].

Table 7:

Relationship between the adult and pediatric populations in terms of the association with CS, mortality, and recurrence

DISCUSSION

Since the first case of LDD was reported in 1920 by Lhermitte and Duclos,[ 24 ] many cases have been subsequently reported, especially with advances in neurological imaging techniques. As of August 2022, more than 300 cases have been reported. A milestone in the history of LDD was the discovery of an association between LDD and CS, called Cowden–Lhermitte–Duclos (COLD) disease. To the best of our knowledge, this systematic review is the first for LDD in English literature.

Age, sex, and demographics

The mean age of presentation was consistent with LDD occurring mainly in the 2^nd and 4^th decades of life.[ 29 ] LDD being primarily an adult disease might explain the predominance of COLD syndrome in adult-onset LDD. In addition, LDD occurs more frequently in females.

CS and genetic association

LDD was associated with CS and PTEN mutations in one-third and one-fifth of cases, respectively. However, many of these cases were diagnosed before the international consortium of CS criteria for diagnosis was developed.[ 11 ] Based on the revision of the criteria by Pilarski et al.,[ 31 ] fewer patients would be eligible for a CS diagnosis given the lack of required information in some reported cases. We believe that the data are too heterogeneous to evaluate the diagnostic accuracy solely based on the reported information about patient status.

Pérez-Núñez et al.[ 30 ] suggested that LDD be considered a typical lesion of CS. They, further, indicated that LDD was often comorbid with “other” pathologies rather than as an isolated case, suggesting that LDD is a component of CS. However, only one-third of the cases in our review were associated with CS. Moreover, we believe that this percentage is exaggerated because many of these cases did not meet the diagnostic criteria proposed by Pilarski et al.[ 31 ] In contrast, almost two-thirds of our patients had isolated LDD.

CS and the onset of LDD

The association of CS with LDD is further complicated by the distinction between adult- and childhood-onset LDD. Zhou et al.[ 50 ] found that none of the pediatric patients with LDD (n = 3) exhibited CS features or PTEN mutations, suggesting that adult-onset LDD should be considered a pathognomonic criterion for CS. Our review identified 13 pediatric patients with LDD associated with CS; four reported PTEN gene mutations, one denied any mutations, and eight did not report data regarding PTEN mutations. These data suggest that the distinction between adult- and childhood-onset LDD might have a weak scientific basis [ Table 8 ].

Table 8:

Pediatric LDD cases associated with Cowden syndrome

In addition, no significant difference between adult and pediatric patients was found for the prevalence of CS, recurrence, or mortality. However, given the heterogeneity of the reported data, the retrospective nature of this review, and the short follow-up duration, we could not determine the exact differences between these age groups. Moreover, definitions for the pediatric population have been inconsistent. In our review, we applied the relatively common definition of an age <18 years for the pediatric population. Zhou et al. described 18 patients, among whom 15 had confirmed germline mutations in the PTEN gene, and all were adults. This result demonstrates the importance of differentiating between adult- and pediatric-onset LDD. On immunohistochemistry, 75% of cases showed a loss of PTEN protein expression.[ 50 ] Most of the mutations were germline, but some patients also had somatic mutations.[ 50 ]

Bilateral involvement and the genetic origins of LDD

This review identified 46 patients with CS and PTEN mutations, representing 46.5% of those with both LDD and CS. This result is consistent with the previous reports and supports the overall premise of focusing less on the role of PTEN in the pathogenesis of isolated LDD.[ 32 ] This idea is, further, demonstrated in cases with bilateral LDD involvement; 12 patients (5.7%) showed bilateral involvement, but none had proven PTEN mutations, and only two were diagnosed with CS. This finding is inconsistent with previous suggestions that the pathogenesis of LDD involves PTEN mutation primarily[ 50 ] and raises skepticism regarding the widely reported genetic origins of the disease.[ 23 ] Furthermore, a low recurrence rate was observed in patients with bilateral lesions; although only two patients showed recurrence, both were diagnosed with CS [ Table 9 ].

Table 9:

LDD characteristics of patients with bilateral involvement of the cerebellum

Radiological appearance

The appearance of LDD is usually described as a non-enhancing, well-circumscribed lesion, unilateral in the cerebellum, with low signal on T1WI, high signal on T2WI, and fluid-attenuated inversion recovery, and presenting the tiger-stripe appearance.[ 32 , 47 ]

Tiger-stripe appearance and enhancement

This review is the first large-scale report on the prevalence of enhancement, tiger-stripe appearance, and mass effect of LDD on MRI. The finding that lesion enhancements and linear striations were observed in 14.9% and 58.7% of cases is consistent with a previous small-scale review of 21 patients that found that 61.9% of the patients manifested the classical layered pattern.[ 16 ] However, the tiger-stripe appearance is not unique to LDD, and it should be combined with other typical signs of LDD to enhance diagnosis.[ 16 ] Although MRI seems to have a reasonable level of specificity for LDD, recognizing that other lesions may mimic the MRI findings of LDD is important.[ 8 , 21 ]

Enhancement is not rare in LDD. Different enhancement patterns were observed in 14.9% of cases; however, most had mild enhancement. In the aforementioned review, only 5 patients (23.8%) showed heterogeneous enhancement,[ 16 ] further supporting the argument for the diverse nature of LDD.

Magnetic resonance spectroscopy (MRS) and LDD malignancy

MRS can assess the chemical content of a given lesion, enabling differentiation of malignancy degrees through the measurement of chemical metabolites such as choline, N-acetylaspartate (NAA), and lactate.[ 15 ] In general, increasingly malignant tumors usually have increased choline/NAA and lactate levels.[ 49 ]

Zhang et al.[ 49 ] recently described the use of MRS for LDD. They confirmed that all patients with LDD showed a peak in lactate levels, which usually indicates a more anaerobic neuronal metabolism commonly associated with malignant transformation. However, they observed a decrease in the choline/NAA ratio in most patients, a characteristic finding of tumors with low malignancy. They concluded that using MRS and susceptibility-weighted imaging (SWI), along with conventional MRI, could be beneficial in differentiating LDD from other malignant mimickers.[ 49 ]

Management, postoperative course, and recurrence

Most patients in our review (64.2%) underwent surgical management, with 19.5% undergoing STR. The extent of resection seems to have a strong correlation with LDD recurrence.[ 1 ] An immunohistochemical analysis of 31 cases of LDD suggested that LDD recurrence might be attributed to two primary elements: the spatial heterogeneity of LDD, which yields non-concentrated and multifocal involvement of the cerebellar hemisphere, and partial lesion resection, as some of the genetically affected cells can look completely normal.[ 1 ] Very few studies have conducted long-term follow-up assessments. In a series of 12 patients, nine had a subtotal or partial resection with an average follow-up of 89 months, and only one case reported recurrence.[ 46 ] Similar results were found in another series of eight patients who underwent partial resection or STR.[ 20 ]

Of the 26 patients that experienced recurrence, 11 had a CS mutation and one had a PTEN mutation; 15 underwent subtotal or partial resection, four underwent GTR, and seven lacked information regarding the extent of resection. After treatment, four patients died, and seven experienced posttreatment complications.

Nonsurgical interventions and conservative management

Chemotherapy and radiotherapy were reported in two and one case, respectively. One patient had received ten cycles of metronomic temozolomide over 12 months; the patient developed nausea and vomiting. The second patient received rapamycin, a first-generation mechanistic target of rapamycin (mTOR) kinase inhibitor. The mTOR protein controls cell growth, survival, and proliferation.[ 38 ] However, surgical management and GTR remain the main treatment.[ 17 , 27 - 35 ] Conservative management was performed in 4.6% of cases. Since LDD shows slow growth and usually does not invade adjacent structures, a wait-and-see approach can be feasible as an alternative for GTR.

Limitations of this study

First, given the rarity of LDD, most of the literature consists of subjective reports of isolated cases. Second, we could not establish causal relationships due to the heterogeneity of the reported data, the review’s retrospective nature, and the rarity of the disease. Further, research should investigate the differences between pediatric- and adult-onset LDD regarding CS association and follow-up. Moreover, the lack of consensus on the diagnosis of CS and differences in the definition of pediatric populations further restrict our understanding of LDD.

CONCLUSION

LDD is a rare tumor with many uncertainties and mimickers but generally has a good prognosis. One-third of the cases are associated with CS, and a highly specific radiological appearance can sometimes be observed. This systematic review found no apparent differences between adult- and pediatric-onset LDD for their association with CS. However, further prospective evaluations of this association should be conducted to enhance understanding of this disease.

Declaration of patient consent

Patients’ consent not required as patients’ identities were not disclosed or compromised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The author(s) confirms that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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