KISEP J Korean Neurosurg Soc 34 : 375-378, 2003

Case Report Lhermitte-Duclos Disease Associated with Cowden Disease

Eun Seok Choi, M.D., Bong Arm Rhee, M.D., Jun Seok Koh, M.D., Tae Sung Kim, M.D. Department of Neurosurgery, School of Medicine, Kyung-Hee University, Seoul, Korea

Lhermitte-Duclos disease, or dysplastic gangliocytoma of the cerebellum, is a peculiar hamartoma arising from the cerebellar cortex. Cowden disease, which is also termed as a multiple hamartoma-neoplasia syndrome, is an unusual autosomal dominant disorder characterized by mucocutaneous lesions, including facial papules, gingival papillomas, and acral keratoses. Other systemic hamartomas are frequently present, and there are high incidence of breast, thyroid, and genitourinary malignancies. Recently, it is accepted that Lhermitte-Duclos disease is a part of Cowden disease, a new phakomatosis. Recognition of this association has clinical significance, because diligent long-term follow-up monitoring of individuals with Lhermitte-Duclos disease and Cowden disease may lead to the early detection of malignancy.

KEY WORDS : Lhermitte-Duclos disease Cowden disease Phakomatosis.

Introduction Case report

fter first description by Lhermitte and Duclos2) in 32-year-old female patient presented with a history of A 1920, Lhermitte-Duclos disease have been reported A progressive visual loss, intermittent headache, and more than 80 cases9), and in 1994, it was first reported by dizziness for 9 months. Ophthalmological examination Park et al in Korea8). Cowden disease was reported in 1963 revealed marked decreased visual acuity(OD 0.04, OS by Lloyd and Dennis and more than 150 cases were subseq- Finger count 30cm), constricted visual field, and papille- uently reported in the literature4,5). These two disease entities were extremely rare. The association between Lhermitte- Duclos disease and Cowden disease was first recognized by Padberg et al., in 19917). In the review of the literature, Lhermitte-Duclos disease was found to be associated with Cowden disaese in 22 cases9). Recognition of this association supports the conten- tion that these two disorders are parts of a spectrum consti- tuting a single phakomatosis. There are attempts to redefine Lhermitte-Duclos disease and Cowden disease on the mole- cular basis, in addition to the clinical and histopathological features9) Authors report a case of Lhermitte-Duclos disease associated with Cowden disease, a new phakomatosis.

Received：March 13, 2003 Accepted：July 9, 2003 Address for reprints : Bong Arm Rhee, M.D., Department of Neurosurgery, School of Medicine, Kyung-Hee University, Hoegi- Fig. 1. Upper left, macrocephalus (head circumference>95 dong, Dongdaemun-gu, Seoul 130-702, Korea percentile). Upper right, café-au-lait spot on antebrachium. Lower Tel : 02) 958-8389, Fax : 02) 02-958-8380 left, two cold nodules at the midportion of right thyroid lobe and at E-mail : [email protected] lower pole of left lobe on thyoid scan. Lower right, echoless lobulated nodule on left throid gland on ultrasonogram of the thyroid gland.

VOLUME 34 October, 2003 375 Lhermitte - Duclos Disease

A B C D E F

Fig. 2. T1-weighted (A) and gadolinium-enhanced (B) magnetic resonance images show laminated low-signal intensity on right cerebellar hemisphere with minimal enhancement. On T2-weighted image (C), bright signal is noted and folia is widened. Non-enhanced images of the computed tomography(CT) (D, E) show a low density lesion compressing the brain stem and the fourth ventricle, causing a noncommunicating hydrocephalus. Contrast-enhanced image of the CT (F) shows no definite enhancement. dema in both eyes. Physical examination revealed macroc- Table 1. International Cowden consortium diagnostic criteria (6)a rania of more than 95 percentile in head circumference, Diagnosis by mucocutaneous lesions tongue papules(squamous cell papilloma), many cafe-au- Any one of the following : lait spots, and multiple nodules(schwannoma) on the skin. Six or more papules, at least three of which are trichilemmomas Cutaneous facial papules plus oral papillomatosis Multiple thyroid nodules which were revealed by ultrasono- Oral papillomatosis plus acral keratoses gram of the thyroid gland for screening were aspirated and Six or more palmoplantar keratoses these specimen showed no malignant cells (Fig. 1). Pathognomonic mucocutaneous lesions Mammography revealed fibroadenoma which showed Multiple facial trichilemmomas hyperplasia of epithelial cell. Ultrasonogram of the abdomen Acral keratoses showed no specific abnormal finding except hydronephrosis. Papillomatous lesions On her pedigree, skin lesions were presented in father, Oral lesions on the gingival and buccal mucosa and tongue siblings, and her cousins, but there were no family member Diagnosis by indicative (nonmucocutaneous) criteria Any one of the following : who has been diagnosed to have systemic cancer or expired Lhermitte-Duclos disease and thyroid or breast cancer due to this cause. Computed tomographic and MRI scans of Macrocephaly and thyroid or breast cancer the patient revealed noncommunicating hydrocephalus and One major criterion and three minor criteria a large, nonenhancing, right cerebellar mass with an indistinct Four minor criteria border (Fig. 2). The clinical diagnosis of Lhermitte-Duclos Major criteria disease was established by a characteristic imaging findings Breast cancer and that of Cowden disease by the international Cowden Thyroid cancer disease consortium diagnostic criteria(Table 1)6). Macrocephaly Lhermitte-Duclos disease The patient underwent suboccipital craniectomy and Minor criteria subtotal resection of the mass. At the time of surgery, the Thyroid lesions occipital bone was markedly thinned as a result of chronic Mental retardation (intelligence quotient < 75) pressure. The right cerebellar lesion exhibited widened pale GI hamartomas folia. The mass blended into normal cerebellar tissue. The Fibrocystic disease of the breast histological examination revealed a dysplastic cerebellar Lipomas or fibromas gangliocytoma, demonstrating the hyperplasia of the Genitourinary tumors or malformations a granule cell layer due to focal collections of abnormal The diagnosis of Cowden disease is established clinically by the presence of pathognomonic mucocutaneous lesions or by a combination of major dysplastic ganglion cells. Most ganglion cells are enlarged and minor criteria and show plump cytoplasm, large nuclei, and prominent nucleolus (Fig. 3). The frozen and permanent slides were ventriculo-peritoneal shunt. Headache, dizziness, and consulted to 3 neuropathologists (Drs. Suh YL, Kim SP, truncal ataxia were improved, but visual symptom was not and Park SH) and there opinions were all consistent with improved, significantly. On her chromosomal study, normal dysplastic gangliocytoma in frozen slide. Postoperative two female karyotype was reported in blood specimen and weeks later, her brain CT showed continued hydrocephalus abnormality in the number of chromosome in tumor tissue in spite of subtotal mass removal and so she underwent (mosaicism, 45, XX, -10/ 46, XX/ 48, XXXX).

376 J Korean Neurosurg Soc 34 ES Choi, et al.

has not yet been observed. The only effective therapy for symptomatic lesions is surgical excision. With advances in neuroimaging, the prognosis for patients with Lhermitte- Duclos disease has been improved.

Cowden disease Cowden disease, which is also termed the multiple hamar- A B toma-neoplasia syndrome, is an unusual autosomal dominant disorder characterized by mucocutaneous lesions, including Fig. 3. Photomicrograph of a dysplastic cerebellar gangliocytoma, demonstrating the hyperplasia of the granule cell layer due to focal facial papules, gingival papillomas, acral keratoses, and Cafe collections of abnormal dysplastic ganglion cells. Most ganglion cells au lait spots. Other systemic hamartomas are frequently are enlarged and show plump cytoplasm, large nuclei, and present, and there are high incidences of breast, thyroid, and prominent nucleolus. (H & E stain : A, X 100, B, X 400). genitourinary malignancies (Table 1). This disease may occur as an inherited disorder or may occur spontaneously. Discussion The susceptibility gene for Cowden disease was designa- ted PTEN (phosphatase and tensin homologue deleted on Lhermitte-Duclos disease chromosome10) by Li et al. in 19973). PTEN is a powerful Lhermitte-Duclos disease, or dysplastic gangliocytoma of tumor suppressor gene because it affects all three primary the cerebellum, is a peculiar hamartoma arising from the modes of tumor progression, i.e., cell division, survival, and cerebellar cortex. It is considered to be a congenital malfor- migration. PTEN plays a crucial role in the development of mation, hamartoma, or true neoplasm. The clinical presen- multiple hamartomas, as well as benign and malignant tation is typically characterized by progressive headaches, tumors. Cowden disease shares many characteristics with gait disturbances, and cranial nerve dysfunctions in young other autosomal dominant cancer syndromes that are belie- adults, although the age at presentation has ranged from ved to be related to the inactivation of tumor suppressor birth to the sixth decade. There is no sex predilection. gene. Most of these disorders demonstrate neurological, Brain CT feature of Lhermitte-Duclos disease is poorly dermatological, and systemic involvement. They include delineated, nonenhancing hypodense lesion in the cerebe- von Hippel-Lindau disease, neurofibromatosis Types I and llum. MRI scanning is considered the technique of choice, II, tuberous sclerosis complex, and juvenile polyposis producing a low signal intensity in T1-weighted images, a syndrome. high signal intensity in T2-weighted images, and a charac- teristic lamellate presentation compatible with thickened Lhermitte-Duclos disease and Cowden folia. Hydrocephalus is demonstrated frequently. disease Microscopically, the most pronounced feature of Lhermitte- The association between Lhermitte-Duclos disease and Duclos disease is replacement of the granular cell layer by a Cowden disease was first reognized by Padberg et al. in hamatomatous mass of large pleomorphic ganglion cells 19917). In the review of the literature, Robinson et al. without invasive characteristics. Enlarged and irregularly identified a total of 22 previously reported patients with this myelinated axons run from ganglion cells into the widened unusual association9).With the advancement of neuroimag- molecular layer, parallel to the surface. There is often no ing technique, the incidence of the Cowden-Lhermitte- Purkinje cell layer1). Duclos complex became increased, based on the MRI Despite its benign nature, Lhermitte-Duclos disease was findings and diagnostic criteria6) by the international associated with poor prognoses before recent advances in consortium for Cowden disease (Table 1). neuroimaging. One-third of the approximately 80 reported patients with Lhermitte-Duclos disease died due to direct Conclusion mass effect. MRI is very useful tools in making more reliable preoperative diagnosis and deciding appropriate he Cowden-Lhermitte-Duclos complex represents a surgical treatment. Recurrence several years after surgical T true neurocutaneous syndrome, that is, a new phako- treatment have been reported, but malignant transformation matosis. The association between Lhermitte-Duclos disease

VOLUME 34 October, 2003 377 Lhermitte - Duclos Disease and Cowden disease has been under-recognized and under- 3. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al : PTEN, a putative protein tyrosin phosphatase gene mutated in human brain, reported. Recognition of this association has direct clinical breast, and prostate cancer. Science 275 : 1943-1947, 1997 relevance, because diligent long-term follow-up monitoring 4. Lloyd KM, Dennis M : Cowden disease : A possible new symptom of individuals with Lhermitte-Duclos disease and Cowden complex with multiple system involvement. Ann Intern Med 58 : 136-142, 1963 disease may lead to the early detection of malignancy. 5. Longy M, Lacombe D : Cowden disease : Report of a family and a review. Ann Genet 39 : 35-42, 1996 6. Nelen MR, Padberg GW, Peters EAJ, Lin AY, van den Helm B, Frants Acknowledgement RR : Localization of the gene for Cowden disease to chromosome The summary of this paper was presented at the Annual Meeting 10q22-23. Nat Genet 13 : 114-116, 1996 of KNS, autumn 2002. 7. Padberg GW, Schot DL, Vielvoye GJ, Bots GTAM, de Beer FC : Lhermitte-Duclos disease and Cowden disease : A single phakoma- References tosis. Ann Neurol 29 : 517-523, 1991 8. Park JY, Park YK, Chung HS, Chu JW, Lee KC, Lee HK, et al : 1. Ambler M, Pogacar S, Sidman R : Lhermitte-Duclos disease (granule Lhermitte-Duclos disease : A case report with review of the literature. cell hypertrophy of the cerebellum) : Pathological analysis of the first J Korean Neurosurg Soc 23 : 1436-1442, 1994 familial cases. J Neuropathol Exp Neurol 28 : 622-647, 1969 9. Shenandoah R, Alan RC : Cowden disease and Lhermitte-Duclos 2. Lhermitte J, Duclos P : Sur un ganglioneurome diffus du cortex du disease : Characterization of a new phakomatosis. Neurosurgery 46 : cervelet. Bull Assoc Fr Etud Cancer 9 : 99-107, 1920 371-383, 2000

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