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Gallbladder cancer with ascites in a child with metachromatic leukodystrophy

      Abstract

      Introduction

      Metachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder.
      Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer.

      Case report

      The patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range.

      Discussion

      Rapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.

      Keywords

      1. Introduction

      Metachromatic leukodystrophy (MLD) (OMIM number #250100) is an autosomal recessive lysosomal storage disease with an estimated incidence of 1.4–1.8/100,000 live births [
      • Rosenberg J.B.
      • Kaminsky S.M.
      • Aubourg P.
      • Crystal R.G.
      • Sondhi D.
      Gene therapy for metachromatic leukodystrophy.
      ]. This disease is caused by a deficiency of arylsulfatase A (ARSA), resulting in accumulation of sulfatides (3-O-sulfogalactose-containing glycolipids) including galactosyl sulfatide (SM4) and lactosyl sulfatide (SM3) [
      • Sugita M.
      • Dulaney J.T.
      • Moser H.W.
      Structure and composition of sulfatides isolated from livers of patients with metachromatic leukodystrophy: galactosyl sulfatide and lactosyl sulfatide.
      ]. ARSA is the lysosomal sulfatase essential for sulfatide degradation. Sulfatide accumulation in the nervous system, mainly in the white matter, causes progressive neurological regression. MLD is classified into late-infantile, juvenile, and adult types based on the age of onset [
      • Rosenberg J.B.
      • Kaminsky S.M.
      • Aubourg P.
      • Crystal R.G.
      • Sondhi D.
      Gene therapy for metachromatic leukodystrophy.
      ]. In the late-infantile type, rapidly progressive psychomotor regression usually starts in the second year of life, with death occurring within 5 years [
      • Mahmood A.
      • Berry J.
      • Wenger D.A.
      • Escolar M.
      • Sobeih M.
      • Raymond G.
      • et al.
      Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature.
      ].
      In addition, sulfatides accumulate in other organs such as the peripheral nerves and kidney [
      • Schott I.
      • Hartmann D.
      • Gieselmann V.
      • Lullmann-Rauch R.
      Sulfatide storage in visceral organs of arylsulfatase A-deficient mice.
      ]. Gallbladder involvement is seen most commonly in MLD patients, such as polypoid lesions of gallbladder (PLG), even including gallbladder cancer [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ,
      • Simanovsky N.
      • Ackerman Z.
      • Kiderman A.
      • Fields S.
      Unusual gallbladder findings in two brothers with metachromatic leukodystrophy.
      ]. Accumulation of sulfatides in the gallbladder is considered to induce a proliferative and metaplastic response in the gallbladder epithelium [
      • Schott I.
      • Hartmann D.
      • Gieselmann V.
      • Lullmann-Rauch R.
      Sulfatide storage in visceral organs of arylsulfatase A-deficient mice.
      ]. Although PLG in MLD is prevalent in both adults and children, no pediatric cases of gallbladder cancer have previously been reported [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ,
      • Simanovsky N.
      • Ackerman Z.
      • Kiderman A.
      • Fields S.
      Unusual gallbladder findings in two brothers with metachromatic leukodystrophy.
      ]. Herein, we report what is to the best of our knowledge the first pediatric case of MLD presenting marked ascites and gallbladder cancer.

      2. Case report

      The patient was a 5-year-old girl born of nonconsanguineous parents. Her growth and development were normal until 1 year 6 months (1Y6M). After that, she gradually deteriorated and had difficulty in walking at 2Y0M, in sitting and speech at 2Y2M, and was admitted to our hospital at 2Y3M. Brain magnetic resonance imaging (MRI) demonstrated diffuse high intensity areas on T2-weighted image in deep white matter, with the horizontal stripes sign, which is termed the “tiger stripe sign” (Fig. 1). ARSA activity from white blood cells was low with 23.9 nmol/mg/h (range: 109–217 nmol/mg/h). After obtaining informed consent from the patient’s parents, we analyzed the ARSA gene for mutation using Sanger sequencing and found a known homozygous mutation of c.302G>A (p.Gly101Asp). Based on these results, the patient was diagnosed with MLD. At 2Y6M, the time of diagnosis, she was already bedridden and needed tube feeding. Therefore, we did not choose hematopoietic stem cell transplantation. Home oxygen was introduced at 3Y6M and a gastrostomy and a tracheotomy were performed at 3Y10M and 5Y8M, respectively. Abdominal bloating had gradually worsened from 4Y10M; however, an abdominal X-ray performed at 5Y3M did not reveal a distribution of abnormal gas pattern. Clinical findings such as fever and jaundice were not present. At 5Y4M, the patient was hospitalized with aspiration pneumonia and severe abdominal bloating (Fig. 2A).
      Figure thumbnail gr1
      Fig. 1T2-weighted brain MRI at 2 years and 3 months of age showed diffuse high signal intensity and tiger stripes sign in white matter.
      Figure thumbnail gr2
      Fig. 2A. Progressive abdominal swelling at 5 years and 4 months of age. B. Abdominal echo showed large tumor (arrows) and massive ascites. C. Gross appearance of the excised gallbladder revealed a papillary tumor. D, E. High-degree dysplasia in the cylindrical epithelial cells with papillary extension (arrows) was found on the mucosal surface of the gallbladder.
      Abdominal ultrasound and CT revealed a giant tumor in the gallbladder (9 × 5 × 5 cm) and massive ascites (Fig. 2B). Laboratory data showed mild liver dysfunction without hyperbilirubinemia (T-Bil: 0.26 mg/dL, AST: 52 U/L, ALT: 67 U/L, LDH: 319 U/L, ALP: 630 U/L). Notably, the value of CA 19–9 was 1363 U/mL in the blood test (healthy reference range: 0–37 U/mL). We removed the gallbladder along with the tumor. The gross appearance of the excised gallbladder revealed a papillary tumor with mucus production (Fig. 2C). Pathological examination showed high-degree dysplasia in the cylindrical epithelial cells with papillary extension; serosal invasion was found on the mucosal surface of the gallbladder (Fig. 2D-E) and she was diagnosed with adenocarcinoma in the gallbladder. There was no surgical or pathological evidence of inflammatory cells or wall thickening in the gallbladder suggestive of cholecystitis. Ascites was also evaluated but malignant cells were not detected. Ascites fluid analysis revealed turbid appearance, neutrophil 3.1/mm3 (1.5%), lymphocytes 29.4/mm3 (14%), macrophages 169/mm3 (80.5%): protein content 4.2 g/dl (range: 2.5–4 g/dL), and LDH 178 U/L (reference: <200 U/L). The serum ascites albumin gradient was 0.7 g/L, which means ascites was not associated with elevated portal pressure. In addition, we measured the serum sulfatide concentration according to the published method [
      • Li G.
      • Hu R.
      • Kamijo Y.
      • Nakajima T.
      • Aoyama T.
      • Inoue T.
      • et al.
      Establishment of a quantitative, qualitative, and high-throughput analysis of sulfatides from small amounts of sera by matrix-assisted laser desorption ionization-time of flight mass spectrometry.
      ], after obtaining informed consent. Two types of sulfatide, SM4 and SM3 were detected as major molecular species. Serum sulfatide concentrations from the patient were elevated (SM4/SM3; 19.0/5.2 µM) compared to those in the normal control (SM4/SM3; 7.5/0.7 µM). We used commercially-available pooled normal human serum (Ronza 14-490E and Cosmobio 12181201; data were averaged) as normal control. Four months after the operation, the CA19-9 level was decreased to 23 U/mL and there was no metastasis or recurrence at 1 year and 10 months following surgery.

      3. Discussion

      We report the case of a 5-year-old patient with MLD accompanied by gallbladder cancer. PLG is common in MLD, and 76% of MLD patients reportedly developed PLG [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ]. However, there are only two case reports of MLD with gallbladder cancer and they were both adults: 18- and 29-year-old males [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ,
      • Simanovsky N.
      • Ackerman Z.
      • Kiderman A.
      • Fields S.
      Unusual gallbladder findings in two brothers with metachromatic leukodystrophy.
      ]. One 18-year-old male patient was diagnosed with juvenile type MLD. He was admitted to the hospital because of continuous vomiting, and multiple PLGs (8 cm diameter) were observed on abdominal US. One year later, gallbladder adenocarcinoma with ascites and liver metastases were found; the disease progressed rapidly and was ultimately fatal [
      • Simanovsky N.
      • Ackerman Z.
      • Kiderman A.
      • Fields S.
      Unusual gallbladder findings in two brothers with metachromatic leukodystrophy.
      ]. Another patient was diagnosed with adult MLD at 20 years old and received a hematopoietic stem cell transplant. At age 32, he presented with acute abdominal pain of abdomen; abdominal US revealed dilation of the intrahepatic and extrahepatic bile ducts. A cholecystectomy was performed and the patient was diagnosed with gallbladder adenocarcinoma. Eventually, ascites and liver metastases were found, and the patient died seven months after the initial cancer diagnosis [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ].
      Clinically, large (>5 cm) neoplastic lesions in the gallbladder and rapidly worsening ascites were characteristic of this MLD case. In primary PLG, the presence of polyps larger than 5 mm is a risk factor for gallbladder cancer [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ]. In addition, cases of MLD with gallbladder cancer were reported to have ascites, similar to our case [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ,
      • Simanovsky N.
      • Ackerman Z.
      • Kiderman A.
      • Fields S.
      Unusual gallbladder findings in two brothers with metachromatic leukodystrophy.
      ]. These reports, including ours, suggest that large gallbladder tumors and ascites in MLD patients are risk factors for cancer, even in pediatric patients. If a large PLG with concomitant ascites is present, it should be removed immediately due to the associated oncological risk.
      Biochemically, increased serum sulfatide concentration was detected. Sulfatide has been hypothesized to be associated with gallbladder lesions in MLD [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ]. ARSA-deficient mice showed sulfatide storage in organs, especially in the gallbladder [
      • Schott I.
      • Hartmann D.
      • Gieselmann V.
      • Lullmann-Rauch R.
      Sulfatide storage in visceral organs of arylsulfatase A-deficient mice.
      ]. It has been reported that sulfatide synthase (i.e., cerebroside sulfotransferase), which catalyzes the key step of sulfatide biosynthesis (i.e., sulfation of glycolipid galactose residue), is expressed in the gallbladder epithelia [

      The Human Protein Atlas [Internet]. GAL3ST1. [cited 2020 Mar 11]. Available from: https://www.proteinatlas.org/ENSG00000128242-GAL3ST1.

      ]. Sulfatide, excreted in the bile, is postulated to induce proliferative and metaplastic response within the gallbladder [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ,
      • McFadden K.
      • Ranganathan S.
      Pathology of the gallbladder in a child with metachromatic leukodystrophy.
      ].
      In our case, we detected two types of sulfatide in the serum: SM4 and SM3. It has been already reported that serum SM4 levels increase in MLD cases [
      • Spacil Z.
      • Babu Kumar A.
      • Liao H.C.
      • Auray-Blais C.
      • Stark S.
      • Suhr T.R.
      • et al.
      Sulfatide analysis by mass spectrometry for screening of metachromatic leukodystrophy in dried blood and urine samples.
      ], but SM3 has not been measured previously. We found that serum SM3 levels were high in patients with MLD, similar to the increase in SM4 levels. The pathogenicity of SM3 to PLG needs further study. The gene mutation in this case was not associated with PLG or gallbladder cancer since c.302G>A (p.Gly101Asp) has already been reported as a common genotype of MLD in Japan [
      • Kurosawa K.
      • Ida H.
      • Eto Y.
      Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy: identification of two novel mutations.
      ]. In addition, genetic variants in MLD cases with gallbladder disease have been detected but showed no association with PLG [
      • van Rappard D.F.
      • Bugiani M.
      • Boelens J.J.
      • van der Steeg A.F.
      • Daams F.
      • de Meij T.G.
      • et al.
      Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.
      ]. Therefore, it remains unclear why our patient developed gallbladder cancer in childhood.
      In conclusion, we report the first known pediatric MLD case with gallbladder cancer. In MLD, continuous attention to PLG is needed. Future elucidation of the role of sulfatide in PLG in MLD is required.

      4. Disclosure

      The authors declare no conflicts of interest associated with this manuscript.

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