Medicina, Vol. 58, Pages 1715: Insights on Lipomatosis after Platinum-Based Chemotherapy Use in Pediatric Oncology: A Case Report

1. IntroductionLipomas are benign, most often encapsulated, noninvasive soft tissue tumors composed of mature adipocytes. They represent about half of all the adipocytic tumors in the pediatric population and, depending on their size and location, and they vary from being asymptomatic to causing various non-specific symptoms. Cytogenetic aberrations can often be described in these tumors, most of them affecting the chromosome 12q. The term “lipomatosis”, on the other hand, describes tumors comprised of matured adipose tissue with an infiltrative growth pattern, ill-defined margins, and a tendency toward symmetry [1,2,3].While the cause of these tumors remains mostly unknown, there are some etiologically and clinically described subtypes of lipomatosis, such as Madelung’s disease associated with alcohol consumption and metabolic problems; lipomatosis dolorosa, potentially associated with improper lymph drainage; or Dercum’s disease and Roch–Leri mesosomatous lipomatosis, which are considered very rare lipomatoses of unknown etiology [4,5]. There have been cases reported where it seems that the medical intervention, whether through the administered medication or surgery, might have either caused or exacerbated the growth of lipomatous tumors [6,7,8]. Among the incriminated drugs lies cisplatin, a platinum-based compound with a cytotoxic effect used in the treatment of various cancers [9,10,11,12]. Due to its side effects and drug resistance, cisplatin is currently used in combination with other antineoplastic agents. Through oxidative stress, high doses of this drug can induce nephrotoxicity and hepatotoxicity, demonstrated by elevated creatinine levels, hepatic enzyme levels, and bilirubin levels. Necrosis and inflammatory cell infiltration of the portal area are some of the histopathological changes observed in patients treated with cisplatin [13]. Other platinum-based agents have been demonstrated to induce hepatosteatosis, a condition that has been linked to the growth of lipomas [14,15].

In this case report, we present a very rare case of a 16-year-old girl diagnosed with a giant ovarian GCT of mixed histology with extension into the abdominal cavity and asymptomatic amputation of the contra-lateral ovary, who developed lipomatosis after chemotherapy with cisplatin. A thorough literature search was also performed to find similar cases, since this rare occurrence of peritoneal and liver lipomas as a possible and specific side effect of platinum-based chemotherapy is scarcely described in pediatric patients.

2. Case PresentationA 16-year-old Caucasian girl was admitted to our hospital, presenting with abdominal pain and abdominal distension, fever, and a dry cough. Upon clinical examination, the patient was found moderately pale and febrile, with a body mass index (BMI) of 28.6 kg/m2, being in the 95th percentile for girls her age, corresponding to class I obesity. The abdomen was distended and moderately painful upon palpation, the puddle sign was present, and percussion notes varied between tympanic and dull, raising suspicion of ascites. Lab values were significantly modified, suggesting a severe inflammatory process, as described in Table 1.

It was observed that CRP levels were 3215 mg/l, ferritin 1118 ng/mL, fibrinogen 629 mg/dL, and ESR was 92 mm/h, all of which ranged much higher than the normal threshold. Besides the severe inflammatory status of the patient, the girl was also suffering from anemia, with a red blood cell count (RBC) measured at 4.0 million, and a hemoglobin level of 10.5 g/dL. Apart from class I obesity, the adolescent patient had an elevated serum glucose (109 mg/dL), correlating with a metabolic syndrome. The serum lipid levels were also above the normal range for adolescents, although without a significant increase (total cholesterol = 183 mg/dL, triglycerides = 155 mg/dL). The patient did not have any documented endocrinological problems.

A chest X-ray found bilateral interstitial reticular coarseness and opacification of the right costophrenic angle, suggestive of pleural effusion. The patient was further investigated in our ultrasound department; the abdominal sonogram raised suspicion of an abdominal–pelvic tumor mass with mild ascites in the abdominal cavity, particularly pronounced in the perihepatic and peri-splenic spaces.

Surgery was considered and computer tomography (CT) was performed on the same day to better assess the extension of the tumor mass. The CT examination of the abdominal and pelvic cavities found a gigantic heterogeneous mass of 18/13/9 cm (Figure 1). The tumor did not invade the abdominal organs or retroperitoneal vascular structures, but manifested a compressive effect on the intestinal loops and urinary bladder. While the right ovary could not be visualized, a calcified mass of 26/14/12 mm was identified within the right anterolateral side of the recto-uterine pouch.

The major findings could be summarized as massive mixed solid-cystic tumors occupying the abdominal and pelvic cavities of suspected ovarian origin, abdominopelvic ascites, minimal right pleural effusion, and para-aortic lymphadenopathy. The patient underwent surgery on the third day of hospitalization. A midline laparotomy found peritoneal fluid that was drained and sampled for cytology and a massive septated cystic tumor occupying the abdominal and pelvic cavity with left ovarian origin. A surgical biopsy was performed along with ablation of the ovarian tumor and epiploectomy. Upon further inspection of the pelvic cavity, a calcified amputated right ovary of approximately 3cm in diameter was found, most likely a sequela of compression due to the massive volume of 1101.43mm3 from the tumor originating in the contralateral ovary. The patient was transferred to our intensive care unit for post-surgery monitoring awaiting the pathology and cytology results.

The cytologic examination of the peritoneal fluid identified hemorrhagic fluid with high heterogeneous cellularity of 75% neutrophils, 15% monocytes, 10% lymphocytes, reactive mesothelial cells, and several old mesothelial cells with “signet ring cell” phenotype, raising suspicion of peritoneal dissemination. Pathology findings revealed on macroscopic examination the tumor appeared as a round, encapsulated multi-cystic mass of 18.5/13.8/9.5 cm, with grey to light pink solid/gelatinous components. Immunohistochemistry (IHC) analysis found a glial fibrillary acidic protein (GFAP), alpha-fetoprotein, CD10, macro creatine kinase (MCK), and vimentin, all intensely positive, beta-HCG-negative, and KI-67-positive in 10% of solid tumor areas [16,17,18].The pathology findings identified the tumor as a mixed germ cell tumor with three components, as observed in Figure 2: mature teratoma (25%), immature teratoma, high-grade G3 (60%), and yolk sack tumor (15%). The tumor was graded at stage IV (pT1cNxM1) due to evidence of metastasis, according to the TNM staging system [19], where “p” and “c” stand for staging based on the histopathological assessment of a surgical specimen and evidence acquired by clinical and paraclinical procedures, respectively.A second pathology examination was requested, and the result indicated a high-grade immature teratoma. The final diagnosis was set after careful consideration of clinical, paraclinical, histopathological, and IHC data. The tumor was labeled stage IIIC according to the FIGO staging system that identified peritoneal metastasis [20], and a high-grade/G3 immature teratoma of the ovary [1].

Therapy and follow-up: the patient underwent chemotherapy treatment (MAKEI 2005 protocol) with four PEI cycles (cisplatin, etoposide, and ifosfamide). The chemotherapy was well tolerated with no significant events, and complete tumor remission was accomplished after the completion of the four PEI cycles. Shortly after completing the last cycle of chemotherapy, a routine MRI showed elements previously absent four months prior: a small oval peripheral intrahepatic mass of ~0.8 cm under the Glisson capsule and several smaller cysts in the perihepatic space. A PET scan was further performed and found no signs of malignancy but identified the liver mass as a possible lipoma. The tumor markers AFP and beta-HCG were within normal values; thus, a “watch and wait” approach was decided upon.

The routine check-ups involving physical examination, lab values, tumor markers, and imaging studies showed no signs of relapse or significant changes in the patient’s health, apart from mild hepatic steatosis and significant weight gain (IMC = 35.4 kg/m2), advancing the previously diagnosed obesity to class II. No endocrine causes for the patient’s weight gain were found. The iatrogenic menopause following bilateral adnexectomy was well controlled by hormone substitution therapy, therefore the weight gain was attributed to genetics, an admittedly unbalanced diet, and a sedentary lifestyle.

In the 18th month since the end of chemotherapy, a routine MRI found that the perihepatic masses had increased in number and dimension. The investigation found intrahepatic, perihepatic, and subdiaphragmatic fat-containing lesions of a maximum of 2/1.5 cm (Figure 3C,D), a smaller mass of approximately 1.1/0.6 cm in the hepatorenal recess, and another of 0.4 cm in the gastrosplenic recess. Tumor markers AFP, b-HCG, and CA-125 were normal; therefore, the rare growing teratoma syndrome (GTS) was feared as a severe outcome [21,22]. Five tumor masses were removed by exploratory laparotomy two weeks later, and the pathology exam found all the lesions to be lipomas.

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