Malignant Peritoneal Mesothelioma in a 16-Year-Old Girl ...

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170 Case Report

Malignant Peritoneal Mesothelioma in a 16-Year-Old Girl: Presentation of a Rare Disease Malignes peritoneales Mesotheliom bei einem 16-jährigen Mädchen: Manifestation einer seltenen Erkrankung

Authors

I. B. Brecht1, A. Agaimy2, M. Besendörfer3, R. Carbon3, F. C. Thiel4, O. Rompel5, D. Osinski1, T. Langer1, M. Metzler1, W. Holter1

Affiliations

Affiliation addresses are listed at the end of the article

Key words

▶ malignant peritoneal ● ▶ ● ▶ ● ▶ ●

mesothelioma rare tumors pediatric ovarian carcinoma

Schlüsselwörter ▶ malignes peritoneales ● Mesotheliom ▶ seltene Tumoren ● ▶ pädiatrisch ● ▶ Ovarialkarzinom ●

Bibliography DOI http://dx.doi.org/ 10.1055/s-0032-1308987 Published online: April 18, 2012 Klin Padiatr 2012; 224: 170–173 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Dr. Ines B. Brecht Pediatric Hematology and Oncology University Hospital Erlangen Loschgestraße 15 91054 Erlangen Germany Tel.: +49/9131/853 3118 Fax: +49/9131/853 6286 [email protected]

Abstract

Zusammenfassung

Background: Malignant peritoneal mesothelioma is extremely rarely seen in young patients. Patient: A 16 year-old girl presented with appendicitis-like acute abdominal pain. Intra-operatively, multiple confluent peritoneal nodules were seen on the entire greater omentum and in the pelvis infiltrating the uterus and both ovaries. Biopsies were obtained and interpreted as serous ovarian carcinoma. Radical surgical resection and hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin was performed and followed by 2 cycles of carboplatin/paclitaxel. Histological reevaluation showed characteristic features of epithelioid peritoneal mesothelioma and ruled out serous ovarian cancer. Therapy was continued with 6 cycles of pemetrexed/cisplatin. Results: 3 months after end of chemotherapy vital tumor tissue was found in the recess behind the liver, which could be resected completely. The patient is currently disease-free 17 months after initial diagnosis. Conclusion: Malignant peritoneal mesothelioma in young female patients might be underrecognized and possibly misdiagnosed as ovarian serous carcinoma in some cases. International and interdisciplinary cooperation is necessary in order to provide evidence based guidelines for diagnosis and treatment in the future.

Hintergrund: Das maligne peritoneale Mesotheliom wird bei jungen Patienten extrem selten beobachtet. Patient: Ein 16-jähriges Mädchen präsentierte sich mit appendizitisartigem akutem Bauchschmerz. Intraoperativ fanden sich konfluierende Tumormassen im gesamten Omentum und im Beckenperitoneum mit Infiltration beider Ovarien und des Uterus. Biopsien wurden durchgeführt und diese als seröses Ovarialkarzinom interpretiert. Es wurde eine radikale chirurgische Resektion mit anschließender hyperthermer intraperitonealer Chemoperfusion (HIPEC) mit Carboplatin durchgeführt, gefolgt von 2 Blöcken Carboplatin/Paclitaxel. Eine histopathologische Reevaluation zeigte den charakteristischen Befund eines epitheloiden malignen peritonealen Mesothelioms. Ein seröses Ovarialkarzinom konnte ausgeschlossen werden. Die Therapie wurde fortgeführt mit 6 Zyklen Pemetrexed/Cisplatin. Ergebnisse: 3 Monate nach Ende der Chemotherapie wurde vitales Tumorgewebe im Recessus hinter der Leber gefunden, welches komplett reseziert werden konnte. Die Patientin lebt derzeit rezidivfrei (17 Monate nach Primärdiagnose). Schlussfolgerung: Das maligne peritoneale Mesotheliom ist bei jungen Patientinnen möglicherweise unterdiagnostiziert, einige Fälle könnten als seröse Karzinome fehlinterpretiert werden. Internationale und interdisziplinäre Kooperation ist notwendig, um in Zukunft evidenzbasierte Leitlinien für Diagnose und Behandlung erstellen zu können.

Introduction

are published in the literature; the incidence is estimated to be 0.5–1.0 cases/10 million/year [6]. The female: male ratio is 2:1. The median age at diagnosis is 11.9 years, the youngest known girl with peritoneal mesothelioma was diagnosed at





Malignant peritoneal mesothelioma is a rare aggressive tumor of adulthood, which is extremely uncommon in children. Only few pediatric cases

Brecht IB et al. Malignant Peritoneal Mesothelioma in … Klin Padiatr 2012; 224: 170–173



Case Report 171

the age of 6 weeks [6]. Malignant mesothelioma originates from the surface of the pleural and peritoneal cavities, less often also from the tunica vaginalis testis or the pericardium. Although a strong link with prior exposure to asbestosis is well known in adult malignant mesothelioma, an association of pediatric malignant mesothelioma with asbestos exposure is not confirmed. The histopathological diagnosis is known to be difficult and primary misdiagnoses are often seen [10]. The decision for the optimal treatment for individual patients remains a great challenge for pediatric oncologists because of the lack of clinical experience and scientific knowledge on this exceedingly rare subset of mesothelioma. The current report aims at demonstrating the difficulties related to histological diagnosis and treatment of the orphan disease in the pediatric population.

Case presentation



Presenting symptoms A 16-year-old girl primarily presented with acute right lower abdominal pain since the previous day which was initially interpreted as premenstrual discomfort. Clinical examination showed spontaneous pain in the right lower quadrant while standing and walking, as well as pronounced tenderness of the abdominal wall to pressure and percussion. The psoas sign was positive. The girl was otherwise in good condition and did not show any B symptoms like night sweats, weight loss or fever.

Diagnosis and course of treatment Under the suspected diagnosis of acute appendicitis a laparoscopy and subsequent laparotomy was performed. Intraoperatively, multiple diffuse confluent peritoneal nodules were seen on the entire greater omentum and on both ovaries. While no dominant tumor mass could be identified, the right iliac fossa ▶ Fig. 1). Cysts, which seemed to be predominantly involved (● were contorted, hemorrhagic and partially ruptured, were documented. Tumor markers were evaluated: CEA, CA19-9 and alpha-fetoprotein were in normal range; CA-125 was elevated with 115 U/ml ( < 35 U/ml). Pathological evaluation of the tissue by the local pathologist and a by another pathologist (second opinion) rendered a diagnosis of a moderately to poorly differentiated serous adenocarcinoma arising from the ovaries.

Fig. 1 Intra-operative laparoscopy demonstrates coalescent nodules involving the whole greater omentum and both ovaries.

The patient was then transferred to our center for staging and planning of further treatment. A CT-Scan showed solid and cystic tumorous masses within the abdomen, mainly occupying the pelvic cavity and right abdomen and infiltrating the ovaries ▶ Fig. 2, 3). Despite the wide-spread disease in the abdominal (● cavity, no further organ metastases were found. Radical tumor excision was performed by an interdisciplinary team of gynecologists and pediatric surgeons and included salpingooophorectomy and hysterectomy, omentectomy, partial peritonectomy and pelvic, iliac and paraaortic lymphadenectomy. Macroscopically, the tumor mass could be removed completely (grossly R0). Histopathological evaluation of the resected specimens showed that the tumor had infiltrated extensively the superficial peritoneum of the pelvic cavity, the greater omentum, the serosal tissue of the uterus and the appendix and both ovaries corresponding to a stage pT3c according to the AJCC/TNM system for ovarian cancer. 10 of 53 para-aortal and pelvic lymph nodes showed metastatic deposits. Cryopreservation of ovarian tissue was performed [8]. Hyperthermic intraperitoneal chemotherapy (HIPEC) (104 mg Cisplatin, heated to 41 °C) was applied intraoperatively for 60 min. The patient was planned to receive adjuvant chemotherapy with 6 cycles of carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 21 days. First cycles of this chemotherapy were well tolerated. Positron emission tomography [F18]fluordesoxyglucose (FGD) and computed tomography (PET/ CT) was performed after 2 cycles of chemotherapy (approx. 2 months after diagnosis) and showed positive areas in the ventro-basal thorax consistent with thymus tissue and a small area in the upper right quadrant of the abdomen – at this time interpreted as nonspecific tracer uptake most likely due to tissue repair following extended surgery.

Revision of diagnosis Because of the unusual presentation of the tumor at an unusually young age, the slides of the resection specimens and of the previous excisional biopsy were reevaluated after interdisciplinary tumor board discussions. In the course of this pathological re-evaluation the tumor was described as a malignant neoplasm with predominant tubulopapillary growth pattern occasionally blending with solid tumor areas with striking superficial resemblance to serous papillary carcinomas. Close assessment revealed the tumor cells to be low columnar or polygonal in shape

Fig. 2 The coronal CT-scan shows solid tumorous masses a with small cystic components b and few ascitic fluid occupying the pelvic cavity around the uterus c.

Brecht IB et al. Malignant Peritoneal Mesothelioma in … Klin Padiatr 2012; 224: 170–173

172 Case Report

Fig. 3 The axial CT-scan shows tumorous masses occupying the right lateral paracolic gutter a. Minimal ascitic fluid and some prominent mesenteric lymph nodes b are seen.

othelial line of differentiation and excluded a serous carcinoma (positivity for vimentin, pankeratin, cytokeratin 5 and 7, CA12.5, calretinin, D2-40, HBME-1 and WT1 and negativity for BerEP4, CEA and sex steroid hormone receptors). Finally, a revised diagnosis of a primary peritoneal mesothelioma of the epithelial type ▶ Fig. 4, 5) was made and also confirmed by central referral (● pathology evaluation. Accordingly, the therapy was changed to 6 additional cycles of Pemetrexed 500 mg/m² i. v. over 15 min plus Cisplatin 75 mg/m² i. v. over 2 h plus folic acid and cyanocobalamin (vitamin B12) substitution every 21 days as first line treatment according to the DGHO (German Society for Hematology and Oncology) guidelines for mesothelioma 07/2005 [7]. The therapy was well tolerated and was finished approx. 6 months after diagnosis. At the end of therapy Positron emission tomography [F-18]fluordesoxyglucose (FDG) and computed tomography (PET/CT) showed again the previously described FDG-positive lesion in the recess between liver and right kidney, however with less activity compared to the previous images. Despite these results, a CT-guided biopsy was performed to exclude residual mesothelioma. The biopsy showed no evidence of mesothelioma.

Follow-up

Fig. 4 Histological sections indicating characteristic tubulopapillary structures within the ovary adjacent to a follicle cyst (lower left). This finding closely mimics serous ovarian cancer.

The patient received close follow-up. 3 months after the end of therapy, imaging revealed the persistence of the known FDGpositive area in the recess between liver and kidney with this time enhanced glucose metabolism. CT-guided biopsy was performed and histologic evaluation showed vital mesothelioma tissue. The tumor measured 0.6 cm and could be removed completely; R0-status was confirmed by pathology. At present, 17 months after diagnosis, the patient is still in complete remission. Unfortunately, the performed intensive therapy left the patient with infertility due to hysterectomy and a hypergonadotropic hypogonadism after removal of both ovaries requiring hormone replacement therapy with estrogen.

Discussion



Fig. 5 Characteristic luminal reactivity for the mesothelial marker HBME-1.

with relatively bland looking nuclei and pale staining cytoplasm that showed peripheral condensation reminiscent of reactive mesothelial cells. Most importantly, the similarity of the neoplasm to epithelioid pleural mesothelioma prompted further immunohistochemical examination, which confirmed the mes-

Clinicians being confronted with the extremely rare diagnosis of pediatric mesothelioma have to deal with several problems, which are diagnostic difficulties, extended disease at the time of diagnosis, lack of clinical guidelines for treatment and a generally poor prognosis. The presented case illustrates several specific aspects of pediatric mesothelioma and general problems occurring in cases of rare pediatric tumors [4]. Peritoneal mesothelioma typically presents as advanced disease and lack of symptoms is the cause of delayed detection. With advanced disease, patients show unspecific symptoms such as weight loss, abdominal distension and ascites [10]. Our patient presented with extended disease within the peritoneal cavity, although the history of symptoms was very short. In CT images, peritoneal mesotheliomas are described to either have a “dry” appearance, consisting of peritoneum-based masses, or a “wet” appearance, consisting of irregular or nodular peritoneal thickening and one or several omental masses accompanied by as▶ Fig. 2 and , 3) illustrate cites [9]. The CT images of our patient (● the bulky tumour type, which is less often seen in children. For this type, the tumor mass is frequently more pronounced in the pelvic peritoneum while invading the ovaries, which can result in misinterpretation as advanced ovarian cancer.

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The pathological diagnosis of mesothelioma is difficult. Cases should be evaluated by a panel of pathologists including one with experience in adult mesothelioma. Histologically, epitheloid (56 %), sarcomatoid (32 %) and biphasic (13 %) subtypes of mesothelioma can be differentiated. The majority of pediatric peritoneal mesotheliomas are of the epitheloid type as it was the case in our patient [6]. Sheets of medium-sized or large epitheloid cells with well-developed tubulo-papillary structures are typically seen. The cells show a moderate amount of pale-eosinophilic, frequently vacuolated cytoplasm, round nuclei and inconspicuous nucleoli with rare mitotic figures [2]. These morphologic aspects might lead to misdiagnosis as serous carcinoma ▶ Fig. 4). Whereas the expression of WT-1, CK7 of the ovaries (● and CA-125 is seen in both, mesothelioma and serous carcinoma, peritoneal mesothelioma typically co-expresses vimentin, calretinin, podoplanin (D2-40), mesothelin (HMBE-1) and vari▶ Fig. 5 illustrates staining for mesothelin in ably cytokeratin 5 (● our case). In contrast, PAX8 is expressed in serous carcinomas but not in mesothelioma. Limited familiarity with the morphological spectrum of adulthood peritoneal and pleural mesothelioma can lead to misdiagnosis of peritoneal mesothelioma, particularly in women, as advanced serous ovarian cancer or as primary serous carcinoma of the peritoneum. However, if one is aware of the typical features of adulthood mesothelioma, peritoneal mesothelioma can be recognized more consistently. Because of the disease rarity, no evidence-based standard treatment strategy is available for adults and children with peritoneal mesothelioma. The tumor shows a rapid fatal course in adults (median survival 6–12 months), while recent data suggest a more favorable prognosis for children, if a multimodal therapy approach is applied [5]. In a small French series of pediatric mesothelioma all 8 patients with peritoneal mesothelioma were alive with a mean follow up of 61 months [3]. As demonstrated by our case, durable complete remission is difficult to reach by surgery alone because of the extensive tumor spread within the peritoneal cavity at the time of diagnosis in most cases [13]. Intraoperatively, hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported to show benefit in children. After surgery, adjuvant chemotherapy should be applied. A first line regime for mesothelioma in adults comprises a combination of pemetrexed and cisplatin or pemetrexed and gemcitabine [7, 12] and seems to be well tolerated also in children [3, 9]. This intensive regime in combination with radical resection let to complete remission in our patient. It is difficult to judge the role of chemotherapy, but, interestingly, 3 months after end of treatment vital tumor tissue was found in the recess behind the liver. Though, this area had been FDG positive in PET imaging during the treatment, enhanced glucose metabolism was only seen at the time of relapse. FDG PET is known to be a sensitive diagnostic method for staging of mesothelioma in adults and a high uptake is correlated with an unfavorable prognosis [1]. Final prognosis is difficult to predict for our patient as reliable survival data for pediatric patients do not exist. Anyway, in a small French series of 8 cases of pediatric peritoneal mesothelioma all patients are reported to be alive with a mean follow-up of 61 months. These patients received multimodal therapy and often several sets of chemotherapy regimes [2, 5]. According to the DGHO guidelines for adults [7] , unfavorable prognostic factors include age > 65, no tumor excision, invasion of the tissue > 0.5 mm, residual macroscopic disease > 1.0 cm, and sarcomatoid histological type. Though these prognostic factors are not confirmed for pediatric cases, it is noteworthy that none of

these factors were present in our case. Interestingly, better survival rates were also seen in a case of epitheloid type of mesothelioma, which correlated with a better response to chemotherapy [3]. The few pediatric cases of peritoneal mesothelioma described in the literature show differences in etiology, clinical presentation, histopathology, response to treatment and outcome compared to adult cases. Therefore, experience gained in adulthood cannot simply be transferred to pediatric cases. Worldwide interdisciplinary collaboration and networking is necessary in order to be able to study mesothelioma in children [11]. With the help of clinicians reporting cases to the existing national rare pediatric tumor groups we hope to be able to provide evidence based guidelines for diagnosis and treatment in future.

Conflict of Interest: The authors have no conflict of interest to disclose. Affiliations 1 Pediatric Hematology and Oncology, University Hospital Erlangen, Germany 2 Institute of Pathology, University Hospital Erlangen, Germany 3 Pediatric Surgery, University Hospital Erlangen, Germany 4 Obstetrics and Gynecology, University Hospital Erlangen, Germany 5 Pediatric Radiology, University Hospital Erlangen, Germany

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Brecht IB et al. Malignant Peritoneal Mesothelioma in … Klin Padiatr 2012; 224: 170–173