Cancer Science 2020: Small Round Blue Cell Tumors, management dilemma: A case report on Alveolar Rhabdomyosarcoma in a four year old child - Abeera Mehmood - Yusra Institute of Pharmaceutical Science

Rhabdomyosarcoma is one of the small round blue cell tumors, and though rare, it is the most common soft tissue sarcoma in children. Similar microscopic appearance and similar histochemistry makes differentiation and diagnosis very difficult in these lesions. Here we report a case of a 4 year old boy, who presented with an abdominal mass. Initial investigations confirmed presence of heterogeneously enhancing pelvic mass with no metastasis or local extension. It was confirmed to be rhabdomyosarcoma on ultrasound guided biopsies, though further differentiation was not possible. Patient responded well to initial treatment in the form neo adjuvant chemotherapy with significant reduction in size of tumor. After subsequent surgical resection, the child had a relapse of disease while he was still on adjuvant chemotherapy. The aim to report this case is to highlight the problems associated with diagnosis and management of this rare disease. Introduction: Small round blue cell tumors, is a spectrum of malignancies which have similar appearance on microscopy with small, round relatively undifferentiated cells with prominent round nuclei and scant cytoplasm. Due to undifferentiated nature, these tumors are really difficult to diagnose and in addition to histology and munohistochemistry, techniques like PCR, electron microscopy and special stains may be required.

Case History: A 4 year old boy, resident of Islamabad, Pakistan presented to a local doctor in April 2018, with non-specific symptoms of ongoing fever, abdominal pain and difficulty in micturition. On examination, he was found to have a hard mass in lower abdomen originating from pelvis and was referred to paediatric surgical department. Initial investigations including full blood counts and serum profile were normal. US abdomen and pelvis and following evaluation with a CT scan confirmed the presence of a well-defined, heterogeneously enhancing 10.7x 9.3x 8.1cm pelvic mass, displacing urinary bladder and colon causing bilateral hydronephrosis, with no evident metastasis. Ultrasound guided biopsy was taken, which showed sheets of round blue cells with scanty cytoplasm, and stained positive for Desmin, Myogenin, Myo D1. Histology favoured the diagnosis of RMS. Staging scans and bone marrow aspirate did not show any metastasis. The case was discussed in MDT oncology meeting, considering younger age, proximity to genitourinary system, and lack of obvious anaplastic features and metastasis, the child was classified into standard risk EpSSG group, subgroup C and as per EpSSG 2005 protocol, he was started on IVA regimen. After four cycles of chemotherapy, a repeat staging was performed. It confirmed a good response to treatment and a surgery was planned. He had a laparotomy with an extensive surgical resection of a retroperitoneal mass close to but sparing urinary bladder wall. Subsequent histology showed alveolar type rhabdomyosarcoma with rhabdomyoblastic differentiation and lymphohistiocytic inflammation in keeping with chemotherapy related changes. Margins though visibly clear at the time of surgery, were not commented upon in histology report due to fragmented nature of specimen.

Discussion: Small round blue cell tumors (SRBTs) is a group of malignant mainly childhood neoplasms characterized by intense blue appearance on H/E staining on light microscopy. These consist mainly of undifferentiated cells about double the size of RBCs on air dried smears, with scant cytoplasm and prominent nuclei giving them the characteristic appearance on microscopy. (1,4) The group includes desmoplastic round blue cell tumors, Ewing’s sarcoma, Neuroblastoma, synovial sarcoma, carcinoid tumor, mesothelioma, rhabdomyosarcoma, retinoblastoma, small cell lymphoma, anaplastic form of hepatoblastoma, merkel cell carcinoma, mesenchymal chondrosarcoma. While FNAC/ biopsy plays an important role, similar microscopic appearance and poor differentiation makes differential diagnosis a challenge and reverse transcriptase PCR, flow cytometric immunophenotyping, special stains, immunocytochemistry and new techniques of employing monoclonal antibodies(5B14 mAb) help in diagnoses. Rhabdomyosarcoma is one of SRBTs, thought to arise from skeletal muscle progenitor cells. Though it’s a rare entity, accounting for 3-4% of all childhood cancers it is the commonest soft tissue sarcoma (40%) and third most common solid tumor in children. Most of the cases occur in children under 10 years of age, with male to female ratio of approximately 1.3–1.5:1. Younger age is generally associated with better survival. It has a slightly lower prevalence in Asian and Black children as compared to White races. RMS can occur in any site on the body, but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities. There are no clear risk factors for RMS, but the disease has been associated with some congenital abnormalities. Common site of metastasis include the lungs, bone marrow, and bones. As mentioned earlier, differentiating SRBTs can be very difficult. Features specific to RMS on microscopy include relatively moderate to abundant deep blue staining cytoplasm with occasional vacuoles, eccentric nuclei, bi/multinucleated cells, presence of strap cells/ tadpole cells on a background of mucosubstance, which help in diagnosis. RMS usually stain positive for muscle specific proteins Myogenin, Desmin and PAX5, with variable expression of CD99, S-100 protein. 67% are positive for 5B14 mAb. Still on light microscopy and immunohistochemistry, it’s difficult to differentiate between different forms of RMS. Open biopsy may be required to obtain sufficient tissue to run tests like genetic sequencing. Based on histology, these are currently classified into Embryonal RMS (ERMS) the most common form (60%) which occurs in young children, Alveolar RMS (ARMS) more aggressive form occurring in older children, and Pleomorphic RMS (PRMS), the last being most undifferentiated aggressive form which tends to occur in older adults. Multiple genetic lesions are associated with rhabdomyosarcoma. PAX/FOX01 translocation is especially important, and associated with poorer prognosis and is one factor which helps to differentiate alveolar from embryonal forms. Radiological features are usually non-specific, as are clinical signs and symptoms in most of the cases. There are no known tumor markers. The first mention of RMS in literature was in 1845, by a German physician Weber. It was later described and classified by Arthur Stout in 1946. Current staging system for RMS International Classification of Rhabdomyosarcoma or ICR was devised by IRSG (Intergroup Rhabdomyosarcoma Study Groups). It combines a modified TNM staging with clinical group based on success of first surgical resection and classifies them into four groups. Children’s Oncology Group (COG) protocols for the treatment of RMS utilize the information about the TNM stage, the clinical group, and the PAX/FOX01 fusion gene status, divide patients into 3 risk groups, while European Pediatric Soft tissue Sarcoma Group (EpSSG) stratifies them into four groups based on age, histological type, location and IRS group and TNM stage to decide treatment options. As with any malignancy, the management approach to RMS is multidisciplinary involving surgery, chemotherapy and radiotherapy with emerging scope of immunotherapy. Although surgery has a limited role in debulking of tumor, as less than 20% resection achieve negative resection margins. Nowadays chemotherapy is indicated for all cases as RMS are highly chemo-sensitive. Evolution of multi-agent neoadjuvant and adjuvant chemotherapy, the survival outcomes have improved significantly from <20% with surgery alone to 60 – 70% with adjuvant treatment. There are two main chemotherapy regimens that are used for treatment of RMS, that are given in 9-15 cycles, VAC regimen (vincristine, actinomycin D, and cyclophosphamide), and IVA regimen (isofosfamide, vincristine, and actinomycin D). Addition of doxorubicin to VAC has been shown to further improve survival rate in early stage alveolar RMS, and bladder salvage in advanced RMS of bladder. Radiotherapy has been shown to improve disease free survival rates. It usually follows chemotherapy and is indicated in cases where complete resection is not possible due to sensitive location or tumor burden. Though, primary radiotherapy is indicated in cases of para-meningeal tumors involving skull, brain, or spinal cord. It can be administered in the form of seeds, or brachytherapy esp. in tumors involving sensitive areas e.g. testicles, bladder, vagina. Prognosis in rhabdomyosarcoma patients has been shown to be dependent on age, tumor site, resectability of tumor, tumor size, regional lymph node involvement, presence of metastasis, site and extent of metastasis, and biological and histopathological characteristics of the tumor cells. Even with the multimodality approach, the 5 year survival rates may vary significantly with different subtypes.

Conclusion: Rhabdomyosarcoma, a rare malignancy, poses quite a challenge in the diagnosis and therefore management. This is especially important in cases where genetic and other new investigations are not widely available. Same happened in the case of our patient, where the initial biopsy was not diagnostic of alveolar type RMS, and tumor was not evidently involving the pelvic organs. Thereby he was treated initially as a standard risk patient (as ERMS) to which he had a good response. Subsequently he had a complete surgical resection, though the tumor relapsed within 6 months while the patient was still on adjuvant chemotherapy, and behaved more aggressively like an alveolar RMS. Recent advances in the field of genetics and immunocytochemistry help in more accurate diagnosis of these rare tumors, and updated treatment guidelines help improve the survival rates significantly.

Author(s): Abeera Mehmood  

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