Unusual abdominal metastases in osteosarcoma

Abstract

Intraabdominal metastases in the setting of osteosarcoma are very rare. We describe a case of a 17-year-old boy with high-grade right distal femur osteosarcoma who two years after diagnosis developed extensive intra abdominal metastases involving the omentum, peritoneum, bowel serosa, psoas muscles and abdominal soft tissue. Awareness of and surveillance for unusual patterns of metastasis may allow for earlier detection, intervention, and palliative care decision-making, which may affect survival and quality of life. This report underlines the need for prospective studies evaluating surveillance guidelines for patients after medical and surgical management of osteosarcoma, especially in cases complicated by pulmonary metastases.

INTRODUCTION

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, comprising 56% of all bone cancers in individuals younger than 20 years [1]. The highest incidence occurs in patients ages 12 to 16 years, coinciding with the adolescent growth spurt [2]. The most common sites of osteosarcoma are the metaphyses of long bones, especially the distal femur (75% of cases in one large population-based series), proximal tibia and proximal humerus [3, 4]. The majority (80–90%) of patients present with localized disease at diagnosis. Distant metastases develop in 10% to 20% [5], and recurrent disease is observed in 30% to 50% of patients [6–7]. Hematogenous spread accounts for the majority of osteosarcoma metastases. Lymphatic spread to regional lymph nodes has also been reported [8]. The lung is the most common site of metastasis (98%), followed by bone (37%), pleura (33%), heart (20%), kidney and liver (17%), diaphragm (15%), and mediastinum (11%) [12]. Peritoneal metastases are extremely rare [9–13].

CASE REPORT

We present a case of a 17-year-old male who presented with right knee pain exacerbated by exercise. Imaging revealed a blastic lesion in the distal right femoral meta-diaphysis (Figure 1). CT of the chest and a bone scan were negative for metastatic disease. The patient received neoadjuvant chemotherapy as part of an institutional research protocol (MSKCC IRB# 03-074) for a phase II study of a combined regimen of doxorubicin, cisplatin, methotrexate, and pamidronate after confirmatory biopsy of high-grade osteosarcoma. Nine weeks after induction therapy, a radical resection with arthroplasty reconstruction of the right distal femur was performed. Histopathologic analysis supported a grade of II (75%–80%) on the Huvos necrosis grading system and a skip lesion was noted in the growth plate [14]. Following surgery, maintenance therapy was continued with cisplatin/doxorubicin and high-dose methotrexate. Bilateral pulmonary metastases were found on surveillance CT 4 months after surgical resection of the primary tumor. After staged bilateral thoracotomies and pulmonary metastasectomy, maintenance chemotherapy was continued. The patient developed recurrent bilateral pulmonary disease 5 months following the thoracotomies. Sorafenib treatment was initiated, but a subsequent transition to ifosfamide and etoposide was necessary due to a persistent rash in his upper extremities and face. Experiencing significant toxicities, he was started on a study with pembrolizumab, which was discontinued when the patient developed acute interstitial nephritis. Although pulmonary metastases were present, surveillance imaging was negative for extrapulmonary disease for 2 years following initial presentation.

Fig 1.

Conventional radiographs of the right knee demonstrate a blastic lesion in the distal femoral meta-diaphysis.

Two years and 10 months after initial diagnosis, the patient presented with abdominal pain, distention, and shortness of breath. CT of the chest, abdomen and pelvis showed extensive ossification in the omentum, peritoneum, psoas muscles, soft tissue nodules and new sclerotic bone metastasis (Figures 2 and 3). Because of the extent of metastasis, the patient was discharged to hospice care and died a few weeks later.

Fig. 2.

CT imaging of the chest, abdomen, and pelvis demonstrates omental calcification/ossification, extensive peritoneal calcification/ossification, and calcified/ossified psoas masses. Numerous calcified/ossified soft tissue nodules and sclerotic bone metastasis in the spine are evident.

Fig. 3.

A bone scan performed 15 months after diagnosis showed no evidence of extrapulmonary metastasis. A subsequent bone scan, taken 2-1/2 years post diagnosis, demonstrates new ^99mTc-MDP uptake in multifocal bone metastases and omental metastasis (black arrow), as well as serosal calcification involving the sigmoid colon (white arrows) and soft tissue calcification in the left thigh (curved black arrow).

DISCUSSION

Multimodal chemotherapy in the management of osteosarcoma has affected survival rate and recurrence pattern. Unusual sites of metastasis may evolve with prolonged survival and novel therapeutic approaches. Alterations in the metastatic pattern of osteosarcoma were first described by Giuliano and colleagues [15]. In their study, 94.7% who received surgery alone developed only pulmonary metastases, whereas 27.5% of patients treated with additional adjuvant chemotherapy had extrapulmonary recurrences. Westar and colleagues suggested that those rare but increasingly frequent extrapulmonary localizations of osteosarcoma metastasis may be the result of new chemotherapy regimens, which may trigger phenotypic drift and facilitate bloodstream invasion of selected cells with a capacity to form metastatic lesions in uncommon places [12]. Bacci and colleagues have shown that different protocols of neoadjuvant chemotherapy are associated with differences in time to relapse, event-free survival rate, and location of recurrent lesions [16], supporting observations made by Jaffe and colleagues, who analyzed the effect of adjuvant chemotherapy on the pattern of pulmonary relapse [17]. Our case further highlights the possibility of altered metastasis patterns in patients with osteosarcoma and the development of extrapulmonary recurrent disease. However, extrapulmonary recurrences are very rare, with only five published case reports describing intraabdominal metastases in the peritoneum and soft tissue (Table 1) [9–13].

Table 1.

Summary of all case reports of extrapulmonary metastases in young adolescents with osteosarcoma

Paper	Year of publication	Age at diagnosis (years)	Gender	Location of primary disease	Location of recurrence	Time between primary diagnosis, pulmonary and extrapulmonary recurrence	Management	Outcome
Chan et al [9]	2013	16 y	Female	Proximal tibia	Pulmonary, pleural, peritoneal, cutaneous and breast metastases	Not available	Surgical resection with adjuvant chemotherapy	Lost to follow up
Yeh et al [10]	2005	14 y	Male	Distal femur	Peritoneal	27 – 38 mo	Surgical resection with adjuvant chemotherapy	Not available
Oñoro et al [11]	2011	17 y	Male	Distal femur	Peritoneal, pleural, vertebral, chest wall and psoas major	Not available	Surgical resection with neoadjuvant (6 cycles of ifosfamide, doxorubicin, methotrexate and cisplatin) and adjuvant (9 cycles of ifosfamide, doxorubicin, methotrexate and cisplatin) chemotherapy	Death
Westra et al [12]	1998	19 y	Male	Distal femur	Peritoneal	15 – 28 mo	Surgical resection with neoadjuvant (3 cycles of cisplatin and doxorubicin combined with filgrastim) and (3 cycles of cisplatin and doxorubicin combined with filgrastim) chemotherapy	Death
Lin et al [13]	2003	17 y	Male	Proximal tibia	Hepatic, pleural and omental	48 – 50 mo	Surgical resection with neoadjuvant (cisplatin and doxorubicin) and adjuvant (ifosfamide and etoposide in addition to cyclophosphamide, cisplatin and BCNU) chemotherapy	Death
Current case	2017	17 y	Male	Distal femur	Pulmonary, omentum, peritoneum, bowel serosa, psoas, masses and abdominal soft tissue nodules	7 – 32 mo	Surgical resection with neoadjuvant (doxorubicin, cisplatin, methotrexate and pamidronate) and adjuvant (cisplatin/doxorubicin and HDMTX – sorafenib – pembrolizumab) chemotherapy	Death

As with our patient, the majority of patients previously reported in the literature were treated with multimodal neoadjuvant and adjuvant chemotherapy. Furthermore, similar to the current patient, 80% of patients described in the literature developed extrapulmonary metastases after the occurrence of pulmonary manifestations. Currently, there are no data supporting a particular follow-up schedule or appropriate selection of tests for surveillance after initial treatment for localized disease in osteosarcoma. The Children’s Oncology Group guidelines recommend an initial technetium bone scan or PET scan at diagnosis to identify bone metastases; however, whole-body imaging with technetium-99m methylene diphosphonate (^99mTc-MDP) bone scintigraphy or fluorodeoxyglucose positron emission tomography (FDG-PET) for surveillance is only recommended if the patient is symptomatic or in the case of abnormal imaging [18]. In addition, there are currently no data comparing bone scans with PET scans for surveillance after completion of therapy.

The management of pulmonary and extrapulmonary metastases in patients with osteosarcoma who received neoadjuvant and/or adjuvant chemotherapy is a very challenging situation. The prognosis of adolescents with intra-abdominal metastatic disease remains poor, with a mortality of 100% [9–13]. Awareness of unusual patterns of metastasis may lead to timely detection of these atypical recurrences and may provide options for earlier surgical intervention that may possibly prolong survival. However, given the rarity of intra-abdominal osteosarcoma metastasis, as well as its poor prognosis, specific surgical and chemotherapeutic options should be considered on a case-by-case basis within the framework of an interdisciplinary tumor board, ideally at an institution with expertise in pediatric surgical oncology. Further palliative approaches can also be evaluated early in the decision-making process, with the goal of maximizing the patient’s quality of life.

The value of whole-body surveillance imaging to identify extrapulmonary metastases in patients with pulmonary metastases should be investigated. Bone scintigraphy may allow detection of rare multifocal variants of osteosarcoma or unusual metastatic patterns of this tumor, as presented in this patient case (Fig. 3); however, the potential for late adverse effects associated with radiation exposure is a limiting factor. Franzius and colleagues have shown that sensitivity, specificity, and accuracy of FDG-PET in comparison to whole body scanning in the detection of osseous metastases can vary depending on the primary tumor [19]. Although FDG-PET seems to be a valuable imaging tool in detecting osseous metastases from Ewing sarcoma, it appears to be less sensitive in the detection of osseous metastases from osteosarcoma. However, radiation exposure is an important consideration, especially in pediatric patients who are already weakened by radiation and/or chemotherapy regimens [20]. Diffusion-weighted whole-body MR imaging with background body signal suppression seems to be a highly promising imaging modality for whole-body surveillance [20, 21]. However, additional prospective studies are warranted to further evaluate the optimal type of imaging modality and timing of screening for extrapulmonary recurrence, as well as to generate much-needed evidence to guide the selection of multimodal therapeutic options that may improve the prognosis for these patients.

HIGHLIGHTS.

• Patients with abdominal metastases of osteosarcoma have a poor prognosis

• Whole-body imaging allows early detection and treatment of rare OS metastasis patterns

• Interdisciplinary tumor board guidance for managing these metastases is recommended