Highly malignant soft tissue sarcoma of the extremity with a delayed diagnosis

Seven cases of synovial sarcoma, three cases each of alveolar soft part sarcoma and malignant fibrous histiocytoma, two cases each of myxofibrosarcoma and high-grade leiomyosarcoma, and one case of clear cell sarcoma were diagnosed. Four of the seven cases of synovial sarcoma, two of the three cases of alveolar soft part sarcoma, two cases of myxofibrosarcoma, and one case each of high-grade leiomyosarcoma and clear cell sarcoma were transferred to our hospital after surgery or biopsy at another hospital. For the remaining 8 cases, all procedures from biopsy to final surgery were performed at our hospital. Affected areas included the thigh (four cases), the lower leg (six cases), the foot and ankle joint (three cases), the forearm (four cases), and the popliteal area (one case). Pulmonary metastasis was detected at diagnosis in all alveolar soft part sarcoma cases and in one clear cell sarcoma case. However, no distant metastasis was detected in the other tumor cases. In six cases, primary tumors were located in a deep region, and in twelve cases, they were located superficially. All three malignant fibrous histiocytoma cases occurred in patients in their 70 s, whereas the alveolar soft part sarcomas occurred in one child (> 10 years old), and in one 20 and one 30 year old. Synovial sarcomas occurred in individuals with ages at onset ranging from the second to the sixth decade, but it occurred preferentially in adults. Delays between tumor recognition by a patient to diagnosis were between 1 and 3 years in most cases. However, in three cases of synovial sarcoma, it took more than 10 years to reach a diagnosis, and in another case of synovial sarcoma, it took more than 5 years. In one case of synovial sarcoma, recurrence occurred at the primary tumor location several times over 20 years. No common characteristic findings were evident by plain radiography, although one case of synovial sarcoma (Figure 1) and one case of alveolar soft part sarcoma showed calcification on plain radiographs. In all three cases of alveolar soft part sarcoma, the characteristic MRI finding was of high signal intensity with signal voiding on T1 and T2 images (Figure 2), which was attributed to the presence of abundant blood vessels. However, no other tumor-specific findings were evident. A diagnostic biopsy was only performed in one of the seven synovial sarcoma cases. In this case, a relatively large tumor was fixed in the superficial layer prior to final operation. However, in the other six cases, simple excision was performed without a pre-surgical biopsy because tumors were small or superficially located. In contrast to synovial sarcoma cases, diagnostic biopsies were performed in all malignant fibrous histiocytoma and alveolar soft part sarcoma cases due to a relatively large tumor size or a deep location.

Some types of soft tissue sarcoma that develop in the limbs or axial skeleton grow slowly over several years, or remain the same size for years or even decades, and then suddenly start to grow. Because these tumors are painless and movable by palpation in many cases, they are often misdiagnosed as benign tumors, and simple excision is performed without adequate pre-surgical evaluation. Importantly, if simple excision is performed without biopsy, the tumor can recur several years later, when all concerned will be taken aback by its aggressive nature. Both physicians and patients have a preconceived idea that malignant tumors are painful and grow rapidly. Furthermore, soft tissue sarcomas are much rarer than benign tumors, and thus, physicians often fail to recommend appropriate tests or perform a comprehensive biopsy. In addition, patients may not even consider consulting a physician in some cases because they do not consider the tumor to be serious. Tumors that do not change or change only slowly over time are often considered benign, but tumor growth rate should not form the basis of a diagnosis. According to Lawrence et al. [3], approximately 50% of soft tissue sarcoma patients are diagnosed at about 4 months after patient recognition, and an additional 20% are diagnosed after 6 months. Furthermore, because the literature provides no precise definition of 'slowly-growing' sarcoma, we considered a slow-growing tumor to be one known to the patient for more than one year prior to diagnosis. Synovial sarcoma is a representative type of slowly growing highly malignant tumor, and it has been reported that in synovial sarcoma cases, a substantial proportion of patients have an average symptomatic period of 2 to 4 years, though in some rare cases, this period has been reported to be longer than 20 years [4]. Of the 18 subjects enrolled in the present study, one case had a symptomatic period of 20 years, and four of the seven synovial sarcoma cases had a symptomatic period of 5-6 years (Table 1). For the reasons listed above, the diagnosis of synovial sarcoma is frequently delayed. In some previous studies, ~20-30% of patients have presented with calcification on plain radiographs [5–7]. Similarly, in our study, calcific density was observed by plain radiography in one case with a tumor in the popliteal area. Sixty percent of soft tissue sarcoma cases occur in the limbs, and the most prevalent affected region is the distal femoral area around the knee joint [8]. Consistent with previous studies, we found that these tumors occurred in individuals with diverse ages ranging from adolescents to adults. To determine the disease stage of soft tissue sarcoma, tumor growth rate and size, and location within tissue should be considered. Characteristics worth noting are that most highly malignant sarcomas are located deep within limb muscles, and that tumor sizes are larger than 5 cm [9]. In the present study, six of seven synovial sarcoma cases were located in superficial areas, but these were small tumors with a long axis of less than 5 cm in four cases. For these reasons, six of the seven were excised without sufficient biopsy or examination. The characteristics of the alveolar soft portions of sarcomas are that they comprise only 0.5-1.0% of soft tissue sarcomas, grow slowly, have metastasized in 20-25% of cases at diagnosis, respond poorly to chemotherapy, and have a poor prognosis [10, 11]. Onset usually occurs during adolescence or in young adults, and the only symptom is restriction of joint movement. In our study, one of the three cases of alveolar soft part sarcoma occurred in adolescence, and the other two occurred in young adults. In two of these three cases, the chief complaint was of a painless tumor, whereas the third admitted restricted joint movement with mild pain. At time of diagnosis, pulmonary metastasis was detected in all three cases. In contrast to other soft tissue sarcomas, alveolar soft part sarcomas have characteristic radiologic features, that is, MRI T1- and T2-weighted images have high signal intensities and signal voids due to the presence of abundant blood vessels [12–14]. Accordingly, these tumors can be misdiagnosed as hemangiomas or A-V malformations. In the present study, one case was attributed to hemangioma at initial examination. In alveolar soft part sarcomas, solid tumor tissues are surrounded by vascular tissues and blood flow wash-out is slow. In contrast, A-V malformations are comprised of pure vascular tissue without accompanying tissues, and blood flow wash-out is rapid, which enables the differentiation of these two conditions [14–16].

No	Gender	Age (Yrs)	Duration (Yrs)	Diagnosis	Pain	Location	Depth	Size	Previous biopsy
1	M	42	6	S S	No	thigh	deep	12 × 7 × 7	N
2	M	27	20	S S	No	forearm	superficial	3 × 2 × 2	N
3	F	53	2	S S	mild	ankle	superficial	1.8 × 1.2 × 0.5	N
4	F	53	10	S S	mild	foot	superficial	5 × 5 × 6	Y
5	M	15	1	S S	No	ankle	superficial	3 × 3	N
6	F	28	1	S S	mild	forearm	superficial	2 × 2	N
7	M	40	10	S S	Yes	popliteal	superficial	5 × 5	N
8	M	70	1	MFH	No	thigh	superficial	9 × 4	Y
9	F	79	3	MFH	No	forearm	superficial	15 × 7	Y
10	M	69	1	MFH	No	lower leg	superficial	5 × 2	Y
11	F	16	1	Alv SS	mild	thigh	deep	5 × 4 × 3	Y
12	M	27	3	Alv SS	yes	lower leg	deep	7 × 4 × 11	Y
13	M	32	3	Alv SS	yes	lower leg	deep	15 × 7 × 6	Y
14	M	72	3	HGL	No	thigh	deep	4 × 4 × 5	Y
15	F	68	3	HGL	No	lower leg	superficial	5 × 4 × 3	N
16	F	52	2	MFS	mild	lower leg	superficial	14 × 9	Y
17	M	31	1	MFS	mild	lower leg	deep	10 × 5	Y
18	F	50	1	CS	No	forearm	superficial	2 × 3	N

M: male, F: female, S S: synovial sarcoma, MFH: malignant fibrous histiocytoma, HGL: high grade leiomyosarcoma, Alv SS: alveolar soft part sarcoma, CS: clear cell sarcoma, MFS: myxofibrosarcoma