Low-Grade Fibromyxoid Sarcoma of the Distal Upper Extremity: A Systematic Review

Abstract

Background:

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue tumor that usually occurs in the proximal extremities and trunk. The purpose of this systematic review was to assess patient demographics, treatment approach, and outcomes for patients with LGFMS of the distal upper extremity.

Methods:

We performed a literature review of case reports and patient reports of LGFMS using Medical Literature Analysis and Retrieval System Online (MEDLINE) and PubMed. Inclusion criteria included case reports and case series of patients with LGFMS of the distal upper extremity. Animal studies, comments, and non-English publications were excluded. Data on available patient demographics, treatment regimen, recurrence, and metastasis were collected.

Results:

A total of 365 publications were reviewed. After applying the inclusion and exclusion criteria, 19 articles were included. There were 24 unique patients with LGFMS of the distal upper extremity. The median age was 32 years, and most patients were treated with a surgical excision. Of the 15 reported outcomes, 4 patients had local recurrences, and no patient had metastases or died due to the tumor.

Conclusions:

Although LGFMS of the distal upper extremity is less common, it is critical for surgeons to consider it as a differential. The current approach is a wide excision with negative margins, and chemotherapy or radiotherapy may not be necessary. We found decreased proportions of local recurrence and metastases in the distal upper extremity compared with other anatomical regions. We recommend that surgeons follow up with their patients indefinitely given the slow mitotic rate of LGFMS.

Introduction

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue tumor that occurs in the proximal extremities and trunk among young adults. ¹ Low-grade fibromyxoid sarcoma has been described as a distinct entity from other soft-tissue neoplasms by Evans ² in 1993. It represents fewer than 5% of soft-tissue sarcomas (STS). ³ One study in Western Denmark suggested that LFGMS affects about 0.18 per million and comprises 0.6% of diagnosed STS. ⁴

Low-grade fibromyxoid sarcoma can be distinguished from similar sarcomas by its well-circumscribed contour and a fibrous to myxoid cut surface. ² Histologically, it has low to moderate cellularity, with spindle cells arranged in whorled pattern. ¹ Low-grade fibromyxoid sarcoma may appear deceptively benign in its histology, but its course tends to be malignant with poor outcomes. ² In a long-term follow-up of 33 patients with LGFMS, local recurrence was observed in 21 cases and metastasis in 15 cases. ⁵ The course can be prolonged, with reported metastasis extending up to 45 years after diagnosis. The most common sites of metastases are the lungs, pleura, and chest wall.^3,5

Hyalinizing spindle cell tumor with giant rosettes (HSTGR) is a closely related tumor that is characterized by its giant collagen rosettes. ⁶ These tumors tend to be painless and slow-growing and occur in young-to-middle-aged adults. ⁷ Hyalinizing spindle cell tumor with giant rosettes shares many histological similarities with LGFMS, and both have a common t(7;16) (134; p11) mutation. Given the similarities, HSTGR is considered a benign variant of LGFMS, rather than a separate entity. ⁸

Most LGFMS occurs in young adults in the proximal extremities and the trunk. ¹ Little is known about the occurrence of LGFMS in the distal upper extremity, defined as the region distal from, and excluding, the elbow. However, in a previous study, 3 (20%) of the 15 cases of LGFMS occurred in the forearm (1) and hand (2), suggesting that LGFMS of the distal upper extremity is not uncommon. ⁹ Treatment of LGFMS in the distal upper extremity differs from other regions due to the lack of redundant adjacent soft tissue and complex nearby anatomy. ¹⁰ In certain instances, marginal resection has been used, allowing for digit or limb salvage. ⁴ Given the paucity of data for this patient group, there is a critical need for a systematic review that addresses the significant gaps in knowledge. Therefore, the purpose of this systematic review was to assess patient demographics, treatment approach, and outcomes for patients with LGFMS of the distal upper extremity. This review, to the best of our knowledge, is the first to discuss LGFMS that occurs in the distal extremities and its management.

Methods

This systematic review is in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.^11,12 A comprehensive literature search of the Medical Literature Analysis and Retrieval System Online (MEDLINE) and PubMed databases was conducted for cases of LGFMS and HSTGR published through December 2020 with search terms related to low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes. Hyalinizing spindle cell tumor with giant rosettes was included as it is considered a type of LGFMS in the current literature. ⁸ Animal studies, comments, and non-English publications were excluded. Articles that included LGFMS and HSTGR of the distal upper extremity were selected through assessment of titles, abstracts, tables, and reference lists of related articles. Inclusion criteria included case reports and case series that had at least 1 patient with confirmed diagnosis of LGFMS of the distal upper extremity. Pertinent articles were selected and reviewed. Duplicates or recurrent cases were excluded. Data on available patient demographics, treatment regimen, recurrence, and metastasis were collected. Authors resolved any disagreements regarding study eligibility by consensus.

Results

Our search yielded 365 articles on LGFMS and/or HSTGR. There were 2 patient duplicates. Eighty-six publications were either not in English or not about LGFMS/HSTGR, and therefore were excluded. English articles that discussed LGFMS but did not include any patient cases were similarly excluded. There were 205 articles focusing on regions other than distal upper extremity that were excluded. A total of 19 articles including 24 unique patients with LGFMS/HSTGR of the distal upper extremity were selected for review (Figure 1). All patients included in the review had a diagnosis of LGFMS/HSTGR based on histopathology,^13,14 immunohistochemistry, ¹⁵ molecular genetics, ¹⁶ fluorescence in situ hybridization (FISH) for FUsed in Sarcoma (FUS) rearrangement, ¹⁷ or a combination. ¹⁸ Three of the 24 patients had giant rosette-like structures, classifying the tumors as HSTGR. The rest were diagnosed as LGFMS.^7,19

Figure 1.

Study selection.

As shown in Table 1, not all articles presented patients’ demographics, treatment approaches, and outcomes. Based on the available data, the median age was 32 years, and the range was between 6.8 and 91 years. Women predominated (59.1%). Within the distal upper extremity, the most common site of tumor was the forearm (11), followed by the hand (6), wrist joint (3), finger (2), and nail (2). Fifteen cases reported treatment approaches. Most patients were treated with surgical excision of the tumor. Nine reported marginal excision, 2 wide excisions, and 4 unspecified excisions. Two of the patients treated with marginal excision showed recurrence. Two patients underwent radiotherapy or chemotherapy. One of these 2 patients had a local relapse after 17.5 years. No patient had an amputation. Similarly, 15 cases reported outcomes. Local recurrence occurred in 4 patients. Local relapse occurred between 5 months and 17.5 years after their initial diagnosis. Eleven patients did not experience any recurrence or metastasis. One patient died 80 months after diagnosis due to unrelated causes. ²⁰ No patient experienced metastasis or death related to LGFMS/HSTGR.

Table 1.

Patient Demographics, Treatment, and Outcomes.

Reference (year)	No. of patients	Age	Sex	Site	Depth	Size	Surgery	Radiation	Length of f/u, y	Outcome
Maretty-Nielsen et al 4	1	38	Female	Hand	Subfascial	8 cm	Marginal excision	Yes (50 Gy in 25 fractions)	21.7 y	Local recurrence at 17.5 y
Evans 5	1	23	Male	Hand	Subcutaneous	1.5 cm	Marginal excision (positive margins)	Yes	16 y	Recurrence at 5 mo, followed by radiotherapy. Alive and NED at 16 y
Lane et al 7	2 a	25	Male	Forearm	Periosteum of radius	3.5 cm	Marginal excision	NR	6.5 y	NED
		50	Male	Hand	NR	2.3 cm	Marginal excision	NR	1.75 y	NED
Billings et al 8	1	13	Male	Forearm	Superficial	NR	NR	NR	5 y	NED
Antonescu and Baren 9	2	34	Female	Forearm	Deep	NR	NR	NR	5.3 y	NED
		24	Male	Hand	Deep	NR	NR	NR	10 y	Local recurrence at 117 mo and NED at 120 mo
Scheer et al 13	2	9.1	Male	Wrist	NR	2.5 cm × 1.0 cm × 1.8 cm	Marginal excision (free margins)	NR	1.3 y	NED
		6.8	Female	Forearm	NR	20 cm × 5.5 cm × 5.5 cm	Marginal excision (free margins)	NR	0.1 y	NED
Li et al 14	1	33	Female	Wrist	Subaponeurotic	0.7 cm	Marginal excision (negative margins)	NR	5.08 y	NED
Mustafa et al 15	2	38	Female	Forearm	NR	6.5 cm	Unspecified excision	No	6 y	NED
		23	Female	Forearm	NR	9 cm	Unspecified excision	No	5 y	NED
Hisaoka et al 16	1	39	Female	Forearm	Intermuscular	5.0 cm × 3.5 cm	Marginal excision (negative margins)	NR	NR	NR
Papp et al 17	1	18	Male	Forearm	Deep	5.5 cm × 4.5 cm × 4 cm	Wide local excision (negative margins)	NR	NR	NR
Thway et al 18	1	65	Male	Forearm	NR	NR	NR	NR	NR	NR
Ludvikova et al 19	1 a	22	Female	Wrist	NR	2.5 cm × 2 cm × 2.5 cm	Unspecified excision	NR	16 y	Recurred twice within 2 y after excision. Afterward, NED
Puls et al 20	1	91	Female	Finger	Subcutaneous	2.5 cm	Marginal excision	No	6.7 y	Death of unrelated causes
Matsuyama et al 21	1	48	Female	Forearm	Intramuscular	NR	NR	NR	NR	NR
Cabibi et al 22	2	NR	NR	Nails	Dermis	NR	NR	NR	NR	NR
		NR	NR	Nails	Dermis	NR	NR	NR	NR	NR
Zamecnik and Michal 23	1	44	Female	Forearm	Subcutaneous	3 cm × 3 cm ×4 cm	NR	NR	NR	NR
Rubin et al 24	1	21	Female	Hand	NR	5.2 cm × 2.7 cm	Unspecified excision	NR	1.5 y	NED
Han et al 25	1	46	Male	Finger	Dermis	1.4 cm × 1.4 cm	NR	NR	NR	NR
Swanson et al 26	1	31	Female	Hand	Superficial	3.4 cm	Wide local excision (negative margins)	NR	NR	NR

Note. NED = no evidence of disease; NR = not reported.

^aHyalinizing spindle cell tumors with giant rosettes.

Discussion

Low-grade fibromyxoid sarcoma of the distal upper extremity is a rare STS. Only one-fifth of all STS occur in the upper extremities. More common tumors include epithelioid sarcoma, synovial sarcoma, clear cell sarcoma, and malignant fibrohistiocytoma. ²⁷ Thus, the diagnosis of LGFMS is often missed and misdiagnosed as infection, ganglion, and lipoma. Its distinction from benign or low-grade fibromyxoid lesions may be challenging but critical because of the metastasizing potential. ²¹ Thus, surgeons must consider LGFMS as a differential when encountering a mass in the distal upper extremities. ²² In this article, we review cases of LGFMS of the distal upper extremity to assess patient demographics, current treatment regimen, and outcomes.

Demographics

Most patients in our study were young adults, with a median age of 32 years. Our study included 3 pediatric patients (15.8%), which is more than found in previous studies of LGFMS not limited to distal upper extremities. Evans reported that of the 33 LGFMS cases, 3 (9.1%) were pediatric patients. However, none of them included the distal upper extremity, and instead were LGFMS of the inguinal area, neck, and deltoid, respectively. ⁵ Chamberlain et al ³ reported 102 patients treated for LGFMS, and no patient was below the age of 18 years. In children, LGFMS often presents as superficial tumors, confined to the superficial soft tissue (dermis and/or subcutis). Patients’ young age and superficial location incline physicians to initially suggest a benign clinical diagnosis, which may delay and worsen patient outcomes. ⁸ Although LGFMS may be rare in pediatric patients, our study suggests that LGFMS of the distal upper extremity can occur and needs to be considered as a differential.

Most of the previous articles indicate that LGFMS either has a predilection for men or has equal incidence in both sexes.^3,5,6 One study reported that up to 75% of the LGFMS cases were in men. ²³ However, in our study, 59.1% cases occurred in women. One LGFMS study not limited to 1 anatomical region also observed a strikingly increased female predominance with a ratio of 3:1. ¹⁵ Further studies are necessary to elucidate if and why LGFMS of the distal upper extremity is more common in women.

Treatment

Treatment of LGFMS of the distal upper extremity can be challenging due to its complex anatomy and lack of redundant tissues. It is also important to maintain the functionality of the forearm, wrist, hands, and fingers that can affect the quality of life.^10,28

Our study suggests that the current traditional approach to LGFMS is a surgical excision. ⁴ Wide excision with negative margins has been shown to help to avoid local recurrence.^24,25 Negative margins are the most critical component in treating LGFMS and should not be sacrificed to preserve function or for radiation therapy. ²⁹ In our review, one case with a positive margin after excision reported a recurrence after 5 months, supporting this notion. ⁵ When considering all types of STS, patients with negative marginal resections, age ≤64 years, tumor located in the extremities and superficial trunk, and without prior local recurrence have significantly better local control. ³⁰ Overall, individuals after resection with free margins have better 5-year local-relapse-free survival rates than those with microscopic or macroscopic residual tumor after surgical resection. ¹³ The risk for residual tumor after unplanned primary excision is high because of the complex regional anatomy in the upper extremities. Thus, patients should have complete diagnostic and frequent follow-ups, and surgeons should have clear and planned procedures because of the risk of close or positive margins. ³¹

There is less known about the efficacy of radiotherapy or chemotherapy on LGFMS. In our review, 2 patients underwent radiotherapy. One patient received radiotherapy after a marginal excision and had a local recurrence at 17.5 years. ⁴ Another patient underwent radiation after a recurrence and had no evidence of an additional recurrence after 16.5 years. ⁵ Current thought is that due to the low mitotic rate of LGFMS, it may not be very chemosensitive or radiosensitive, and adjuvant therapy is not necessary. ⁴ Chamberlain et al examined treatment outcomes and efficacy of chemotherapy in 102 patients with LGFMS. A vast majority (92.2%) of the patients underwent surgical excision, and 20 patients completed preoperative or postoperative radiotherapy. Other treatment modalities included endocrine therapy, chemotherapy, targeted systematic therapy, such as oral tyrosine kinase inhibitors, and locoregional therapy. Locoregional therapy includes radiofrequency ablation, cryoablation, and isolated limb perfusion. The authors found that conventional systematic therapies have limited efficacy in LGFMS. ³ Nevertheless, additional studies examining the efficacy of surgical resection alone or with adjuvant therapy in the distal upper extremity are necessary.

Although there is no specific treatment regimen for LGFMS of the distal upper extremity, insights can be gathered from studies on treatment of STS of these locations. Previously, amputations were the criterion standard treatment for STS of the forearm, wrist, and hand. ²⁸ No patient in this systematic review underwent an amputation. Amputations can be the definitive treatment especially for larger and more invasive tumors. However, one study found that amputations of LGFMS in both lower and upper extremities offered only a marginal advantage in local recurrence when compared with limb salvage surgeries. There were no benefits regarding distant metastasis and disease-specific survival. ³²

Limb salvage surgeries require complete resection because patients with positive margins have a higher rate of local disease recurrence, distance recurrence, and overall mortality rate.^29,33 Hand salvage procedures are especially difficult because of the minimal area of adjacent tissues and the risk of compromising vital nearby structures. ¹⁰ It is challenging to maintain adequate local control of the tumor while reaching functional and aesthetic goals. Multistage reconstructions may be required to achieve successful outcomes. ³⁴ Treatment modality also depends on the location of the tumor. Superficial tumors or those that are on the dorsal side of the hand could be managed with reconstruction techniques, whereas tumors that are deep or palmer may need to be amputated. ²⁸ Nevertheless, studies show that limb salvage surgeries can result in excellent functional outcomes. It requires the surgeons’ creativity and experience to reach the most optimum outcome. For example, microsurgical techniques, such as nerve or vessel repair and grafting, are necessary. ¹⁰ In cases of tumors that invade the nerve as seen in one of our cases, epineural dissection is a safe means of nerve preservation. ³⁵ It is also important to work with a team of experts, including reconstructive surgical teams and oncologists. ¹⁰ Moreover, the use of radiotherapy in STS of the distal upper extremities is uncertain. One study of STS treated with limb salvage surgeries and radiation found that any postoperative complications were due to radiation. The radiation-related complications included a soft-tissue defect over the carpus 3 weeks after reconstruction and a radiation burn to the free radial forearm flap. ¹⁰ Thus, given the low mitotic rate of LGFMS and radiation-related complications in STS of the hands, adjuvant radiation may not be necessary.

Outcomes

In our analysis, local recurrences were reported in 4 patients (26.7%) after initial treatment (range: 5 months to 17.5 years). No metastases were reported. Available literature on LGFMS not limited to the distal upper extremity demonstrated greater proportions of local recurrence and metastasis. For example, Evans reported that 21 (63.6%) of 33 patients had recurrence after a median of 3.5 years and 15 had metastases, with the majority in the lungs and pleura. The metastases occurred after periods of up to 45 years and median of 5 years. ⁵ A large LGFMS study from the French Sarcoma group found that 6 (21.4%) of 28 patients had local recurrences after a median of 33 months (range: 6-290 months). Metastases occurred in 6 patients: 4 in the lung, 1 in the pleura, and 1 in the soft tissue. The overall 5-year disease-free survival was 55%. ³⁶ Finally, another study demonstrated that 4 (57.1%) of the 7 cases of LGFMS had recurrence and 1 had metastasis. Follow-up of patients ranged for 3.5 to 22 years. ³⁷ No patient in our review died due to the tumor. Current literature not limited to the distal upper extremity varies in the mortality and survival rates for LGFMS. Folpe et al ⁶ found that 2% of their patients died from LGFMS, while the overall median survival was approximately 28 to 30 years in the review by Evans ⁵ of 33 patients. Another report of patients with a hybrid of sclerosing epithelioid fibrosarcoma and LGFMS had a mortality rate of 37% after 66 months of follow-up. ³⁸

Our study revealed decreased proportions of local relapse, metastasis, and death among patients with LGFMS in the distal upper extremity. However, it is too premature to conclude that the behavior of LGFMS in this location tends to be slow-growing. Although there are less data on LGFMS of the distal upper extremity, STS of the hand may have a higher recurrence rate and worse survival than sarcomas in other upper extremity sites. ¹⁰ Brien et al ²⁹ found that 69% of those who had a nonmetastatic STS of the hand survived after 43 months, whereas 93% of those with STS in other extremities survived after the same time period. On the other hand, Buecker et al ³⁹ showed that primary malignancies of the hand have a statistically significantly improved survival rate than malignancies in other skeletal sites. Our analysis may have decreased proportions of recurrence and metastasis due to limited length of follow-up, especially given the indolent clinical behavior of LGFMS. Rates may be higher with long-term follow-up as metastases can occur even after 45 years. ⁵ Thus, indefinite clinical follow-ups are recommended. ²⁶

This review has several limitations. Given the paucity of studies on LGFMS of the distal upper extremity, there were limited reports of treatments and outcomes with adequate follow-up. It is difficult to draw absolute conclusions in a small cohort of data. However, the goal of this article was to summarize the available data for the treatment and possible outcomes of LGFMS for future patients. In addition, this search was limited to articles written in English language. The evidence reported within this study depended on the quality and accuracy of the articles reviewed. Finally, the definition of LGFMS is not clearly established. Hyalinizing spindle cell tumor with giant rosettes was included in this review because the latest evidence suggests that HSTGR is a variant of LGFMS, although future studies may contradict this. Our local relapse, metastasis, and mortality rates may be lower than those found in the existing literature because we combined LGFMS and HSTGR. However, HSTGR is a variant of LGFMS that also has a tendency for local recurrence and metastasis, and its behavior resembles that of LGFMS. ⁴⁰ The study by Folpe et al ⁶ similarly evaluated both LGFMS and HSTGR and found 5 recurrences, 3 metastasis, and 1 death. When excluding the 3 HSTGR from our review, there are 3 local recurrences (25%) of 12 reported LGFMS outcomes, which is comparable to our original finding of 26.7%. Overall, further studies on LGFMS of the distal upper extremity are necessary to establish a treatment regimen.

Therefore, although LGFMS of the distal upper extremity is a rare tumor, it is critical for surgeons to consider it as a differential and to determine the most optimal treatment regimen for the patient. Our findings suggest that LGFMS of the distal upper extremity commonly occurs in young adults but should be considered among pediatric patients as well. The current approach is a wide excision with negative margins, and chemotherapy or radiotherapy may not be necessary. We found decreased proportions of local recurrence and metastases. Nevertheless, surgeons must follow up with their patients indefinitely given the slow mitotic rate of LGFMS.