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Primary low-grade fibromyxoid sarcoma of the breast: a rare case report with immunohistochemical and fluorescence in situ hybridization detection
Human Pathology (2018) 79, 208–211
www.elsevier.com/locate/humpath
Case study
Primary low-grade fibromyxoid sarcoma of the breast: a rare case report with immunohistochemical and fluorescence in situ hybridization detection☆ Yutao Zhang MS a,⁎,1 , Dan Wan MS a,1 , Fuping Gao MS b,1 a
Department of Pathology, The First People's Hospital of Zigong, 643000 Zigong, China Department of Pathology, The People's Hospital of Gaochun, 211300 Nanjing, China
b
Received 12 October 2017; revised 29 January 2018; accepted 6 February 2018
Keywords: Low-grade fibromyxoid sarcoma; Breast; Differential diagnosis; Immunohistochemistry; Fluorescence in situ hybridization
Summary Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor with a bland histologic appearance but malignant biological behavior. Primary LGFMS of the breast has not been described in the English-language literature. Here, we report a 58-year-old Chinese female patient who presented with a painless mass in the right breast for more than 30 years. The tumor consists of spindle cells resembling fibroblasts and includes 2 kinds of morphologic change, which are alternating collagenized hypocellular zone and cell-rich myxoid area. There are more arcades of curvilinear blood vessels. The spindle cells are not heteromorphic, and mitotic figures are scarce. Immunostaining shows that tumor cells are positive for vimentin, mucin4, CD99, and Bcl-2, but negative for smooth muscle actin, desmin, S100, CD34, ALK, and myogenin. FUS gene rearrangement is positively detected by fluorescence in situ hybridization. The patient has been followed up for 59 months and is in a favorable condition. This rare location of LGFMS should be noted. © 2018 Elsevier Inc. All rights reserved.
1. Introduction Low-grade fibromyxoid sarcoma (LGFMS) was a special subtype of fibrosarcoma and first described by Evans [1] in 1987. This tumor was also called Evans tumor in some past literatures and designated formally as LGFMS in 1993 [2]. When it presents with prominent and well-formed collagen rosettes, it is called hyalinizing spindle cell tumor with giant ro-
☆ Disclosures: The authors have no competing interests to declare. This research does not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Department of Pathology, The First People's Hospital of Zigong, 643000 Zigong, Sichuan, China. E-mail address: [email protected] (Y. Z. Master). 1 These authors make equal contribution to this work.
https://doi.org/10.1016/j.humpath.2018.02.013 0046-8177/© 2018 Elsevier Inc. All rights reserved.
settes. LGFMS and hyalinizing spindle cell tumor with giant rosette are identical and considered morphologic variants of the same tumor. Their cytogenetic hallmarks are t(7; 16) (q33; p11) and presentation of fusion gene FUS-CREB3L2 [3]. Classical LGFMS presents with a mix of heavily collagenized hypocellular zones and cell-rich myxoid nodules. Short fascicular and characteristic whorling growth patterns are often seen. In addition, there are more arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration. LGFMS has a bland morphologic appearance; however, it is easily confused with other spindle cell soft tissue tumor because of its morphologic diversity and nonspecific immunophenotype. Usually, LGFMS occurs in the proximate extremities and trunk, but rarely in the breast. Here, we report a case of primary LGFMS of the right breast and review the related literature.
Primary low-grade fibromyxoid sarcoma of the breast
Fig. 1 LGFMS showed alternating collagen zone and myxoid area (hematoxylin and eosin staining, original magnification ×4).
2. Case report A 58-year-old Chinese woman presented in August 2012 with a painless mass of 10 × 10 × 6 cm in the external upper quadrant of the right breast for more than 30 years. The mass grew gradually. Upon physical examination, the size and external appearance of bilateral breast were different. A hard mass with smooth surface and distinct margin could be felt behind the right nipple. Ultrasound examination showed an inhomogeneous lowecho area of 11 × 5.2 cm in the right breast, and there were fluid opaca area and girdle-shaped bloodstream signal. Computed tomography and magnetic resonance imaging were not performed after being refused by the patient. Then, revised radical correction of right breast cancer was performed. Under macroscopic observation, the tumor was 10 × 10 ×6 cm and appeared as a well-circumscribed mass. Cross section was grayish-white and part of the section had a translucent
209
Fig. 3 FUS gene rearrangement (arrows) was positively detected by FISH at the Department of Pathology, West China Hospital of Sichuan University.
appearance. The mass had a moderate mucus-like quality. The tumor consisted of spindle cells that resembled fibroblasts and included 2 kinds of morphologic change, namely, alternating collagenized hypocellular zones and a cell-rich myxoid area (Fig. 1). There were more arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration. The spindle tumor cells had a bland appearance with no heteromorphism, and mitotic figures were scarce. We found no typical giant collagen rosettes. Immunostaining showed that the tumor cells were positive for vimentin, mucin4 (MUC4), CD99, and Bcl-2, but negative for smooth muscle actin (SMA), desmin, S100, CD34, ALK, and myogenin (Fig. 2). FUS gene rearrangement was positively detected by fluorescence in situ hybridization (FISH) at the Department of Pathology, West China Hospital of Sichuan University (Fig. 3). The patient was followed up for 59 months and in a favorable condition.
3. Discussion 3.1. Clinical features
Fig. 2 Spindle tumor cells were positive for MUC4 in immunostaining (diaminobenzidine, original magnification ×10).
LGFMS is a rare spindle cell tumor with a predilection for deep soft tissue. It often has a subfascial location and involves the lower limb and trunk muscles in young adults. Age of onset is from 8 months to 81 years. This tumor occurs equally frequently in men and women, although some researchers have found that the incidence is slightly higher in men. The frequent clinical manifestation is a slowly growing painless mass, and recurrence frequently occurs at 5 years postoperatively. Otherwise, LGFMS can develop in some rare sites, such as the jawbone, malar bone, hard palate, nasal cavity, intracalvarium, and sigmoid colon. There is even an individual report of LGFMS in the abdominal cavity with peritoneal and liver metastasis [4]. There is also a report of radiation-induced LGFMS
210 of the chest wall at 9 years subsequent to radiotherapy for breast carcinoma [5].
3.2. Radiologic features To date, few imaging studies have been reported and there is one article on LGFMS in 29 patients. The authors have summarized that LGFMS is commonly single at initial diagnosis and multiple at local recurrence. LGFMS frequently shows areas of computed tomographic attenuation hypodense to muscle and gyriform patterns of signal intensity and contrast enhancement at magnetic resonance imaging [6].
3.3. Histologic characteristics and immunophenotype LGFMS is always well circumscribed, with a diameter of 1 to 23 cm (median, 9.5 cm). Cross sections are gray or gray-yellow with a fibrous or mucus-like appearance. In the present case, LGFMS has a bland histologic appearance but with an infiltrative growth pattern. The tumor consists of spindle cells that resembled fibroblasts, and there are 2 kinds of morphologic change, namely, heavily collagenized hypocellular zones and cell-rich myxoid nodules. Short fascicular and characteristic whorling growth patterns are also seen. There are more arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration. There is a case report of LGFMS with unusual central necrosis in a 77-year-old man [7]. The spindle tumor cells have a bland appearance with no heteromorphism, and mitotic figures are scarce. Approximately 30% of otherwise typical cases show the focal presence of collagen rosettes, consisting of a central core of hyaline collagen surrounded by a cuff of epithelioid fibroblasts. Occasional cases have shown a hybrid lesion of LGFMS and sclerosing epithelioid fibrosarcoma (SEF) [8]. Researchers have tried to find an antibody with specificity for LGFMS, but so far, only vimentin, CD99, Bcl-2, and MUC4 are positive for this tumor [9]. Epithelial membrane antigen, keratin, desmin, SMA, S100, CD34, and myogenin are negative for LGFMS [10]. There is an especially interesting finding that 50% (5/10) of LGFMS are positive for DOG-1 [11]. Hence, gastrointestinal stromal tumors should be considered as a differential diagnosis for LGFMS.
3.4. Differential diagnosis Histologic appearance of LGFMS is similar to several other kinds of soft tissue tumors with spindle tumor cells and myxoid structure. Hence, it is easy to make a wrong diagnosis. Here, we summarize the differential diagnoses for LGFMS. 3.4.1. Sclerosing epithelioid fibrosarcoma LGFMS resembles SEF morphologically because both of them can present with rich eosinophilic collagenized zones and myxoid areas. However, sclerotic changes are more noticeable in SEF than in LGFMS. Moreover, small epithelioid
Y. Zhang et al. cells are organized as nest, streak, and aciniform structure in SEF, but spindle tumor cells of LGFMS are arranged in a whorling structure. LGFMS has distinctive arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration, but SEF always presents with vessels with a hemangiopericytoma-like pattern. Rearrangement of EWSR1 gene can be detected in 90% of pure SEF, but FUS-CREB3L2 gene is rearranged in LGFMS. It should be stated that rearrangement of FUS-CREB3L2 gene can also be detected in hybrid SEF/LGFMS [12]. 3.4.2. Solitary fibrous tumor Alternating hypocellular and cell-rich areas can be seen in solitary fibrous tumor (SFT), and those areas are separated by gross scar-like collagen with hyaline degeneration and branching vessels with hemangiopericytoma-like pattern. SFT is positive for STAT-6, CD34, CD99, and Bcl-2, but LGFMS is negative for STAT-6 and CD34 [13]. Nevertheless, there is a report of LGFMS that presents with vessels with hemangiopericytoma-like pattern and is easily misdiagnosed as SFT [14]. An LGFMS variation with vessels with hemangiopericytoma-like pattern should be considered when the tumor is negative for CD34. 3.4.3. Low-grade myxofibrosarcoma LGFMS should be discriminated from low-grade myxofibrosarcoma because of their different clinical behaviors. Low-grade myxofibrosarcoma mainly affects patients in the sixth to eighth decades of life, whereas this tumor is exceptionally rare under the age of 20 years. Low-grade myxofibrosarcoma shows multinodular growth with a prominent myxoid matrix, and frequent findings include atypical fibroblastic cells, elongated curvilinear capillaries, and pseudolipoblasts. Tumor cell proliferation index of low-grade myxofibrosarcoma, including MIB-1 and cyclin E LI, is obviously higher than that of LGFMS in immunostaining, but lower than LGFMS for p21 LI and p27 LI. In addition, there is no FUSCREB3L2 fusion gene in low-grade myxofibrosarcoma. 3.4.4. Mammary-type myofibroblastoma Mammary-type myofibroblastoma is a kind of benign mesenchymal neoplasm with sharply circumscribed margin, composed of spindle cells with features of myofibroblasts, embedded in a stroma that contains coarse bands of hyalinized collagen and conspicuous mast cells, admixed with a variable amount of adipose tissue. Otherwise, the spindle cells are consistently immunopositive for desmin and CD34. Expression of SMA is present in a third of cases. However, LGFMS is immunonegative for desmin, CD34, and SMA. All tumors have followed a benign course after marginal local excision. It is different from malignant behavior of LGFMS. 3.4.5. Borderline or malignant phyllodes tumor of the breast Malignant phyllodes tumor of the breast presents with an infiltrated growth pattern and obvious sarcomatoid stroma–
Primary low-grade fibromyxoid sarcoma of the breast like fibrosarcoma. Borderline phyllodes tumor of the breast has intermediate characteristics between benign and malignant phyllodes tumor, and sometimes has stroma that resembles well-differentiated fibrosarcoma. Both borderline and malignant phyllodes tumors of the breast should be discriminated from rare LGFMS because collagenized hypocellular zones and myxoid areas also can be seen in phyllodes tumor stroma. Neither borderline nor malignant phyllodes tumor shows FUS-CREB3L2 fusion gene, so FISH detection can clarify the diagnosis. 3.4.6. Myxoid liposarcoma Myxoid liposarcoma is composed of uniform round- to ovalshaped primitive nonlipogenic cells and a variable number of small signet-ring–like lipoblasts in a prominent myxoid stroma with a characteristic branching vascular pattern. There is no alternating arrangement between myxoid areas and sarcoma cells in liposarcoma, but well-defined nodular growth pattern. Like LGFMS, myxoid liposarcoma also lacks nuclear pleomorphism, giant tumor cells, and significant mitotic activity. Myxoid liposarcoma has a delicate arborizing “chicken-wire” capillary vasculature and lacks the distinctive arcades of curvilinear blood vessels of LGFMS. Myxoid liposarcoma usually shows either FUS-DDIT3 or EWS1-DDIT3 rearrangement. It is different from rearrangement of FUS-CREB3L2 gene in LGFMS. Besides above, some other tumors and tumor-like lesions like peripheral nerve tumor (neurofibroma or perineurioma), myxoma, and nodular fasciitis are also worth adding this note to the differential diagnosis.
3.5. Therapy Although radical, wide-margin surgical excision is recommended, the ideal goal of a large safety margin of healthy tissue might be unattainable if it requires resection of vital anatomical structures. LGFMS has a low mitotic rate; therefore, neither chemotherapy nor radiotherapy is expected to have a significant effect on long-term prognosis.
3.6. Prognosis Recurrence of LGFMS is not uncommon at 5 years after surgery, and there are case reports of broad ligament and liver metastasis from LGFMS [4,15]. The relapse, metastasis, and case fatality rates of LGFMS are 9%, 6%, and 2%, respectively, according to a retrospective analysis of 73 cases. Long-term follow-up is necessary because LGFMS can develop metastasis and recurrence many years after primary pathological diagnosis. In summary, LGFMS is a rare soft tissue tumor, especially in the breast. It has a bland histologic appearance but malignant biological behaviors, including recurrence and metastasis, are always seen. Careful histologic observation and pertinent immunohistochemical detection are helpful to make a precise pathological diagnosis. We recommend FISH detection of
211 FUS-CREB3L2 fusion gene and rare FUS-CREB3L1 fusion gene in LGFMS.
Acknowledgments We thank Dr HongYing Zhang in the Department of Pathology, West China Hospital of Sichuan University, for FISH detection and diagnosis. Written consent for publication is obtained from the patient.
References [1] Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987;88:615-9. [2] Evans HL. Low-grade fibromyxoid sarcoma. A report of 12 cases. Am J Surg Pathol 1993;17:595-600. [3] Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7; 16)(q34; p11) translocation. Am J Surg Pathol 2003;27:1229-36. [4] Konecna J, Liberale G, Haddad J, de Saint-Aubain N, El Nakadi I. Diffuse intra-abdominal low grade fibromyxoid sarcoma with hepatic metastases: case report and review of the literature. Int J Surg Case Rep 2015; 14:40-3. [5] Shibata S, Shiraishi K, Yamashita H, Kobayashi R, Nakagawa K. Radiation-induced low-grade fibromyxoid sarcoma of the chest wall nine years subsequent to radiotherapy for breast carcinoma: a case report. Oncol Lett 2016;11:2520-4. [6] Hwang S, Kelliher E, Hameed M. Imaging features of low-grade fibromyxoid sarcoma (Evans tumor). Skelet Radiol 2012;41:1263-72. [7] Kurisaki-Arakawa A, Akaike K, Tomomasa R, et al. A case of low-grade fibromyxoid sarcoma with unusual central necrosis in a 77-year-old man confirmed by FUS-CREB3L2 gene fusion. Int J Surg Case Rep 2014;5: 1123-7. [8] Kesrouani C, Zemoura L, Trassard M, Laé M. A hybrid lesion: low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF). Ann Pathol 2016;36:351-4. [9] Doyle LA, Möller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011;35:733-41. [10] Chaudhuri K, Kasimsetty CR, Lingappa A, Gujjar PV. Low-grade fibromyxoid sarcoma involving the mandible: a diagnostic dilemma. J Oral Maxillofac Pathol 2016;20:334. [11] Thway K, Ng W, Benson C, Chapman J, Fisher C. DOG1 expression in low-grade fibromyxoid sarcoma: a study of 11 cases, with molecular characterization. Int J Surg Pathol 2015;23:454-60. [12] Prieto-Granada C, Zhang L, Chen HW, et al. A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/ low-grade fibromyxoid sarcoma: a pathologic and molecular study of 18 cases. Genes Chromosomes Cancer 2015;54:28-38. [13] Yoshida A, Tsuta K, Ohno M, et al. STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol 2014;38:552-9. [14] Papp S, Dickson BC, Chetty R. Low-grade fibromyxoid sarcoma mimicking solitary fibrous tumor: a report of two cases. Virchows Arch 2015;466:223-8. [15] Chatterjee J, Howden S, Saso S, Ghaem-Maghami S, McIndoe A, Dina R. Metastatic low-grade fibromyxoid sarcoma of the broad ligament: a case report and literature review. J Obstet Gynaecol 2016;36:852-4.
www.elsevier.com/locate/humpath
Case study
Primary low-grade fibromyxoid sarcoma of the breast: a rare case report with immunohistochemical and fluorescence in situ hybridization detection☆ Yutao Zhang MS a,⁎,1 , Dan Wan MS a,1 , Fuping Gao MS b,1 a
Department of Pathology, The First People's Hospital of Zigong, 643000 Zigong, China Department of Pathology, The People's Hospital of Gaochun, 211300 Nanjing, China
b
Received 12 October 2017; revised 29 January 2018; accepted 6 February 2018
Keywords: Low-grade fibromyxoid sarcoma; Breast; Differential diagnosis; Immunohistochemistry; Fluorescence in situ hybridization
Summary Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor with a bland histologic appearance but malignant biological behavior. Primary LGFMS of the breast has not been described in the English-language literature. Here, we report a 58-year-old Chinese female patient who presented with a painless mass in the right breast for more than 30 years. The tumor consists of spindle cells resembling fibroblasts and includes 2 kinds of morphologic change, which are alternating collagenized hypocellular zone and cell-rich myxoid area. There are more arcades of curvilinear blood vessels. The spindle cells are not heteromorphic, and mitotic figures are scarce. Immunostaining shows that tumor cells are positive for vimentin, mucin4, CD99, and Bcl-2, but negative for smooth muscle actin, desmin, S100, CD34, ALK, and myogenin. FUS gene rearrangement is positively detected by fluorescence in situ hybridization. The patient has been followed up for 59 months and is in a favorable condition. This rare location of LGFMS should be noted. © 2018 Elsevier Inc. All rights reserved.
1. Introduction Low-grade fibromyxoid sarcoma (LGFMS) was a special subtype of fibrosarcoma and first described by Evans [1] in 1987. This tumor was also called Evans tumor in some past literatures and designated formally as LGFMS in 1993 [2]. When it presents with prominent and well-formed collagen rosettes, it is called hyalinizing spindle cell tumor with giant ro-
☆ Disclosures: The authors have no competing interests to declare. This research does not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Department of Pathology, The First People's Hospital of Zigong, 643000 Zigong, Sichuan, China. E-mail address: [email protected] (Y. Z. Master). 1 These authors make equal contribution to this work.
https://doi.org/10.1016/j.humpath.2018.02.013 0046-8177/© 2018 Elsevier Inc. All rights reserved.
settes. LGFMS and hyalinizing spindle cell tumor with giant rosette are identical and considered morphologic variants of the same tumor. Their cytogenetic hallmarks are t(7; 16) (q33; p11) and presentation of fusion gene FUS-CREB3L2 [3]. Classical LGFMS presents with a mix of heavily collagenized hypocellular zones and cell-rich myxoid nodules. Short fascicular and characteristic whorling growth patterns are often seen. In addition, there are more arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration. LGFMS has a bland morphologic appearance; however, it is easily confused with other spindle cell soft tissue tumor because of its morphologic diversity and nonspecific immunophenotype. Usually, LGFMS occurs in the proximate extremities and trunk, but rarely in the breast. Here, we report a case of primary LGFMS of the right breast and review the related literature.
Primary low-grade fibromyxoid sarcoma of the breast
Fig. 1 LGFMS showed alternating collagen zone and myxoid area (hematoxylin and eosin staining, original magnification ×4).
2. Case report A 58-year-old Chinese woman presented in August 2012 with a painless mass of 10 × 10 × 6 cm in the external upper quadrant of the right breast for more than 30 years. The mass grew gradually. Upon physical examination, the size and external appearance of bilateral breast were different. A hard mass with smooth surface and distinct margin could be felt behind the right nipple. Ultrasound examination showed an inhomogeneous lowecho area of 11 × 5.2 cm in the right breast, and there were fluid opaca area and girdle-shaped bloodstream signal. Computed tomography and magnetic resonance imaging were not performed after being refused by the patient. Then, revised radical correction of right breast cancer was performed. Under macroscopic observation, the tumor was 10 × 10 ×6 cm and appeared as a well-circumscribed mass. Cross section was grayish-white and part of the section had a translucent
209
Fig. 3 FUS gene rearrangement (arrows) was positively detected by FISH at the Department of Pathology, West China Hospital of Sichuan University.
appearance. The mass had a moderate mucus-like quality. The tumor consisted of spindle cells that resembled fibroblasts and included 2 kinds of morphologic change, namely, alternating collagenized hypocellular zones and a cell-rich myxoid area (Fig. 1). There were more arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration. The spindle tumor cells had a bland appearance with no heteromorphism, and mitotic figures were scarce. We found no typical giant collagen rosettes. Immunostaining showed that the tumor cells were positive for vimentin, mucin4 (MUC4), CD99, and Bcl-2, but negative for smooth muscle actin (SMA), desmin, S100, CD34, ALK, and myogenin (Fig. 2). FUS gene rearrangement was positively detected by fluorescence in situ hybridization (FISH) at the Department of Pathology, West China Hospital of Sichuan University (Fig. 3). The patient was followed up for 59 months and in a favorable condition.
3. Discussion 3.1. Clinical features
Fig. 2 Spindle tumor cells were positive for MUC4 in immunostaining (diaminobenzidine, original magnification ×10).
LGFMS is a rare spindle cell tumor with a predilection for deep soft tissue. It often has a subfascial location and involves the lower limb and trunk muscles in young adults. Age of onset is from 8 months to 81 years. This tumor occurs equally frequently in men and women, although some researchers have found that the incidence is slightly higher in men. The frequent clinical manifestation is a slowly growing painless mass, and recurrence frequently occurs at 5 years postoperatively. Otherwise, LGFMS can develop in some rare sites, such as the jawbone, malar bone, hard palate, nasal cavity, intracalvarium, and sigmoid colon. There is even an individual report of LGFMS in the abdominal cavity with peritoneal and liver metastasis [4]. There is also a report of radiation-induced LGFMS
210 of the chest wall at 9 years subsequent to radiotherapy for breast carcinoma [5].
3.2. Radiologic features To date, few imaging studies have been reported and there is one article on LGFMS in 29 patients. The authors have summarized that LGFMS is commonly single at initial diagnosis and multiple at local recurrence. LGFMS frequently shows areas of computed tomographic attenuation hypodense to muscle and gyriform patterns of signal intensity and contrast enhancement at magnetic resonance imaging [6].
3.3. Histologic characteristics and immunophenotype LGFMS is always well circumscribed, with a diameter of 1 to 23 cm (median, 9.5 cm). Cross sections are gray or gray-yellow with a fibrous or mucus-like appearance. In the present case, LGFMS has a bland histologic appearance but with an infiltrative growth pattern. The tumor consists of spindle cells that resembled fibroblasts, and there are 2 kinds of morphologic change, namely, heavily collagenized hypocellular zones and cell-rich myxoid nodules. Short fascicular and characteristic whorling growth patterns are also seen. There are more arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration. There is a case report of LGFMS with unusual central necrosis in a 77-year-old man [7]. The spindle tumor cells have a bland appearance with no heteromorphism, and mitotic figures are scarce. Approximately 30% of otherwise typical cases show the focal presence of collagen rosettes, consisting of a central core of hyaline collagen surrounded by a cuff of epithelioid fibroblasts. Occasional cases have shown a hybrid lesion of LGFMS and sclerosing epithelioid fibrosarcoma (SEF) [8]. Researchers have tried to find an antibody with specificity for LGFMS, but so far, only vimentin, CD99, Bcl-2, and MUC4 are positive for this tumor [9]. Epithelial membrane antigen, keratin, desmin, SMA, S100, CD34, and myogenin are negative for LGFMS [10]. There is an especially interesting finding that 50% (5/10) of LGFMS are positive for DOG-1 [11]. Hence, gastrointestinal stromal tumors should be considered as a differential diagnosis for LGFMS.
3.4. Differential diagnosis Histologic appearance of LGFMS is similar to several other kinds of soft tissue tumors with spindle tumor cells and myxoid structure. Hence, it is easy to make a wrong diagnosis. Here, we summarize the differential diagnoses for LGFMS. 3.4.1. Sclerosing epithelioid fibrosarcoma LGFMS resembles SEF morphologically because both of them can present with rich eosinophilic collagenized zones and myxoid areas. However, sclerotic changes are more noticeable in SEF than in LGFMS. Moreover, small epithelioid
Y. Zhang et al. cells are organized as nest, streak, and aciniform structure in SEF, but spindle tumor cells of LGFMS are arranged in a whorling structure. LGFMS has distinctive arcades of curvilinear blood vessels accompanied by perivascular hyaline degeneration, but SEF always presents with vessels with a hemangiopericytoma-like pattern. Rearrangement of EWSR1 gene can be detected in 90% of pure SEF, but FUS-CREB3L2 gene is rearranged in LGFMS. It should be stated that rearrangement of FUS-CREB3L2 gene can also be detected in hybrid SEF/LGFMS [12]. 3.4.2. Solitary fibrous tumor Alternating hypocellular and cell-rich areas can be seen in solitary fibrous tumor (SFT), and those areas are separated by gross scar-like collagen with hyaline degeneration and branching vessels with hemangiopericytoma-like pattern. SFT is positive for STAT-6, CD34, CD99, and Bcl-2, but LGFMS is negative for STAT-6 and CD34 [13]. Nevertheless, there is a report of LGFMS that presents with vessels with hemangiopericytoma-like pattern and is easily misdiagnosed as SFT [14]. An LGFMS variation with vessels with hemangiopericytoma-like pattern should be considered when the tumor is negative for CD34. 3.4.3. Low-grade myxofibrosarcoma LGFMS should be discriminated from low-grade myxofibrosarcoma because of their different clinical behaviors. Low-grade myxofibrosarcoma mainly affects patients in the sixth to eighth decades of life, whereas this tumor is exceptionally rare under the age of 20 years. Low-grade myxofibrosarcoma shows multinodular growth with a prominent myxoid matrix, and frequent findings include atypical fibroblastic cells, elongated curvilinear capillaries, and pseudolipoblasts. Tumor cell proliferation index of low-grade myxofibrosarcoma, including MIB-1 and cyclin E LI, is obviously higher than that of LGFMS in immunostaining, but lower than LGFMS for p21 LI and p27 LI. In addition, there is no FUSCREB3L2 fusion gene in low-grade myxofibrosarcoma. 3.4.4. Mammary-type myofibroblastoma Mammary-type myofibroblastoma is a kind of benign mesenchymal neoplasm with sharply circumscribed margin, composed of spindle cells with features of myofibroblasts, embedded in a stroma that contains coarse bands of hyalinized collagen and conspicuous mast cells, admixed with a variable amount of adipose tissue. Otherwise, the spindle cells are consistently immunopositive for desmin and CD34. Expression of SMA is present in a third of cases. However, LGFMS is immunonegative for desmin, CD34, and SMA. All tumors have followed a benign course after marginal local excision. It is different from malignant behavior of LGFMS. 3.4.5. Borderline or malignant phyllodes tumor of the breast Malignant phyllodes tumor of the breast presents with an infiltrated growth pattern and obvious sarcomatoid stroma–
Primary low-grade fibromyxoid sarcoma of the breast like fibrosarcoma. Borderline phyllodes tumor of the breast has intermediate characteristics between benign and malignant phyllodes tumor, and sometimes has stroma that resembles well-differentiated fibrosarcoma. Both borderline and malignant phyllodes tumors of the breast should be discriminated from rare LGFMS because collagenized hypocellular zones and myxoid areas also can be seen in phyllodes tumor stroma. Neither borderline nor malignant phyllodes tumor shows FUS-CREB3L2 fusion gene, so FISH detection can clarify the diagnosis. 3.4.6. Myxoid liposarcoma Myxoid liposarcoma is composed of uniform round- to ovalshaped primitive nonlipogenic cells and a variable number of small signet-ring–like lipoblasts in a prominent myxoid stroma with a characteristic branching vascular pattern. There is no alternating arrangement between myxoid areas and sarcoma cells in liposarcoma, but well-defined nodular growth pattern. Like LGFMS, myxoid liposarcoma also lacks nuclear pleomorphism, giant tumor cells, and significant mitotic activity. Myxoid liposarcoma has a delicate arborizing “chicken-wire” capillary vasculature and lacks the distinctive arcades of curvilinear blood vessels of LGFMS. Myxoid liposarcoma usually shows either FUS-DDIT3 or EWS1-DDIT3 rearrangement. It is different from rearrangement of FUS-CREB3L2 gene in LGFMS. Besides above, some other tumors and tumor-like lesions like peripheral nerve tumor (neurofibroma or perineurioma), myxoma, and nodular fasciitis are also worth adding this note to the differential diagnosis.
3.5. Therapy Although radical, wide-margin surgical excision is recommended, the ideal goal of a large safety margin of healthy tissue might be unattainable if it requires resection of vital anatomical structures. LGFMS has a low mitotic rate; therefore, neither chemotherapy nor radiotherapy is expected to have a significant effect on long-term prognosis.
3.6. Prognosis Recurrence of LGFMS is not uncommon at 5 years after surgery, and there are case reports of broad ligament and liver metastasis from LGFMS [4,15]. The relapse, metastasis, and case fatality rates of LGFMS are 9%, 6%, and 2%, respectively, according to a retrospective analysis of 73 cases. Long-term follow-up is necessary because LGFMS can develop metastasis and recurrence many years after primary pathological diagnosis. In summary, LGFMS is a rare soft tissue tumor, especially in the breast. It has a bland histologic appearance but malignant biological behaviors, including recurrence and metastasis, are always seen. Careful histologic observation and pertinent immunohistochemical detection are helpful to make a precise pathological diagnosis. We recommend FISH detection of
211 FUS-CREB3L2 fusion gene and rare FUS-CREB3L1 fusion gene in LGFMS.
Acknowledgments We thank Dr HongYing Zhang in the Department of Pathology, West China Hospital of Sichuan University, for FISH detection and diagnosis. Written consent for publication is obtained from the patient.
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