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Dedifferentiated soft tissue leiomyosarcoma with heterologous osteosarcoma component: case report and review of the literature

Dedifferentiated soft tissue leiomyosarcoma with heterologous osteosarcoma component: case report... Background: Soft tissue dedifferentiated leiomyosarcoma with heterologous osteosarcomatous component is an extremely rare entity described in only few cases in the literature. Case presentation: We report the case of a 65-year-old male patient who, after initial inadequate surgery of a tumor of the left forearm, developed local recurrence that was treated with neoadjuvant chemotherapy, surgery and postoperative radiation therapy. Histologically the tumor showed an abrupt separation of two different patterns. One component consisted of interlacing fascicles of spindle cells with cigar-shaped nuclei strongly positive for smooth muscle actin, desmin and H-caldesmon. The other component consisted of a high-grade pleomorphic sarcoma with osteoid and chondroid matrix production, which positive for SATB2. Thus, a final diagnosis of dedifferentiated leiomyosarcoma was rendered. Fifteen months after treatment, the patient presented further local and distant relapse with pulmonary metastases and died 23 months after the first presentation. Discussion and conclusions: Dedifferentiated leiomyosarcoma is a highly malignant neoplasm with a poor out - come. Extensive sampling of soft tissue leiomyosarcomas is recommended to detect possible dedifferentiated areas as they represent a crucial prognostic parameter. Keywords: Soft tissues, Leiomyosarcoma, Dedifferentiated, Osteosarcoma Background secondary tumor localization from distant sites, although Leiomyosarcoma (LMS) is an aggressive soft tissue sar- the former is rare, with about 0.7% incidence of all pri- coma that accounts for about 7 to 10% of all soft tissue mary malignant bone tumors [5]. sarcomas and usually occurs in adult and elderly patients The term ‘dedifferentiated leiomyosarcoma’ was first [1]. The most common involved site is the retroperito - used by Schmookler and Lauer in 1983 [6] and refers neum [2], but it can also affect internal organs (e.g. uterus to a tumor morphologically characterized by an abrupt or stomach), whereas localization at the limbs is unusual transition from classic leiomyosarcoma to high-grade [3]. Moreover, sinonasal tract LMSs are exceptionally sarcoma which does not express immunohistochemical rare with no more than 100 cases reported in the English muscular markers. In rare cases, the non-myogenic com- literature [4]. LMS can also occur in bone, as primary or ponent of the tumor presents heterologous differentia - tion. Here we describe a case of a leiomyosarcoma with an osteosarcomatous dedifferentiated component and we *Correspondence: raffaele.gaeta@med.unipi.it review the clinico-pathologic features of the previously Department of Translational Research and of New Technologies reported cases. in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gaeta et al. Clin Sarcoma Res (2020) 10:6 Page 2 of 6 Case presentation A 65-year-old man came to our observation with a solid-elastic mass of about 4.5  cm maximum diameter on the proximal region of the left forearm, ulnar side, that appeared hypomobile on the underline planes. He reported being affected by this “bump” for at least 20  years, but it had recently shown a rapid growth. Furthermore, he reported having already undergone another excision in local anesthesia after an ultrasound examination about 1  year before at another hospital. An X-ray of the forearm showed a soft tissue mass with irregular calcifications (Fig.  1) and CT scan of the limb confirmed this finding. Magnetic Resonance Imaging (MRI) showed a soft tissue mass arising in the subcu- tis and involving the skin and the subfascial and mus- cular planes, with partial invasion of wrist and fingers flexor muscles and partially surrounding the bone (lat - eral side of the ulna). The mass was isointense to mus - cle in T1-weighted sequence (Fig.  2a), hyperintense on T2-weighted sequence (Fig.  2b), with contrast medium enhancement on T1-weighted sequence (Fig.  2c) and highly vascular (Fig. 3). Staging exams (total body Com- puted Tomography scan and Positron Emission Tomog- raphy scan), showed no other tumor localizations. After preoperative needle biopsy, surgical excision of the tumor was performed, including skin (with the scar of the previous surgery), fascia, muscles and a portion of the ulna. Reconstruction was performed with plate, Fig. 2 Magnetic Resonance Imaging (MRI) showing a soft tissue mass in the subcutis. The lesion is isointense to muscle in T1-weighted sequence (a), hyperintense on T2-weighted sequence (b), and shows contrast medium enhancement on T1-weighted sequence (c) Fig. 1 X-ray of the forearm showing a soft tissue tumor with areas of calcification (arrows) G aeta et al. Clin Sarcoma Res (2020) 10:6 Page 3 of 6 Fig. 4 Low power view showing the two abruptly separated components of the tumor. Well-differentiated leiomyosarcoma is shown in the lower and high-grade osteosarcoma in the upper right (40×) a marker of osteoblastic differentiation was positive only in the osteosarcomatous component, whereas leiomyo- sarcoma areas were negative (Fig. 7c, d). The final diagnosis was leiomyosarcoma grade 2, according to the French Federation of Comprehensive Cancer Centers (FNCLCC) grading system [7] with areas of high-grade osteosarcoma (so-called dedifferentiated leiomyosarcoma). The tumor infiltrated the dermis, the subcutis and the striated muscle. Surgical margins were Fig. 3 Maximum intensity projections with dynamic contrast free of tumour. The review of the histologic slides from enhanced magnetic resonance imaging (DCE-MRI) showing high the previous surgical excision showed similar histo- vascularization in the arterial phase logical aspects, although the tumor consisted mainly of leiomyosarcoma with a very limited osteosarcomatous component. screws and cement and coverage with a microsurgical rotation flap. Gross examination of the surgical specimen revealed a solid white neoplasm with a maximum diameter of 6 cm in the soft tissues. Histologically, the tumor showed two different, abruptly separated components (Fig.  4). One consisted of a proliferation of atypical spindle or ovoid cells with cigar-shaped nuclei and eosinophilic cytoplasm arranged in long interlacing fascicles, an appearance con sistent with leiomyosarcoma (Fig.  5). The other compo - nent consisted of atypical pleomorphic cells producing osteoid matrix in disorganized trabeculae with focal cal- cification (Fig.  6). Areas of cartilage matrix production were identified as well. Immunohistochemically, areas with leiomyosarcoma- tous appearance were strongly positive for alpha smooth muscle actin (Fig.  7a) and desmin (Fig.  7b), whereas the osteosarcomatous component was negative. Both com- Fig. 5 Well-differentiated leiomyosarcoma consisting of spindle cells ponents were negative for cytokeratins (AE1/AE3 and arranged in intersecting fascicles (200×) CAM5.2), EMA, S100 protein, CD34 and CD31. SATB2, Gaeta et al. Clin Sarcoma Res (2020) 10:6 Page 4 of 6 Fig. 6 High-grade osteosarcoma consisting of highly atypical cells with osteoid matrix production (a; 200×). In other areas neoplastic cells produced cartilage matrix (b; 100×) After the surgical treatment, the patient received three cycles of high-dose adjuvant chemotherapy with adria- mycin and iphosphamide and local sequential radiother- apy (66 Gy). After an interval of 15 months, MRI showed multiple local recurrences at the site of previous exci- sions and a PET CT total body scan highlighted bilateral pulmonary nodules, for which he underwent a new cycle of chemotherapy with gentamicin. The patient died after 23  months from presentation due to the progression of Fig. 7 The leiomyosarcoma component (on the right in a and b) the disease. is positive for alpha smooth muscle actin (a, 40×; inset 400×) and desmin (b, 100×), whereas the osteosarcoma component (on the left in a and b) is negative. SATB2 was positive in the nuclei of neoplastic cells in the osteosarcoma component (c, 400×) and negative in the Discussion and conclusions leiomyosarcoma (d, 400×) Even if there is no consensus regarding the exact defi - nition of dedifferentiated leiomyosarcoma, it may be described as a well-differentiated tumor showing typical Dedifferentiation is a well-known occurrence in lipo - features of a smooth muscle neoplasm with a high-grade sarcoma and chondrosarcoma, but this phenomenon undifferentiated pleomorphic sarcoma component lack - has been only rarely reported in LMS. In most cases, ing expression of muscle markers. G aeta et al. Clin Sarcoma Res (2020) 10:6 Page 5 of 6 dedifferentiated LMS presents discrete transition Feeley et  al. [11] described a 60-year old man with from well-differentiated smooth muscle morphology a LMS in the left thigh. The lesion was resected but he to high-grade pleomorphic morphology with loss of presented 2  years later with pulmonary relapse and, smooth muscle differentiation [8 ]. Only exceptionally 18  months later, with metastases in the occipital lobe. the dedifferentiated component shows heterologous This lesion showed extensive osteoid deposition sur - osteosarcomatous differentiation, and review of the lit - rounded by pleomorphic, mitotically active spindle cells, erature revealed only four previously reported extrau- consistent with osteosarcomatous differentiation. This is terine tumors (Table 1). The search of the literature also considered an unusual pattern of tumour progression, included the term ‘malignant mesenchymoma’ that has in which a well-differentiated LMS developed divergent been abandoned because it is ambiguous. osteosarcomatous differentiation in the recurrence. The first case was a 71-year-old man who underwent The main clinical and histological differential diagnosis resection of an intramuscular lesion of the leg, which is with myositis ossificans. This benign lesion presents a had rapidly enlarged in the preceding 8  weeks [9]. The characteristic zonal growth pattern, with a central area tumour was excised widely and postoperative local that consists of a nodular fasciitis-like proliferation of radiotherapy was administered. A local recurrence and bland spindle cells, and progressive deposition of oste- a solitary pulmonary metastasis were excised 8 and oid matrix in the periphery. Malignant bone forming 9 months later respectively. The patient died of dissem - tumors of the soft tissues, including the present case, lack inated disease 22 months after initial excision [9]. this orderly growth pattern and usually present marked Grabellus et al. [10] studied a soft tissue tumor of the cytologic atypia. Another entity that can be considered right groin region of a 35-year-old woman and an initial in the differential diagnosis is dedifferentiated liposar - diagnosis of high grade LMS was made. Lung metas- coma with heterologous smooth muscle and osteo-chon- tases were discovered 6  months after the first surgical droblastic differentiation. This possibility was excluded procedure and 7  months later, the tumor showed local because there was no evidence of a well-differentiated recurrence. Histologically, the recurrence showed high liposarcoma component in both the first specimen and cellularity and was composed by round irregular to in the recurrence, and in addition the tumor was nega- pleomorphic cells with high mitotic activity. Neoplas- tive for MDM2 and CDK4. The possibility that the lesion tic osteoid was deposited in a lacy, trabecular pattern represents a soft tissue osteosarcoma in which spindle and was focally mineralized. The tumor cells resembled cell areas show features of leiomyosarcoma or myofi - malignant osteoblasts. brosarcoma was also evaluated, but it seemed unlikely The large series of 18 dedifferentiated LMSs reported because the two components were always sharply sepa- by Chen et al. [8] included a retroperitoneal mass com- rated, a feature more consistent with the concept of posed by well-differentiated LMS with numerous oste - dedifferentiation. oclastic giant cells and heterologous osteosarcomatous Considering all the cases reported, the average age is differentiation with malignant osteoid formation. The 60 years, with a clear male predominance (4:1). It is very patient was a 66-year old man treated with neoadjuvant important to notice that all the 5 patients had local recur- radiation prior to surgical excision followed by chem- rences and developed distant metastases despite aggres- otherapy, but he developed hepatic metastases and sive treatments. In 3 patients the outcome was fatal died of disease after 8  months. One further retroperi- (death at 8, 22 and 23 months after surgical excision) due toneal LMS in this series presented benign-appearing to the progression of the disease, while no clinical follow- bone and cartilage. This patient was alive with disease up was detailed for the remaining 2 patients. These data 37 months after presentation. confirm that dedifferentiated LMS of the soft parts is a highly aggressive tumor. According to the literature, these Table 1 Summary of the salient clinico-pathologic features of dedifferentiated leiomyosarcomas with osteosarcomatous elements of the peripheral soft tissue reported in the literature Case n. Age Sex Primary site Local Metastases Status References recurrence 1 71 M Leg Yes Lung Deceased after 22 months [9] 2 35 F Groin Yes Lung Unknown [10] 3 66 M Retroperitoneum Yes Liver Deceased after 8 months [8] 4 60 M Thigh Yes Occipital and lung Unknown [11] 5 65 M Forearm Yes Lung Deceased after 23 months Present case Gaeta et al. Clin Sarcoma Res (2020) 10:6 Page 6 of 6 2. Hashimoto H, Tsuneyoshi M, Enjoji M. Malignant smooth muscle tumors neoplasms present 50% to 65.2% of mortality and 89% of of the retroperitoneum and mesentery: a clinicopathologic analysis of 44 incidence of metastasis [12, 13]. It has also been reported cases. J Surg Oncol. 1985;28:177–86. that the loss of myogenic markers in LMS may be a sig- 3. Massi D, Beltrami G, Mela MM, Pertici M, Capanna R, Franchi A. Prognostic factors in soft tissue leiomyosarcoma of the extremities: a retrospective nificant prognostic factor, accounting for a significantly analysis of 42 cases. Eur J Surg Oncol. 2004;30:565–72. higher aggressiveness [14]. For these reasons, extensive 4. Agaimy A, Semrau S, Koch M, Thompson LDR. Sinonasal leiomyosarcoma: sampling is recommended in soft tissue LMS in order to clinicopathological analysis of nine cases with emphasis on common association with other malignancies and late distant metastasis. Head detail the different components that may be present. Neck Pathol. 2018;12:463–70. 5. Wang GY, Lucas DR. Primary leiomyosarcoma of bone: review and update. Acknowledgements Arch Pathol Lab Med. 2019;143:1332–7. Not applicable. 6. Schmookler BM, Lauer DH. Retroperitoneal leyomiosarcoma. A clinico- pathologic analysis of 36 cases. Am J Surg Pathol. 1983;7:269–80. Authors’ contributions 7. Guillou L, Coindre JM, Bonichon F, Nguyen BB, Terrier P, Collin F, Vilain MO, All authors have directly participated in the planning, execution and analysis Mandard AM, Le Doussal V, Leroux A, Jacquemier J, Duplay H, Sastre- of the study, and have approved the final version of the manuscript. The Garau X, Costa J. Comparative study of the National Cancer Institute and contents of this manuscript have not been previously published and have not French Federation of Cancer Centers Sarcoma Group grading systems in been and will not be submitted or published elsewhere. All authors read and a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol. approved the final manuscript. 1997;15:350–62. 8. Chen E, O’Connell F, Fletcher CD. Dedifferentiated leiomyosarcoma: clin- Funding icopathological analysis of 18 cases. Histopathology. 2011;59:1135–43. The authors received no specific funding for this work. 9. Mentzel T, Fletcher CDM. Malignant mesenchymomas of soft tissue asso- ciated with numerous osteoclast-like giant cells mimicking the so-called Availability of data and materials giant cell variant of “malignant fibrous histiocytoma”. Virchows Arch. The datasets during and/or analysed during the current study available from 1994;424:539–45. the corresponding author on reasonable request. 10. Grabellus F, Sheu SY, Schmidt B, Flasshove M, Kuhnen C, Ruchholtz S, Taeger G, Schmid KW. Recurrent high-grade leiomyosarcoma with heter- Ethics approval and consent to participate ologous osteosarcomatous differentiation. Virchows Arch. 2006;448:85–9. The study has been approved by the ethics committee ‘Comitato Etico 11. Feeley C, Gallagher P, Lang D. Osteosarcoma arising in a metastatic leio- Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione: Area myosarcoma. Histopathology. 2005;46:108–17. Vasta Nord Ovest’ (protocol n. 16037). 12. Nicolas MM, Tamboli P, Gomez JA, Czerniak BA. Pleomorphic and dediffer - entiated leiomyosarcoma: clinicopathologic and immunohistochemical Consent for publication study of 41 cases. Hum Pathol. 2010;41:663–71. Not applicable. 13. Oda Y, Miyajima K, Kawaguchi K, Tamiya S, Oshiro Y, Hachitanda Y, Oya M, Iwamoto Y, Tsuneyoshi M. Pleomorphic leiomyosarcoma: clinico- Competing interests pathologic and immunohistochemical study with special emphasis on The authors declare that they have no competing interests. its distinction from ordinary leiomyosarcoma and malignant fibrous histiocytoma. Am J Surg Pathol. 2001;25:1030–8. Author details 14. Demicco EG, Boland GM, Brewer Savannah KJ, Lusby K, Young ED, Ingram Department of Translational Research and of New Technologies in Medicine D, Watson KL, Bailey M, Guo X, Hornick JL, van de Rijn M, Wang WL, and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. Department Torres KE, Lev D, Lazar AJ. Progressive loss of myogenic differentiation in of Orthopaedic Oncology and Reconstructive Surgery, Azienda Ospedaliera leiomyosarcoma has prognostic value. Histopathology. 2015;66:627–38. Universitaria Careggi, Florence, Italy. Department of Diagnostic Imaging, Azienda Ospedaliera Universitaria Careggi, Florence, Italy. Department of Oncology, “S. Stefano” Hospital, Prato, Italy. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- Received: 25 November 2019 Accepted: 9 March 2020 lished maps and institutional affiliations. References 1. Lazar A, Evans HL, Shipley J. Leiomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. Ready to submit your research ? 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Dedifferentiated soft tissue leiomyosarcoma with heterologous osteosarcoma component: case report and review of the literature

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Abstract

Background: Soft tissue dedifferentiated leiomyosarcoma with heterologous osteosarcomatous component is an extremely rare entity described in only few cases in the literature. Case presentation: We report the case of a 65-year-old male patient who, after initial inadequate surgery of a tumor of the left forearm, developed local recurrence that was treated with neoadjuvant chemotherapy, surgery and postoperative radiation therapy. Histologically the tumor showed an abrupt separation of two different patterns. One component consisted of interlacing fascicles of spindle cells with cigar-shaped nuclei strongly positive for smooth muscle actin, desmin and H-caldesmon. The other component consisted of a high-grade pleomorphic sarcoma with osteoid and chondroid matrix production, which positive for SATB2. Thus, a final diagnosis of dedifferentiated leiomyosarcoma was rendered. Fifteen months after treatment, the patient presented further local and distant relapse with pulmonary metastases and died 23 months after the first presentation. Discussion and conclusions: Dedifferentiated leiomyosarcoma is a highly malignant neoplasm with a poor out - come. Extensive sampling of soft tissue leiomyosarcomas is recommended to detect possible dedifferentiated areas as they represent a crucial prognostic parameter. Keywords: Soft tissues, Leiomyosarcoma, Dedifferentiated, Osteosarcoma Background secondary tumor localization from distant sites, although Leiomyosarcoma (LMS) is an aggressive soft tissue sar- the former is rare, with about 0.7% incidence of all pri- coma that accounts for about 7 to 10% of all soft tissue mary malignant bone tumors [5]. sarcomas and usually occurs in adult and elderly patients The term ‘dedifferentiated leiomyosarcoma’ was first [1]. The most common involved site is the retroperito - used by Schmookler and Lauer in 1983 [6] and refers neum [2], but it can also affect internal organs (e.g. uterus to a tumor morphologically characterized by an abrupt or stomach), whereas localization at the limbs is unusual transition from classic leiomyosarcoma to high-grade [3]. Moreover, sinonasal tract LMSs are exceptionally sarcoma which does not express immunohistochemical rare with no more than 100 cases reported in the English muscular markers. In rare cases, the non-myogenic com- literature [4]. LMS can also occur in bone, as primary or ponent of the tumor presents heterologous differentia - tion. Here we describe a case of a leiomyosarcoma with an osteosarcomatous dedifferentiated component and we *Correspondence: raffaele.gaeta@med.unipi.it review the clinico-pathologic features of the previously Department of Translational Research and of New Technologies reported cases. in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gaeta et al. Clin Sarcoma Res (2020) 10:6 Page 2 of 6 Case presentation A 65-year-old man came to our observation with a solid-elastic mass of about 4.5  cm maximum diameter on the proximal region of the left forearm, ulnar side, that appeared hypomobile on the underline planes. He reported being affected by this “bump” for at least 20  years, but it had recently shown a rapid growth. Furthermore, he reported having already undergone another excision in local anesthesia after an ultrasound examination about 1  year before at another hospital. An X-ray of the forearm showed a soft tissue mass with irregular calcifications (Fig.  1) and CT scan of the limb confirmed this finding. Magnetic Resonance Imaging (MRI) showed a soft tissue mass arising in the subcu- tis and involving the skin and the subfascial and mus- cular planes, with partial invasion of wrist and fingers flexor muscles and partially surrounding the bone (lat - eral side of the ulna). The mass was isointense to mus - cle in T1-weighted sequence (Fig.  2a), hyperintense on T2-weighted sequence (Fig.  2b), with contrast medium enhancement on T1-weighted sequence (Fig.  2c) and highly vascular (Fig. 3). Staging exams (total body Com- puted Tomography scan and Positron Emission Tomog- raphy scan), showed no other tumor localizations. After preoperative needle biopsy, surgical excision of the tumor was performed, including skin (with the scar of the previous surgery), fascia, muscles and a portion of the ulna. Reconstruction was performed with plate, Fig. 2 Magnetic Resonance Imaging (MRI) showing a soft tissue mass in the subcutis. The lesion is isointense to muscle in T1-weighted sequence (a), hyperintense on T2-weighted sequence (b), and shows contrast medium enhancement on T1-weighted sequence (c) Fig. 1 X-ray of the forearm showing a soft tissue tumor with areas of calcification (arrows) G aeta et al. Clin Sarcoma Res (2020) 10:6 Page 3 of 6 Fig. 4 Low power view showing the two abruptly separated components of the tumor. Well-differentiated leiomyosarcoma is shown in the lower and high-grade osteosarcoma in the upper right (40×) a marker of osteoblastic differentiation was positive only in the osteosarcomatous component, whereas leiomyo- sarcoma areas were negative (Fig. 7c, d). The final diagnosis was leiomyosarcoma grade 2, according to the French Federation of Comprehensive Cancer Centers (FNCLCC) grading system [7] with areas of high-grade osteosarcoma (so-called dedifferentiated leiomyosarcoma). The tumor infiltrated the dermis, the subcutis and the striated muscle. Surgical margins were Fig. 3 Maximum intensity projections with dynamic contrast free of tumour. The review of the histologic slides from enhanced magnetic resonance imaging (DCE-MRI) showing high the previous surgical excision showed similar histo- vascularization in the arterial phase logical aspects, although the tumor consisted mainly of leiomyosarcoma with a very limited osteosarcomatous component. screws and cement and coverage with a microsurgical rotation flap. Gross examination of the surgical specimen revealed a solid white neoplasm with a maximum diameter of 6 cm in the soft tissues. Histologically, the tumor showed two different, abruptly separated components (Fig.  4). One consisted of a proliferation of atypical spindle or ovoid cells with cigar-shaped nuclei and eosinophilic cytoplasm arranged in long interlacing fascicles, an appearance con sistent with leiomyosarcoma (Fig.  5). The other compo - nent consisted of atypical pleomorphic cells producing osteoid matrix in disorganized trabeculae with focal cal- cification (Fig.  6). Areas of cartilage matrix production were identified as well. Immunohistochemically, areas with leiomyosarcoma- tous appearance were strongly positive for alpha smooth muscle actin (Fig.  7a) and desmin (Fig.  7b), whereas the osteosarcomatous component was negative. Both com- Fig. 5 Well-differentiated leiomyosarcoma consisting of spindle cells ponents were negative for cytokeratins (AE1/AE3 and arranged in intersecting fascicles (200×) CAM5.2), EMA, S100 protein, CD34 and CD31. SATB2, Gaeta et al. Clin Sarcoma Res (2020) 10:6 Page 4 of 6 Fig. 6 High-grade osteosarcoma consisting of highly atypical cells with osteoid matrix production (a; 200×). In other areas neoplastic cells produced cartilage matrix (b; 100×) After the surgical treatment, the patient received three cycles of high-dose adjuvant chemotherapy with adria- mycin and iphosphamide and local sequential radiother- apy (66 Gy). After an interval of 15 months, MRI showed multiple local recurrences at the site of previous exci- sions and a PET CT total body scan highlighted bilateral pulmonary nodules, for which he underwent a new cycle of chemotherapy with gentamicin. The patient died after 23  months from presentation due to the progression of Fig. 7 The leiomyosarcoma component (on the right in a and b) the disease. is positive for alpha smooth muscle actin (a, 40×; inset 400×) and desmin (b, 100×), whereas the osteosarcoma component (on the left in a and b) is negative. SATB2 was positive in the nuclei of neoplastic cells in the osteosarcoma component (c, 400×) and negative in the Discussion and conclusions leiomyosarcoma (d, 400×) Even if there is no consensus regarding the exact defi - nition of dedifferentiated leiomyosarcoma, it may be described as a well-differentiated tumor showing typical Dedifferentiation is a well-known occurrence in lipo - features of a smooth muscle neoplasm with a high-grade sarcoma and chondrosarcoma, but this phenomenon undifferentiated pleomorphic sarcoma component lack - has been only rarely reported in LMS. In most cases, ing expression of muscle markers. G aeta et al. Clin Sarcoma Res (2020) 10:6 Page 5 of 6 dedifferentiated LMS presents discrete transition Feeley et  al. [11] described a 60-year old man with from well-differentiated smooth muscle morphology a LMS in the left thigh. The lesion was resected but he to high-grade pleomorphic morphology with loss of presented 2  years later with pulmonary relapse and, smooth muscle differentiation [8 ]. Only exceptionally 18  months later, with metastases in the occipital lobe. the dedifferentiated component shows heterologous This lesion showed extensive osteoid deposition sur - osteosarcomatous differentiation, and review of the lit - rounded by pleomorphic, mitotically active spindle cells, erature revealed only four previously reported extrau- consistent with osteosarcomatous differentiation. This is terine tumors (Table 1). The search of the literature also considered an unusual pattern of tumour progression, included the term ‘malignant mesenchymoma’ that has in which a well-differentiated LMS developed divergent been abandoned because it is ambiguous. osteosarcomatous differentiation in the recurrence. The first case was a 71-year-old man who underwent The main clinical and histological differential diagnosis resection of an intramuscular lesion of the leg, which is with myositis ossificans. This benign lesion presents a had rapidly enlarged in the preceding 8  weeks [9]. The characteristic zonal growth pattern, with a central area tumour was excised widely and postoperative local that consists of a nodular fasciitis-like proliferation of radiotherapy was administered. A local recurrence and bland spindle cells, and progressive deposition of oste- a solitary pulmonary metastasis were excised 8 and oid matrix in the periphery. Malignant bone forming 9 months later respectively. The patient died of dissem - tumors of the soft tissues, including the present case, lack inated disease 22 months after initial excision [9]. this orderly growth pattern and usually present marked Grabellus et al. [10] studied a soft tissue tumor of the cytologic atypia. Another entity that can be considered right groin region of a 35-year-old woman and an initial in the differential diagnosis is dedifferentiated liposar - diagnosis of high grade LMS was made. Lung metas- coma with heterologous smooth muscle and osteo-chon- tases were discovered 6  months after the first surgical droblastic differentiation. This possibility was excluded procedure and 7  months later, the tumor showed local because there was no evidence of a well-differentiated recurrence. Histologically, the recurrence showed high liposarcoma component in both the first specimen and cellularity and was composed by round irregular to in the recurrence, and in addition the tumor was nega- pleomorphic cells with high mitotic activity. Neoplas- tive for MDM2 and CDK4. The possibility that the lesion tic osteoid was deposited in a lacy, trabecular pattern represents a soft tissue osteosarcoma in which spindle and was focally mineralized. The tumor cells resembled cell areas show features of leiomyosarcoma or myofi - malignant osteoblasts. brosarcoma was also evaluated, but it seemed unlikely The large series of 18 dedifferentiated LMSs reported because the two components were always sharply sepa- by Chen et al. [8] included a retroperitoneal mass com- rated, a feature more consistent with the concept of posed by well-differentiated LMS with numerous oste - dedifferentiation. oclastic giant cells and heterologous osteosarcomatous Considering all the cases reported, the average age is differentiation with malignant osteoid formation. The 60 years, with a clear male predominance (4:1). It is very patient was a 66-year old man treated with neoadjuvant important to notice that all the 5 patients had local recur- radiation prior to surgical excision followed by chem- rences and developed distant metastases despite aggres- otherapy, but he developed hepatic metastases and sive treatments. In 3 patients the outcome was fatal died of disease after 8  months. One further retroperi- (death at 8, 22 and 23 months after surgical excision) due toneal LMS in this series presented benign-appearing to the progression of the disease, while no clinical follow- bone and cartilage. This patient was alive with disease up was detailed for the remaining 2 patients. These data 37 months after presentation. confirm that dedifferentiated LMS of the soft parts is a highly aggressive tumor. According to the literature, these Table 1 Summary of the salient clinico-pathologic features of dedifferentiated leiomyosarcomas with osteosarcomatous elements of the peripheral soft tissue reported in the literature Case n. Age Sex Primary site Local Metastases Status References recurrence 1 71 M Leg Yes Lung Deceased after 22 months [9] 2 35 F Groin Yes Lung Unknown [10] 3 66 M Retroperitoneum Yes Liver Deceased after 8 months [8] 4 60 M Thigh Yes Occipital and lung Unknown [11] 5 65 M Forearm Yes Lung Deceased after 23 months Present case Gaeta et al. Clin Sarcoma Res (2020) 10:6 Page 6 of 6 2. Hashimoto H, Tsuneyoshi M, Enjoji M. Malignant smooth muscle tumors neoplasms present 50% to 65.2% of mortality and 89% of of the retroperitoneum and mesentery: a clinicopathologic analysis of 44 incidence of metastasis [12, 13]. It has also been reported cases. J Surg Oncol. 1985;28:177–86. that the loss of myogenic markers in LMS may be a sig- 3. Massi D, Beltrami G, Mela MM, Pertici M, Capanna R, Franchi A. Prognostic factors in soft tissue leiomyosarcoma of the extremities: a retrospective nificant prognostic factor, accounting for a significantly analysis of 42 cases. Eur J Surg Oncol. 2004;30:565–72. higher aggressiveness [14]. For these reasons, extensive 4. Agaimy A, Semrau S, Koch M, Thompson LDR. Sinonasal leiomyosarcoma: sampling is recommended in soft tissue LMS in order to clinicopathological analysis of nine cases with emphasis on common association with other malignancies and late distant metastasis. Head detail the different components that may be present. Neck Pathol. 2018;12:463–70. 5. Wang GY, Lucas DR. Primary leiomyosarcoma of bone: review and update. Acknowledgements Arch Pathol Lab Med. 2019;143:1332–7. Not applicable. 6. Schmookler BM, Lauer DH. Retroperitoneal leyomiosarcoma. A clinico- pathologic analysis of 36 cases. Am J Surg Pathol. 1983;7:269–80. Authors’ contributions 7. Guillou L, Coindre JM, Bonichon F, Nguyen BB, Terrier P, Collin F, Vilain MO, All authors have directly participated in the planning, execution and analysis Mandard AM, Le Doussal V, Leroux A, Jacquemier J, Duplay H, Sastre- of the study, and have approved the final version of the manuscript. The Garau X, Costa J. Comparative study of the National Cancer Institute and contents of this manuscript have not been previously published and have not French Federation of Cancer Centers Sarcoma Group grading systems in been and will not be submitted or published elsewhere. All authors read and a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol. approved the final manuscript. 1997;15:350–62. 8. Chen E, O’Connell F, Fletcher CD. Dedifferentiated leiomyosarcoma: clin- Funding icopathological analysis of 18 cases. Histopathology. 2011;59:1135–43. The authors received no specific funding for this work. 9. Mentzel T, Fletcher CDM. Malignant mesenchymomas of soft tissue asso- ciated with numerous osteoclast-like giant cells mimicking the so-called Availability of data and materials giant cell variant of “malignant fibrous histiocytoma”. Virchows Arch. The datasets during and/or analysed during the current study available from 1994;424:539–45. the corresponding author on reasonable request. 10. Grabellus F, Sheu SY, Schmidt B, Flasshove M, Kuhnen C, Ruchholtz S, Taeger G, Schmid KW. Recurrent high-grade leiomyosarcoma with heter- Ethics approval and consent to participate ologous osteosarcomatous differentiation. Virchows Arch. 2006;448:85–9. The study has been approved by the ethics committee ‘Comitato Etico 11. Feeley C, Gallagher P, Lang D. Osteosarcoma arising in a metastatic leio- Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione: Area myosarcoma. Histopathology. 2005;46:108–17. Vasta Nord Ovest’ (protocol n. 16037). 12. Nicolas MM, Tamboli P, Gomez JA, Czerniak BA. Pleomorphic and dediffer - entiated leiomyosarcoma: clinicopathologic and immunohistochemical Consent for publication study of 41 cases. Hum Pathol. 2010;41:663–71. Not applicable. 13. Oda Y, Miyajima K, Kawaguchi K, Tamiya S, Oshiro Y, Hachitanda Y, Oya M, Iwamoto Y, Tsuneyoshi M. Pleomorphic leiomyosarcoma: clinico- Competing interests pathologic and immunohistochemical study with special emphasis on The authors declare that they have no competing interests. its distinction from ordinary leiomyosarcoma and malignant fibrous histiocytoma. Am J Surg Pathol. 2001;25:1030–8. Author details 14. Demicco EG, Boland GM, Brewer Savannah KJ, Lusby K, Young ED, Ingram Department of Translational Research and of New Technologies in Medicine D, Watson KL, Bailey M, Guo X, Hornick JL, van de Rijn M, Wang WL, and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. Department Torres KE, Lev D, Lazar AJ. Progressive loss of myogenic differentiation in of Orthopaedic Oncology and Reconstructive Surgery, Azienda Ospedaliera leiomyosarcoma has prognostic value. Histopathology. 2015;66:627–38. Universitaria Careggi, Florence, Italy. Department of Diagnostic Imaging, Azienda Ospedaliera Universitaria Careggi, Florence, Italy. Department of Oncology, “S. Stefano” Hospital, Prato, Italy. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- Received: 25 November 2019 Accepted: 9 March 2020 lished maps and institutional affiliations. References 1. Lazar A, Evans HL, Shipley J. Leiomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. Ready to submit your research ? 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