Abstract
Sclerosing rhabdomyosarcoma (RMS) is a rare subtype of RMS with unique prominent stromal hyalinization and a pseudovascular architecture. It overlaps morphologically with spindle cell RMS and poses both diagnostic and therapeutic challenges because of its rarity and aggressive clinical course. In this article, we report a case of sclerosing RMS arising from a prior craniotomy site, which demonstrated both sclerosing and spindle cell components. A literature review of RMS with sclerosing morphology identified 122 cases. Our review documents the following: sclerosing RMS occurs in both childhood and adult populations, has a predilection for the head and neck areas, and has a worse prognosis in adults. Sclerosing RMS harbors a high frequency of MYOD1 mutations, conferring a poor clinical outcome. Sclerosing RMS and spindle RMS likely represent a morphologic spectrum of one entity.
Keywords
Introduction
Sclerosing rhabdomyosarcoma (RMS) is an uncommon variant of RMS with unique histologic features including prominent stromal hyalinization and a pseudovascular growth pattern.1,2 Along with spindle cell RMS, it is recognized as a provisional entity in the latest classification of soft tissue tumors by the World Health Organization, accounting for 5% to 10% of all RMS cases. 3 Since it was first described in 2000, 2 more than 100 cases have been reported. Sclerosing RMS poses a diagnostic challenge because of its rarity and its morphological overlap with other tumor types. Sclerosing RMS also poses a clinical management challenge given its unclear risk stratification and prognostic factors. In this article, we report a case of sclerosing RMS arising in a prior craniotomy site, and we perform a review of the literature in order to provide an updated understanding of this unique RMS subtype.
Case Report
A 49-year-old man with a history of craniotomy for ruptured intracranial aneurysm 30 years ago presented with complaints of a temporal scalp mass in the region of his surgical site; the mass had doubled in size over the period of 4 weeks. He had been experiencing intermittent sharp pain in the left temporal area for several days prior to examination. A head computed tomography scan showed an enhancing, circumscribed, low-density soft tissue mass measuring 3.7 × 3.7 × 3.5 cm, which was located primarily in the left anterior temporal subcutaneous region. Interestingly, the mass included a small intracranial component, which exerted minimal mass effect on adjacent brain parenchyma, as well as a dominant extracranial component, which extended toward the infratemporal fossa (Figure 1). A fine needle aspiration (FNA) and core biopsy were performed, which both showed a histologically bland, uniform, and monotonous spindle cell neoplasm.
Axial (A) and coronal (B) head computed tomography scans show the mass arising in the prior craniotomy site and presenting with a small intracranial component (arrowheads). The arrow in (A) denotes the clip at the prior aneurysm site.
Due to the nondefinitive diagnostic material obtained by FNA and core needle biopsy, the decision to perform an open biopsy was made. The tumor was identified within the temporalis muscle, and grossly appeared as a pinkish mass with moderate vascularity and a soft consistency. Samples of the tumor, as well as a portion of adjacent temporalis muscle, were sent for frozen and permanent pathological evaluation.
Histologic evaluation of the resected mass revealed different morphologic features compared with the initial material obtained by FNA and core needle biopsy, in that there was a diffuse growth of small nests and linear strings of oval tumor cells embedded in a hyaline sclerotic and myxoid stroma. Micro-alveolar spaces lined by a single layer of neoplastic cells and surrounding intercellular matrix formed a striking pseudovascular pattern (Figure 2A). Most of the tumor cells had scanty cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli. Scattered rhabdoid cells with brightly eosinophilic cytoplasm and eccentric round to oval nuclei were also noted. Some strap-like cells with cytoplasmic tails and multinucleated tumor giant cells were present (Figure 2B); the former lacked any visible cross striations. Spindle cells were seen very focally. Scattered mitotic figures were present (3 per 10 high-power fields), although no necrosis was identified. A variety of differential diagnostic possibilities were considered, including rhabdoid meningioma, angiosarcoma, alveolar rhabdomyosarcoma, and sclerosing epithelioid fibrosarcoma.
(A) An open biopsy of the mass reveals prominent stromal hyalinization and a pseudovascular architecture. (B) Rhabdoid cells with eccentric round to oval nuclei, strap-like cells, and multinucleated tumor giant cells are present. (C) The tumor cells are positive for desmin and myogenin is positive in rare tumor cell nuclei (D).
Immunohistochemical stains were performed on paraffin-embedded sections and showed the tumor cells to be positive for vimentin and desmin (Figure 2C). Myogenin was positive in rare tumor cell nuclei (Figure 2D). A p53 stain showed wild type nuclear staining. BCL2, CD99, and D2-40 were also reactive. Very rare cells were weakly positive for EMA and S100. The tumor was negative for GFAP, PanCK, AE1/3, SMA, HHF35, CD34, STAT6, chromogranin, synaptophysin, INI1 (retained), MUC4, progesterone receptor, and somatostatin receptor (SSTR2, positive in meningiomas). The Ki-67 proliferation index was 20%. Based on the combined morphologic and immunohistochemical features (desmin and myogenin positivity), the diagnosis was considered to be consistent with sclerosing RMS.
The patient underwent a wide surgical resection followed by chemoradiation therapy, due to rapid tumor growth. The resected tumor was a circumscribed but unencapsulated white-tan soft fleshy mass measuring 3.1 × 2.3 × 1.5 cm. The tumor infiltrated into the subcutis, skeletal muscle, and attached portion of dura; however, the margins were free of tumor. The tumor now showed 2 distinct morphologic patterns: a monotonous spindle cell population (similar to the FNA and core needle biopsy), which comprised approximately two thirds of the specimen, and a pseudovascular component (similar to the open biopsy), which comprised a minor portion of the specimen. The 2 components juxtaposed each other somewhat abruptly (Figure 3A-C). Additional immunohistochemistry staining for MyoD1 was performed and showed more tumor cells with nuclear reactivity compared with myogenin (Figure 3D and E). Fluorescence in-situ hybridization for FOXO1 and MDM2 was performed with no evidence of FOXO1 translocation or MDM2 amplification by fluorescence in-situ hybridization. These combined findings confirmed the diagnosis of sclerosing RMS.
(A) The resected tumor exhibits juxtaposed sclerosing and spindle cell components. (B) One third of the tumor demonstrates hyaline sclerotic stroma and a pseudovascular pattern. (C) The rest of the tumor shows a monotonous spindle cell population. (D) and (E) The sclerosing part of the tumor is diffusely positive for MyoD1.
Discussion
To our knowledge, this is the first case of sclerosing RMS arising from a previous craniotomy site. Other sarcomas, including osteosarcoma and malignant peripheral nerve sheath tumors, have been reported in prosthetic implantation sites or related to previous surgical trauma.4-6 Our case of sclerosing RMS displayed characteristic features (hyaline sclerosis and pseudovascular architecture), which were originally described by Mentzel and Katenkamp. 2 Given the tumor’s location at a craniotomy site, along with an intracranial component without invasion through the skull and an enrichment of rhabdoid tumor cells with occasional intranuclear inclusions, the differential diagnosis initially included rhabdoid meningioma, alveolar RMS, sclerosing epithelioid fibrosarcoma, and angiosarcoma.
Rhabdoid meningioma is a high-grade tumor and may present with a pseudovascular papillary architecture and rhabdoid cytology 7 ; however, the tumor cells are usually stained positive for EMA, progesterone receptor, and SSTR2, and typically retain INI1. 8 Alveolar RMS mainly occurs in adolescents and young adults, shows a classical alveolar pattern as opposed to the slit-like pseudovascular morphology of sclerosing RMS, may have wreath-like multinucleated giant cells, 9 and exhibits diffuse nuclear myogenin staining; and characteristic translocations t(2; 13) or t(1; 13) are present in most cases. 10 Typical sclerosing epithelioid fibrosarcoma has a prominent hyalinized, sclerotic collagen matrix with an occasional pseudovascular growth pattern, but lacks muscular differentiation and is immunohistochemically positive for MUC4. 11 Angiosarcoma also lacks myoid markers and stains positive for CD31 and/or CD34. In our case, rhabdomyoblastic differentiation was identified morphologically (brightly eosinophilic cytoplasm, eccentric nuclei, and strap-like cells). Finally, both resection and biopsy specimens showed a focal but definitive myogenin reactivity supporting the diagnosis of sclerosing RMS.
Unlike embryonal and alveolar RMS, which are more common in children and young adults, sclerosing RMS occurs over a wide age distribution. In a large series of pediatric RMS cases, sclerosing features were noted in only 1.1% (13/1207) of all RMS. 12 Our literature review (Table 1) identified 122 cases of sclerosing RMS or RMS with both sclerosing and spindle cell morphologies, including 65 pediatric patients (<18 years, 53%) and 57 adults (47%). The median age was 24 years. There was a bimodal age distribution of sclerosing RMS: the first peak seen in children (<18 years) and young adults (18-29 years; Figure 4), with a second smaller peak in the sixth decade (50-59 years). There were 18 cases of sclerosing RMS in adults more than 50 years old. The male-to-female ratio was 1.5:1 (87 patients). Sclerosing RMS most commonly arose in the head and neck (51/122, 41.8%), followed by the extremities (41/122, 33.6%). Among 71 patients with long-term follow-up data, 16 patients (21%) died of disease within 2 years and 21 patients (29.6%) died within 5 years. In our summary, pediatric cases have a slightly more favorable prognosis: 25.6% (10/39) of pediatric patients died after 5 years compared with 34.4% (11/32) of adults. This tendency is similar to that previous reported. 13
Clinicopathologic Features of Sclerosing Rhabdomyosarcoma.
Abbreviations: ped, pediatric patients; ned, no evidence of disease; awd, alive with disease; dod, died of disease; NA, not tested or unavailable; ext, extremities; GU, genitourinary; met, metastasis.
A literature review of rhabdomyosarcoma (RMS) with sclerosing morphology reveals a bimodal age distribution of sclerosing RMS.
Given its extreme rarity, there are currently no consensus recommendations for the treatment of sclerosing RMS. A retrospective study of all types of adult RMS revealed a poor long-term outcome, due to late tumor stage and a high proportion of less favorable subtypes. 14 However, adult RMS is usually considered to be chemosensitive after risk stratification. While sclerosing RMS initially has a good response to chemotherapy, it often recurs and has a poor prognosis similar to adult alveolar or pleomorphic RMS.15-17 Therefore, patients with sclerosing RMS generally received a combination of surgery, chemotherapy, and/or radiotherapy depending on the extent of resection and status of the surgical margin.15,18 Patients may benefit from wide excision of tumors in the trunk and extremity 19 ; however, this may be impossible for tumors arising in the head and neck. Two case reports have shown that young patients receiving post-chemotherapy allogenic or peripheral stem cell transplantation survived over 6 and 12 years, respectively.20,21 In our case, the patient underwent complete resection of the tumor (without neoadjuvant chemotherapy due to rapid growth) followed by adjuvant chemotherapy and planned radiation of the tumor bed, given both dural involvement and a close surgical margin.
Sclerosing RMS is currently categorized together with spindle cell RMS as one entity in the World Health Organization 2013 classification, though some studies have suggested they may represent distinctive subtypes differing in both pathogenesis and clinical behavior.22,23 A review of the literature shows that sclerosing RMS and spindle cell RMS share some clinicopathological features. They both arise in pediatric and adult patients. Both sclerosing RMS and adult spindle cell RMS 24 have a predilection for the head and neck area, although pediatric spindle cell RMS arises predominantly in the paratesticular region.25,26 Sclerosing RMS and adult spindle cell RMS in the head and neck have a poorer prognosis when compared with pediatric spindle cell RMS.
It is not uncommon that sclerosing RMS shows focal fascicles of spindle cells.2,13,15,17 Ours appears to be the first reported case arising at the site of prior surgery (craniotomy), and it contained a large spindle cell component in addition to the component of sclerosing RMS. It has been speculated that tumors with a variable amount of spindle cells and sclerosis might represent one type of RMS with a spectrum of morphological features. 27 Recent studies, however, have observed a higher frequency of MYOD1 mutation in sclerosing RMS (81.5%, 22/27) as compared with spindle cell RMS (26.9%, 18/67), suggesting they may represent distinctive entities with different molecular pathogenesis.22,28-31 The mutation is partly responsible for the unfavorable outcomes seen in sclerosing and spindle RMS.22,29,30 The mutation status of our case is unknown, but it seems to support the notion that both spindle cell RMS and sclerosing RMS are closely related and may represent a spectrum of the same disease. Future molecular and genetic studies may help better understand the relationship between these 2 subtypes.
Conclusion
Sclerosing RMS is a rare variant of RMS that may be closely related to spindle cell RMS. It occurs frequently in the head and neck in adult patients and displays an aggressive clinical course. This variant of RMS may have lower expression of desmin and myogenin as compared with the usual RMS, but MyoD1 immunohistochemistry is usually positive, which suggests a blockage of rhabdomyoblastic differentiation at an early stage. MyoD1 mutation in sclerosing and spindle cell RMS has been associated with a more aggressive course. Future studies may validate genetic changes specific for sclerosing RMS and may in turn provide potential therapeutic targets.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
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Informed Consent
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Trial Registration
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