Original Article Proliferative Myositis and Nodular Fasciitis: a Retrospective Study with Clinicopathologic and Radiologic Correlation

Int J Clin Exp Pathol 2019;12(12):4319-4328 www.ijcep.com /ISSN:1936-2625/IJCEP0103343

Original Article Proliferative myositis and nodular fasciitis: a retrospective study with clinicopathologic and radiologic correlation

Siyuan Gan1*, Dongqi Xie2*, Haixia Dai3*, Zhi Zhang4*, Xiaoqing Di5, Rujia Li1, Linlang Guo6, Yanqin Sun1

1Department of Pathology, Guangdong Medical University, Xiashan District, Zhanjiang 524023, Guangdong, P. R. China; 2Department of Ultrasound, The Second Affiliated Hospital of Guangdong Medical University, Xiashan Dis- trict, Zhanjiang 524023, Guangdong, P. R. China; Departments of 3Ultrasound, 4Thyroid and Mammary Vascular Surgery, 5Pathology, The Affiliated Hospital of Guangdong Medical University, Xiashan District, Zhanjiang 524023, Guangdong, P. R. China; 6Department of Pathology, Zhu Jiang Hospital, Southern Medical University, Haizhu Dis- trict, Guangzhou 510280, Guangdong, P. R. China. *Equal contributors. Received October 9, 2019; Accepted November 25, 2019; Epub December 1, 2019; Published December 15, 2019

Abstract: Proliferative myositis (PM) and nodular fasciitis (NF) are two diseases easily misdiagnosed as cancer, often promoting unnecessary invasive procedures. To make accurate diagnoses of PM and NF and for the differential diagnosis between them, we performed a retrospective study to evaluate the roles of the clinical, radiologic, and pathologic characteristics of PM and NF. With an emphasis on the clinicopathologic and radiologic characteristics, we conducted a retrospective study of 8 cases of PM and 64 cases of NF that were diagnosed between 2012 and 2018. According to MRI findings, the lesions of PM and NF appeared as homogeneous masses with homogenous hypointensity or isointensity on T1-weighted images and as moderately or markedly hyperintense signals on T2-weighted images compared to skeletal muscle. In terms of histopathologic features, the differences between PM and NF mainly consisted of the presence of ganglion-like myofibroblasts with vesicular nuclei and basophilic cytoplasm in PM. The areas abundant in myxoid stroma with inflammatory infiltration that did not have abundant ganglion-like cells suggest NF. Immunohistochemically, the spindle-shaped cells of PM stained positive for smooth muscle actin (SMA), while the ganglion-like cells were negative. The spindle-shaped cells of NF showed diffuse expression of SMA, calponin, and vimentin. Our comprehensive study further demonstrated that PM and NF had a wide clinicopathologic and radiologic spectrum. Correlation with the clinical, radiologic and pathologic characteristics may help clinicians and pathologists make accurate diagnoses.

Keywords: Proliferative myositis, nodular fasciitis, clinical characteristics, radiological characteristics, pathology

Introduction As they are prone to misdiagnosis, we performed a retrospective study of the clinical, Proliferative myositis (PM) and nodular fasciitis radiologic and pathologic characteristics of PM (NF) are within a spectrum of benign myofibro- and NF. With this work, we hope to deepen the blastic tumor-like lesions [1, 2]. Since they understanding of PM and NF and to broaden appear as rapidly growing masses, PM and NF the differential diagnostic possibilities to help are easily and mistakenly diagnosed as each surgeons, radiologists, and pathologists avoid other or even as sarcoma [1, 3]. The differential misdiagnosing soft tissue masses. diagnosis depends on the consideration of magnetic resonance imaging (MRI) or comput- Materials and methods ed tomography (CT) images and pathologic and clinical characteristics [4-9]. The clinical, radio- Patient cohort logic and pathologic findings are variable, and the distinction between soft tissue masses is With the hospital information management sys- difficult. These challenges may lead to unnec- tem, a retrospective review of the medical re- essary radical surgery as treatment for these cords was performed among all patients with benign lesions. pathological diagnoses of PM or NF that were Characteristics of proliferative myositis and nodular fasciitis evaluated at the Affiliated Hospital of Guang- and hyperintense signal compared to skeletal dong Medical University between Nov 2012 muscle. Imaging interpretations of CT and MRI and Nov 2018. Using the terms “Proliferative scans were conducted by two senior radiolo- myositis” or “Nodular fasciitis”, eight cases of gists. We reexamined all cases’ imaging data to PM as well as sixty-four cases of NF were investigate the imaging characteristics of PM or accrued from the files of the Department of NF. Pathology. A retrospective search of the imaging data features of those patients with histo- Histopathology logically proven PM or NF was then conducted in the files of the Department of Radiology. Six patients with histologically proven PM had Data, including diagnosis, age, sex, presenting records of immunohistochemical examinations in the files of the Department of Pathology. symptoms, comorbidities, diagnostic proce- Smooth muscle actin (SMA), vimentin, S-100 dures and imaging, surgical management, com- protein, cytokeratin (CK), desmin, and myoglo- plications, and follow-up time, were extracted bin were evaluated in those patients’ speci- by the researchers from the medical records mens. Thirty-nine patients with histologically and radiology and pathology reports and were proven NF had records of immunohistochemi- analyzed. cal examinations in the files of the Department Imaging of Pathology. SMA, calponin, vimentin, desmin, CK, CD34 and S-100 protein were evaluated in MRI was performed on a 3.0-T scanner (General those patients’ specimens. Electric Company, Discovery MR750 3.0 Tesla), using spin-echo (SE) T1-weighted [repetition Histopathologic analysis time (TR) 360-610/echo time (TE) 1.6-9.4] and For each case’s pathological diagnosis, the spin-echo (SE) T2-weighted [repetition time pathology specimens were reviewed by two (TR) 2300-5500/echo time (TE) 75-90], with- senior pathologists. We reexamined all cases’ out fat saturation, acquiring imaging sequenc- 4-μm-thick hematoxylin and eosin (H&E)-stain- es in axial, coronal and sagittal planes using ed sections and immunohistochemical sec- 4- to 8-mm slices. tions to investigate the histopathology of PM All CT examinations were performed on spiral and NF. scanners (General Electric Company, Optima Statistical analysis TM CT680 or Siemens, Somatomsensation64) to produce postcontrast axial images with 0.6- GraphPad Prism 5 (GraphPad software, La to 1.0-mm collimation. Jolla, CA, USA) was used for unpaired t-test analyses and to analyze the median and aver- The exclusion criteria include cases with no cor- age ages of patients with NF. responding radiology since this was a correlation study. Of the 8 patients with histologically Results proven PM, they all had recorded examinations on radiology before excision. Three patients Clinical findings received MRIs. CT scans were performed for 5 patients. Of the 64 patients with histologically Clinically, all patients had symptoms of masses proven NF, 21 patients had recorded examina- that grew rapidly for 1 week to 3 months. All tions on radiology before excision. Thirteen patients were treated by surgery. In the patients patients received MRIs. CT scans were per- with follow-up information (ranging from 3 to 65 formed for 8 patients. months), no patient experienced local recurrence. Image analysis The ages at presentation for the sixty-four CT and MR imaging characteristics were inves- patients with NF ranged from 3 to 84 years. tigated regarding the location, size, internal Approximately 64.06% of the patients were content, and margins of the lesion. The degrees between 21 and 50 years old, whereas pediat- of the MRI and CT scans were subjectively ric (aged <10 years, 3 cases) and elderly pa- assessed as being hypointense, isointense, tients (aged >60 years, 4 cases) accounted for

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excision. However, patients with a preoperative duration of several months were not uncommon. One patient presented with a 14-month history. Approximately half of the patients presented with slight pain or tenderness on pal- pation.

With regard to the anatomic site, the lesions were in the neck, armpits, shoulders, wr- ists, hips and other parts of the body. Twenty-five patients (39.06%) had lesions located in the upper extremities, especially the forearm (n=9 cases, 14%). In total, 13 patients (20.3%) had lesions in the head and neck region, 18 patients (28.13%) had lesions in the trunk, 6 patients (9.38%) had lesions in the lower extremities, 1 patient (1.56%) had lesions in the groin and 1 patient (1.56%) had lesions in the vulva. Of the lesions in the trunk, 2 were located in the breast. All patients were treated by surgery. Among the pa- Figure 1. Radiologic examinations of PM and NF. A-C. MRI examinations of tients with follow-up informa- PM. A 4-year-old girl with an irregular soft tissue mass in the right hip mus- tion (ranging from 4 to 98 cle. A. T1WI showed mainly isointense signal and a small patch of slightly high signal. B. T2WI showed high signal, with empty blood vessels. C. En- months), no patient experienc- hanced scanning showed significant enhancement and enhanced vascular ed local recurrence. shadows. D, E. CT examinations of PM. A 28-year-old man with a mass in the right front chest wall. D. A mass with a CT value of 16 Hu, uneven den- Imaging findings sity, unclear boundaries, and expansive growth. E. The mass invaded the fifth front rib, with significant bone destruction. F, G. MRI examinations of Of the 8 patients with PM, 3 NF. A 44-year-old woman with irregular soft tissue masses on the left side of the armpit. F. Enhanced scanning with significant enhancement and tortu- patients received MRIs. One ous vascular shadows. G. T2WI showed high signal in the lesion, with empty patient’s T1-weighted image blood vessels. H. CT examinations of NF, A 56-year-old man with a mass in (WI) mainly presented isoin- the right front chest wall. A large soft tissue mass next to the right small tense signal and a small patchy chest muscle; the signals from the lesions were isodense compared with shadow of slightly hyperin- those from the adjacent muscles. tense signal (Figure 1A); T2WI showed hyperintense signal, 4.7% and 6.3% of all patients, respectively. The with empty blood vessels (Figure 1B), and diffu- mean age of the patients was 37.48 years, and sion-weighted imaging (DWI) showed hyperin- the median age was 38 years. Forty-one tense signal. The other 2 patients’ T1WIs patients in this series were male, and twenty- showed slightly hypointense signal, and T2WIs three patients were female, for a M:F ratio of and DWIs showed hyperintense signal. In the 1.78. Clinically, most patients presented with a MRIs of three patients, the T1WIs with enhanced solitary subcutaneous nodule, which grew rap- scanning were all significantly enhanced (Figure idly for 2 weeks to 3 months before surgical 1C). CT scans were performed for 5 patients.

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One patient’s mass, which was in the chest were ganglion-like basophilic giant cells or gan- wall, presented uneven density, unclear bound- glion-like myofibroblasts in the area of mucoid aries and expansive growth (Figures 1D, S1). degeneration in one sample (Figure 2D). The mass invaded the fifth front rib, leading to significant bone destructionFigures ( 1E, S1). In pathology samples from the 64 patients with The masses in the other 3 patients presented NF, abundant spindle-shaped cells proliferated uneven density with blurred edges. The image in the loose mucus-like matrix and infiltrated of one patient’s mass in the chest wall dis- around the lesion boundary (Figure 2E). The played a slightly hypointense density with proliferating spindle-shaped cells were arr- blurred edges. anged in bundles and intertwined bands (Figure 2F). Vascular hyperplasia, lymphocytic infiltra- Of the 21 patients with NF, 13 patients had tion and red blood cell extravasation were also MRIs before excision. CT data were available in observed. In some cases, large spindle cells 8 cases. The MRI scans usually presented with mitotic figures were found, but there were slightly hypointense or isointense signals on no abnormal mitotic figures Figure( 2G). T1WIs, and the enhanced scans were significantly unevenly enhanced (Figure 1F); T2WIs In the immunohistochemical sections of PM, (Figure 1G) and DWIs usually showed hyperin- the spindle-shaped cells stained diffuse posi- tense signals. On CT, the signals from the tive for vimentin and SMA (Figure 2H), whereas lesions were hypointense or isodense com- the ganglion-like cells stained strong diffuse pared with those from the adjacent muscles positive for vimentin. Meanwhile, the ganglion- (Figure 1H), and the enhanced scanning did not like cells were negative for SMA (Figure 2I). show significant enhancement. Both cell styles were negative for S-100 protein, desmin, CK, myoglobin (Figure 2J), and Pathological findings myoD1 (Figure 2K).

All lesions of PM were described as well circum- In the immunohistochemical sections of NF, the scribed, soft, slightly nodular, masses with pale spindle-shaped cells showed diffuse expres- yellow fat-like tissue or gray translucent tissue sion of SMA (Figure 2L), calponin (Figure 2M) in the foci on cut sections. The excised speci- and vimentin. Other markers, including desmin mens measured from 1.0 to 6.0 cm in diame- (Figure 2N), CK, CD34 (Figure 2O), and S-100 ter, with mean and median sizes of 2.5 and protein, were all negative. 1.83 cm. All lesions of NF were described as well circumscribed, soft, rubbery-to-firm nod- Discussion ules or masses with glistening appearance on cut sections. The excised specimens measured A previous study found that most patients with from 0.3 to 6.0 cm in diameter, with mean and PM were over 45 years old, but there were also median sizes of 2.35 and 2.18 cm, respective- pediatric cases [1, 9-14]. In the 8 cases of PM, ly. Of note, the lesions were smaller than 3.95 other than one case of a 4-year-old child and cm in 64 cases (87.5%). Those with a greatest one case of a 28-year-old man, the other 6 dimension larger than 4 cm were mostly deeply patients were all over 45 years old. Prior to this seated or intramuscular lesions. description, only 11 cases of PM in children had been reported in the literature [11-13, In pathology samples from the 8 patients with 15-17]. PM, fibroblasts were widely proliferated in the interstitium, and the local muscle tissue was There are three patients who had lesions in the atrophic or completely replaced. Fibroblast pro- skeletal muscles of the chest, and one patient’s liferation separated the muscle bundle. Sam- lesion was in the skeletal muscle of the thigh, ples of the eight patients were observed under which are the two most common lesion loca- a low-power microscope, and the transverse tions for PM. However, in our study, we found a section of the lesion had a checkerboard pat- 4-year-old female child with a lesion on the but- tern (Figure 2A, 2B). In all samples, large-sized tock. To the best of our knowledge, no similar spindle cells were observed and were polygonal case has been reported in previous studies [1, or irregular, with a clear nuclear membrane and 11-13, 15-17]. The clinical progress of the visible nucleoli (Figure 2C). Furthermore, there masses seemed to be rapid, with growth peri-

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Figure 2. Pathologic examinations of PM and NF. A-D. A 57-year-old woman with a mass in the left thigh. Micro- scopic examination revealed proliferating spindle-shaped cells, checkerboard-like pattern, and larger basophilic cells that resemble ganglion cells, which are diagnostic features for PM. A. Low-power microscopy view of proliferative myositis. The muscle bundles are separated by endomysial, perimysial, and epimysial proliferation of fibrous connective tissue in a checkerboard-like pattern (hematoxylin-eosin, original magnifications × 100). B. Medium- power microscopy view of proliferating spindle-shaped cells and skeletal muscle fibers with secondary atrophy (hematoxylin-eosin, original magnifications × 200). C. High-power microscopy view of basophilic ganglion-like cells (hematoxylin-eosin, original magnifications × 400). D. Ganglion-like basophilic giant cells or ganglion-like myofibroblasts in the area of mucoid degeneration (hematoxylin-eosin, original magnifications × 200). E-G. A 40-year-old woman with a mass in the chest wall. Microscopic examination revealed areas of uniform bland spindle cells that

4323 Int J Clin Exp Pathol 2019;12(12):4319-4328 Characteristics of proliferative myositis and nodular fasciitis are arranged in short intersecting fascicles within a loose stroma accompanied by extravasated erythrocytes and scattered lymphocytes, which are diagnostic features for NF. E. The lesion was composed of spindle-shaped cells with abundant elastic fibers. The spindle-shaped cells grew in a mucus-like matrix and had irregular infiltrative margins partially extending into the adipose tissue (hematoxylin-eosin, original magnifications × 100). F. Proliferat- ing spindle-shaped cells are arranged in bundles and interlaced bands (hematoxylin-eosin, original magnifications × 100). G. Spindle-shaped cells indicate the proliferation of fibroblasts or myofibroblasts without hyperchromasia or pleomorphism. Extravasated red blood cells are also present (hematoxylin-eosin, original magnifications × 400). H-K. Immunohistochemical results of PM. A 57-year-old woman with a mass in the left thigh. H. The spindle-shaped cells stained diffuse positive for SMA (original magnifications × 200). I. The ganglion-like cells were negative for SMA (original magnifications × 400). J. PM was negative for myoglobin (original magnifications × 200). K. PM was negative for myoD1 (original magnifications × 200). L-O. Immunohistochemical results of NF. A 31-year-old man with a mass in the right thigh. L. The spindle-shaped cells were diffuse positive for SMA (original magnifications × 200). M. The spindle-shaped cells were positive for calponin (original magnifications × 200). N. The spindle-shaped cells were negative for desmin (original magnifications × 200). O. The spindle-shaped cells were negative for CD34 (original magnifications × 200). ods ranging from 1 week to 3 months. Such a and 3 months before surgical excision. This rapid growth rate was similar to that observed time period is generally similar to that of a pre- in previous reports [1, 9, 12, 18]. viously reported series [6, 19, 20, 28, 31]. However, there was one patient with a 14-month The ages of the patients and the locations of clinical duration in our study. the lesions in our study were all typical for NF. Lesions of NF can occur at any age, but presen- PM and NF are rare in children, both in our tation between the ages of 21 and 50 years is study and in the reviewed literature. In our the most common [4, 5, 19]. A retrospective study and previous reviews, most cases of PM study reviewed 272 cases of NF and showed and NF presented with a solitary subcutaneous that the mean and median ages were both 36 nodule that grew rapidly for 1 week to 3 months years (range, newborn-84 years). Approximately before surgical excision. Both entities can dis- 65% of the patients were between 21 and 50 play rapid growth. PM and NF lesions can easily years old, whereas pediatric (aged <10 years, 9 be mistaken for malignancy due to their rapid cases) and elderly patients (aged >60 years, 16 growth [4]. The most common locations for PM cases) accounted for 3.3% and 5.9% of the lesions were the chest in our study. However, patients, respectively. Our study was mostly the shoulder was also a common PM lesion consistent with previous studies on the age of location in our review [14, 32, 33]. These loca- onset for NF [6]. In accordance with previous tions are quite different from those of NF reports, lesions usually occurred in the upper lesions. The most common locations for NF limbs, particularly the forearms, followed by the lesions in our study were the upper extremities, head and neck region and the trunk. Less fre- especially the forearm, followed by the trunk, quently, lesions occurred in the lower extremi- then the head and neck region, and finally the ties, especially on the thigh [6, 14, 20, 21]. lower extremities.

There were occasional cases of lesions that MRIs of PM have been reported in several developed in the breast, mesentery, groin, and cases. Compared with skeletal muscle, the vulva. In these series, there were 11 lesions in lesions appear as hypointense or isointense T1 the breast, 8 lesions in the groin, and 7 lesions signal, with almost homogeneous enhance- in the vulva [22-28]. In these unusual sites, NF ment in contrast-enhanced T1WIs. T2WIs typi- might not be considered for the diagnosis, par- cally demonstrate a moderately or markedly ticularly for patients with unusually long clinical hyperintense soft-tissue mass [8, 9, 11, 12, histories [6]. The importance of recognizing NF 34]. After an intravenous injection of contrast in the breast, vulva, and groin is to prevent its agent, the lesion demonstrated marked en- misdiagnosis as a malignancy [6, 22, 29, 30]. hancement [1, 8, 12]. However, although MRI In our study, approximately half of the patients findings may be suggestive of an inflammatory presented with slight pain or tenderness on pal- process, such as PM, a definite diagnosis of PM pation. The clinical duration for most patients is not always possible with MRI findings alone, who presented with a rapidly growing solitary and histologic confirmation is required [7, 12, subcutaneous nodule ranged between 2 weeks 13].

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No characteristic CT findings have been de- been no similar reports in previous studies [1, scribed for the diagnosis of PM. Some cases, 7-18, 34]. Although bone involvement in NF is including ours, have reported ill-defined, ex- very rare and is easily visualized on CT [4, 35, pansile lesions that appear iso- or hypointense 36], we found a study that reported a case of compared to the surrounding muscle with NF with osseous involvement of the hallux [37]. unenhanced CT scanning [12, 17]. Although the Therefore, these findings remind us that lesion may show homogenous or heteroge- although there are no unique radiologic find- neous enhancement after contrast material ings for PM and NF, these entities must be administration, no enhancement may be de- included in the preoperative differential diagno- tected in some cases [7, 9, 12, 18]. CT may not sis of soft-tissue masses that demonstrate play an unimportant role in the characterization rapid growth. of PM [7]. The characteristics of PM on histology include a On the MRIs of NF, the lesion often appears as checkerboard pattern of myofibroblasts that homogenous T1 signal that is iso- or hypoin- infiltrate the surrounding healthy muscle, gan- tense to the adjacent skeletal muscle and as glion-like basophilic giant cells, and no sign of heterogeneous intermediate to hyperintense atypical mitosis [1, 12, 14, 18, 32, 38]. A previ- signal on T2WIs with enhancement after gado- ous report focused on the presence of gangli- linium administration [4-6, 20]. This is consis- on-like cells and the possibility of these cells tent with the MRI features of our series. leading to a mistaken diagnosis of sarcoma Furthermore, NF lesions also show heteroge- due to their resemblance to rhabdomyoblasts neous intermediate-to-high signals with differ- [33]. In another study, the key distinguishing ent enhancement patterns on T2- or STIR- features between the two entities were the weighted sequences, which are attributable to absence of cytoplasmic cross-striations in the the variable components and cellular histology. ganglion-like cells and the presence of fibro- Some cases may demonstrate distinct and dis- blasts, both of which were useful for excluding crete internal and central high T2W signal areas rhabdomyosarcoma [38]. Although numbers of with low T2W signal intensity in the peripheral factors, including the increase in nuclear size, rim, which represents reticulated perilesional prominent nucleoli and high mitotic rate, can soft tissue edema on fluid-sensitive sequences lead to concern, the smooth nuclear contour [5, 6]. However, one study reported that all of and finely distributed chromatin are indicative the lesions in three patients with NF appeared of the cell’s benign nature [39]. slightly hyperintense compared to skeletal muscle on T1WIs, although T2WIs appeared There are various histological characteristics of hyperintense and enhanced during scanning NF, including plump immature fibroblast-like with heterogeneous contrast enhancement spindle cells, chronic inflammatory cells, capil- [21]. On CT, the image features of NF were usu- lary proliferation, vascular channels with ally fascia-based, oval in shape, and homoge- extravasated red blood cells and myxoid mate- neous and low or isodense compared with the rial [5, 23]. Due to its rapid growth, rich cellular- adjacent muscles. In patients with cystic and ity and increased mitotic activity, NF may be mucoid degeneration, the contrast-enhanced confused with sarcoma [40], but NF can also CT scan showed a heterogeneous appearance, be differentiated by a number of features, with prominent peripheral rim-like enhance- including: (a) the nuclei are not hyperchromatic; ment in some cases [5, 6]. However, no distinc- (b) the lesion does not extend into the skin; (c) tive enhancement patterns have been reported there are a limited number of mitoses (not for CT or MRI [3]. greater than 1 per high-power field) that are not atypical; and (d) there is a smaller amount of Regardless of MRI or CT, there was no definitive collagen in the stroma than in fibrosarcoma image pattern for the diagnosis of PM or NF in [23]. either our series or previous studies. However, in our series, we unexpectedly found a case of NF closely resembles PM. The difference PM, with a mass in the chest wall. On the CT between these two entities mainly consists of scan, the mass had uneven density, unclear the presence of ganglion-like myofibroblasts boundaries, and expansive growth; the mass with vesicular nuclei and basophilic cytoplasm invaded the fifth front rib, leading to significant in PM. These ganglion-like cells are absent in bone destruction (Figure 1D, 1E). There have NF [1]. Furthermore, areas abundant in myxoid

4325 Int J Clin Exp Pathol 2019;12(12):4319-4328 Characteristics of proliferative myositis and nodular fasciitis stroma with inflammatory infiltration that do of diagnosis, but immunohistochemistry is also not have abundant ganglion-like cells suggest a useful auxiliary means of identification. The NF [1]. Similar to a previously reported study characteristic immunostaining patterns of NF [1], our series had one case of PM with mucoid are positive for SMA, calponin, and vimentin, degeneration accompanied by many ganglion- and negative for CD34, S-100, CK, and like myofibroblasts in the stroma Figure ( 2D). β-catenin [6, 24, 28]. Positive staining of SMA However, areas in which the mucoid stroma and calponin suggests myofibroblastic differ- with inflammatory infiltration is prominent but entiation and less possibility of a sarcoma [24, does not have abundant ganglion-like cells 45]. In our series, NF was diagnosed based on suggest NF (Figure 2E). the immunohistochemical results (positive for SMA and calponin, negative for CD34, CK, and Previous studies showed the immunohisto- S-100) in addition to the morphologic findings. chemical profile of PM, which differed between the spindle-shaped cells and the ganglion-like The diagnosis of PM and NF relies on the clini- cells. The spindle-shaped cells stained positive cal, radiologic, and pathologic characteristics. for vimentin and SMA, whereas the ganglion- Considering these, PM and NF can be distin- like cells stained positive for vimentin. Both cell guished from each other and from proliferative types were negative for S-100 protein, CK, des- lesions of soft tissue or even from sarcoma. For min, and myoglobin [32, 38, 41]. Our study was awareness of the rare occurrence of PM and NF mostly consistent with previous studies on the in unusual locations and at uncommon age of immunohistochemical features of PM (Figure 2H-K). The other features of PM, such as sud- onset, image features and clinical settings is den onset, rapid growth rate, tenderness and critical. inconclusive radiological findings, and cytom- Acknowledgements orphological features such as enlarged nuclei, prominent nucleoli, and high mitotic rate, can This study was funded by Guangdong Medical easily lead to a mistaken diagnosis of sarcoma, University Research Fund (grant no. GDMUM such as rhabdomyosarcoma [32, 38]. However, 201818, GDMUM 201922 and GDMUM 2019- the immunohistochemical profile of rhabdo- 36), National Natural Science Foundation of myosarcoma is positive for myoglobin, desmin, China (grant no. 81702285), Natural Science and myoD1 [42-44]. Myogenin and myoD1 are Foundation of Guangdong Province (grant no. myogenic nuclear transcription factors present early in skeletal muscle differentiation and are 2016A030313822) and Funds for the Cons- currently used as a standard approach to diag- truction of Basic Medical Disciplines in Guang- nosis, with a sensitivity exceeding 95% and a dong Medical University (grant no. 4SG190- specificity of virtually 100% [44]. These mark- 47G). All procedures performed in studies ers are considered more sensitive and specific involving human participants were in accor- than desmin, with myogenin showing no reac- dance with the ethical standards of the institu- tivity in other spindle cell proliferations, such as tional and/or national research committee and NF, malignant peripheral nerve sheath tumor, with the 1964 Helsinki Declaration and its later leiomyosarcoma, or myofibrosarcoma, which amendments or comparable ethical standards. may be included in the differential diagnosis The study was approved by the Institutional [44]. Our study demonstrated that desmin, and Ethical Review Board of the affiliated hospital myoglobin and myoD1 in particular, contribute of Guangdong Medical University. Due to the greatly to the differential diagnosis between retrospective design of the current study and PM and NF. patient anonymization, the review board deter- mined that informed consent was not required. The differential diagnosis of NF includes lesions mainly characterized by proliferation of Disclosure of conflict of interest spindle cells; spindle cell carcinoma and sarcoma among malignant lesions and fibromato- None. sis and myofibroblastoma among benign lesions morphologically resemble NF and need to Address correspondence to: Yanqin Sun, Depart- be distinguished [28]. There is no doubt of the ment of Pathology, Guangdong Medical University, importance of morphology for the confirmation Xiashan District, Zhanjiang 524023, P. R. China. Tel:

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Figure S1. Associated pathology images for one case of PM, a 28-year-old man with a mass in the right front chest wall and significant the fifth front rib destruction, radiology imagesFigure ( 1D, 1E). Microscopic examination revealed proliferating spindle-shaped cells, checkerboard-like pattern, and larger basophilic cells that resemble ganglion cells, which are diagnostic features for PM. A. Low-power microscopy view of proliferative myositis. The muscle bundles are separated by endomysial, perimysial, and epimysial proliferation of fibrous connective tissue in a checkerboard-like pattern (hematoxylin-eosin, original magnification × 100). B. Medium-power microscopy view of proliferating spindle-shaped cells and skeletal muscle fibers with secondary atrophy (hematoxylin-eosin, original magnification× 200). C. High-power microscopy view of proliferating spindle-shaped cells and skeletal muscle fibers with secondary atrophy (hematoxylin-eosin, original magnification × 400). D. High-power microscopy view of proliferating spindle-shaped cells (hematoxylin-eosin, original magnification × 400).