Neurofibromatosis type 1 (NF1) is an autosomal dominant heritable tumor predisposition syndrome. The penetrance of the disease is considered complete, and the phenotype is highly variable (1). The gene locus is 17q11.2 (2). According to current knowledge, the gene product, neurofibromin, primarily plays a key regulatory role in controlling the rat sarcoma virus (RAS) protein. Impaired NF1 function limits the negative regulation of RAS, leading to increased proliferative capacity of the affected cells (3, 4). Typical characteristics of NF1 include neoplasms derived from neural crest cells, particularly originating from nerve sheath cells or their precursors (1, 5). Most connective tissue tumors occurring in the peripheral nervous system of NF1 patients are defined as neurofibromas. Some types of neurofibromas are considered precursors to malignant transformation (malignant peripheral nerve sheath tumor, MPNST) (1, 2, 5, 6). MPNST accounts for a substantial proportion of the reduced life expectancy observed in patients with NF1 compared with the general population (7).

Clinical management of patients with NF1 considers rapidly growing and symptomatic tumors as clinically significant findings requiring prompt diagnosis and treatment (1). Both findings represent the most important clinical indicators for the development of MPNST in patients with NF1 (8). However, the range of NF1-associated lesions is broad, and neoplasms rarely seen in this syndrome can be a diagnostic challenge.

This case report is intended to contribute to the understanding of NF1-associated connective tissue tumors.

A male patient was diagnosed with sporadic NF1 as a child and met the current diagnostic criteria for the NF1 syndrome (1). He had been undergoing surgical treatment for his facial plexiform neurofibroma since childhood at the Department of Oral and Craniomaxillofacial Surgery at the University Hospital of Hamburg. The facial diffuse plexiform neurofibroma was localized in the terminal distribution area of the right second branch of the trigeminal nerve and had proliferated particularly para-medially, leading over several years to both the asymmetric development of the ipsilateral nasal wing and invasive destruction of the left nasolabial musculature. The patient’s facial surgery focused on repeated tumor-reduction and contouring procedures in the nasolabial region. The last correction of this region was performed at the age of 29 years. At the same age, the patient underwent a fully endoscopic mitral valve repair for mitral regurgitation.

Eighteen months later, he attended his final follow-up appointment after his facial tumor surgery. At that time, he had no symptoms or abnormal findings in his right shoulder. About two months later, he noticed a tumor growing on his right shoulder. He initially sought treatment in his hometown. During the procedure, after an incision was made in the skin, the surgery was discontinued because the tumor was deemed inoperable under outpatient conditions. No tissue sample was obtained. Following the interrupted surgical exploration, the patient had not observed any further tumor growth. The patient therefore returned to this clinic for further treatment six months after his last outpatient follow-up. The interval between the tumor becoming detectable and visible and the initiation of treatment was approximately four months.

The initial examination revealed a conspicuous tumor at the level of the right shoulder, located beneath intact skin and showing little mobility over the underlying tissue. The scar from the previous incision had healed without complications (Figure 1A). The patient reported neither pain nor paresthesia. No further pathological findings were noted.

Magnetic resonance imaging (MRI). An MRI scan revealed a smooth-bordered, homogeneously enhancing mass measuring 6×2.2×2.6 cm in the anterior deltoid fibers (Figure 1B and 1C). The mass exhibited discrete perifocal edema at its distal border. On the cross-sectional images, the tumor was sharply defined and appeared hyperintense compared to the surrounding muscle tissue in certain sequences. The mass’s morphology was considered consistent with a neurofibroma. However, it was noted that other solid intramuscular tumors can also produce this appearance on MRI. Additionally, a purely cutaneous/subcutaneous mass, located further dorsal to the primary tumor and above the acromion, was identified. This mass also enhanced with contrast and measured approximately 1.7 cm in diameter. This small mass was classified as a neurofibroma (9). No other lesions were detected on the thoracic MRI. Given the patient’s predisposing factors for the development of a malignant tumor and the relatively short history of the tumor, it was not possible to confirm the diagnosis noninvasively, despite MRI findings consistent with a benign lesion.

Based on clinical assessments, the tumor was removed under general anesthesia. Intraoperatively, the tumor appeared as a capsule-like mass beneath a thin layer of muscle. The tumor was completely dissected from the surrounding tissue with minimal bleeding (Figure 1D). The external appearance of the solid tumor was consistent with a nodular neurofibroma. The wound healed without complications. Up to now, i.e., two years after tumor removal, no local recurrence of the lesion has occurred. However, two years after the myxoma was removed, the patient developed a small, exophytic, reddish-pigmented skin tumor within a short period of time near the scar on his right shoulder. The tumor was completely removed. The histological diagnosis was a glomeruloid hemangioma.

Histology. Macroscopically, the tumor appeared solid, firm, and pseudo-capsularly demarcated with dimensions of 5.2×3.1×2.8 cm. Microscopically, the tumor cells were spindle shaped. Focally, adherent muscle fibers were present at the tumor margins. The tumor had a moderately increased cell density on a finely granular, myxoid, and collagen-rich matrix. The tumor cells contained curved nuclei with uniformly stained chromatin. The nuclear division rate was not elevated, and there was no significant nuclear atypia or necrosis. Immunohistochemically, the tumor cells were consistently negative for S100, epithelial membrane antigen (EMA), desmin, smooth muscle actin (SMA), and MUC4. In contrast, the tumor cells expressed CD34. Histone 3 at lysine residue 27 (H3K27) methylation was preserved in the tumor cells. The Ki-67 proliferation index was approximately 1%. In summary, the histological findings were consistent with the characteristics of an intramuscular myxoma of the cellular subtype (Figure 2A). Figure 2B shows, for comparison, an NF1-associated neurofibroma with immunohistochemical antigen detections.

Genetics. The tissue was tested for mutations in the GNAS1 gene, but no mutations were detected (codon 201 of exon 8 and codon 227 of exon 9, Institute of Pathology, Eppendorf University Clinic, Hamburg).

The report describes the rapid development of a subcutaneous tumor that was initially identified by diagnostic tools as an intramuscular lesion and, given the patient’s known diagnosis of a tumor predisposition syndrome, was initially thought to be a neurogenic tumor. Prompt surgical treatment led to a rapid recovery. Histological examination revealed a neoplasm that deviates from the known distribution pattern of tumor diagnoses in patients with NF1. Myxoma appears to be very rare in patients with NF1. Neither review articles (2) nor larger clinical tumor studies on NF1 (10) list myxoma as an associated neoplasm.

Myxoma. Myxoma is a collective term for benign, heterogeneous soft-tissue tumors characterized by a homogeneous, abundant mucoid (myxoid) matrix and sparse, stellate or spindle-shaped cells (11). Histologically, myxoma exhibits loose intercellular connective tissue, often interspersed with sparse neovascularization. Myxoma is not encapsulated but usually presents as a solid mass sharply demarcated from the surrounding tissue. Topographically, a distinction is made between intramuscular (12), juxta-articular (13), and cutaneous types (14). Distinguishing myxoma from other entities with a myxoid matrix can be challenging (11). A distinctive feature of this entity is odontogenic myxoma, which has been given the same designation due to similar microscopic structure (15). However, odontogenic myxoma has a genetic profile that differs from that of myxoma located outside the jaws (16).

Sporadic myxoma. Myxomas are rare tumors. They are most frequently diagnosed with skin and muscles. Intramuscular myxomas are mainly diagnosed in the trunk and are also observed in the large muscles of the extremities, particularly of the lower parts (17). Recent studies suggest that up to 0.3% of the population develops a cardiac tumor, the vast majority of which are myxomas (18). Cardiac myxomas can become acutely symptomatic, potentially leading to cardiac arrhythmias (19). Cutaneous myxomas are typically superficial lesions. In other words, they do not penetrate beyond the subcutaneous fat tissue into deeper parts of the body.

Myxoma of deltoid muscle. Sporadic intramuscular deltoid muscle myxoma eventually is characterized by swelling (20, 21). Local factors such as the history of trauma (22) or evidence of physical stress (23) are considered possible causes of tumor development. The association of myxoma with adjacent osseous lesions indicates transitional forms within the entity’s classification and the need for confirmatory diagnosis (24).

Syndromic myxoma. Myxoma is part of the spectrum of Carney complex disorders. Cutaneous myxomas are the most common type found in the outer layers of the body (25). However, cardiac myxomas are an important finding in this syndrome (14). In very rare cases, myxoma may arise in a patient with extraosseous manifestations of fibrous dysplasia (Mazabraud syndrome) (26). Myxomas of the deltoid muscle have been described on several occasions in Mazabraud syndrome (27-29). The patient in this study had a confirmed diagnosis of NF1 and café-au-lait spots. The diffuse neurofibroma on the right side of the nasolabial region caused only slight deformities to the adjacent bone (deviation of the anterior nasal spine, indentation of the piriform aperture on the tumor side), as has already been described for other locations of diffuse plexiform neurofibromas of the face and adjacent bones (30). He had neither bone deformities nor skeletal structural abnormalities typical of fibrous dysplasia, nor did he exhibit the pigmentation pattern consistent with the non-skeletal manifestations of this non-hereditary syndrome. However, cases of fibrous dysplasia occurring in conjunction with NF1 have been reported (31).

In a large single-center study on the diagnosis and treatment of myxomas, data from 41 patients were analyzed (17). In three cases, the myxoma originated in the deltoid muscle (7.3% of the study group; all female, aged 47, 49, and 53 years). The authors describe one confirmed and one suspected case of Mazabraud syndrome for the entire cohort.

Neurofibroma with myxomatous differentiation. Neurofibromas may contain myxoid components to a considerable extent (32). Myxoma can develop within a nerve (33). Distinguishing between a myxoma and a nerve sheath myxoma can be challenging (34).

In addition to distinguishing tumor components by light microscopy, such as an increased content of bundles of wavy collagen fibers in neurofibroma, immunohistochemical analysis aids in differentiating the two entities. The detection of CD34 is considered an important but nonspecific marker in myxoma (35). Moreover, neurofibroma also expresses CD34 (5, 36). The immunoreaction with anti-S-100 antibody, which is typically used for detection of Schwann cells, is helpful (Figure 2B), although cardiac myxomas may also express S-100 (37).

Genetics. The patient’s constitutive NF1 mutation has been identified. The detection of GNAS1 mutations serves as a diagnostic tool for myxomas. However, GNAS1 mutations were detected at the characteristic gene loci in only 50% of myxomas (38). The detection rate is consistent with data from a recently published study on the diagnosis and treatment of myxomas. The GNAS1 mutation status was investigated in 85.5% of cases. The detection rate was 57.1% (17). Another study detected a GNAS1 mutation (R201H and R201C) in 36.5% of 63 cases of intramuscular myxoma. In contrast, cardiac myxomas showed no evidence of a GNAS1 mutation (39). GNAS1 mutation detection is therefore merely a supplement to histological diagnosis in myxoma. However, comparing myxomas and grade 1 myxofibrosarcomas, GNAS1 mutations were only detected in intramuscular myxomas (38). One possible reason cited for the relatively low detection rate of GNAS1 mutations in intramuscular myxomas is that standard genetic tests do not detect rare pathogenic variants that may occur in this condition (40, 41). While GNAS1 mutations are present in up to 90% of intramuscular/cellular myxoma, a minority of cases present without typical GNAS1 mutations (42, 43). It remains unclear whether the failure to detect a GNAS1 mutation in this NF1 case is related to the underlying disease.

Intramuscular myxoma is a very rare addition to the diagnostic spectrum of rapidly growing soft tissue tumors in NF1. The clinical characteristics of this tumor were indistinguishable from those of a peripheral nerve sheath tumor (44, 45). Timely surgical exploration of the lesion provides the basis for specific diagnosis and appropriate therapy (46). Diagnosing this entity can be challenging. When examining patients with NF1, it should be noted that more than one in five patients may develop non-neurofibroma neoplasms (isolated lesions) (47).

The Authors declare that there are no conflicts of interest with respect to this publication.

R. E. Friedrich: Treatment of the patient, conceptualization, draft and corrections of the manuscript. C. Kresbach: Histologic diagnosis, draft and corrections of manuscript. C. Hagel: Histologic diagnosis, draft and corrections of manuscript. All Authors have agreed to the release of the manuscript for publication.

The patient has given written consent to the publication of the treatment report in an anonymized form.

This research received no external funding.

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.