Thigh

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2022, Case 20, and is intramuscular myxoma in the thigh. The information provided in this case was accurate and correct at the time of publication in 2022. 
Any changes in terminology since the time of publication may not be reflected in this case. 

Histological sections show a demarcated tumor; however, entrapment of skeletal muscle bundles is observed at the periphery. The lesion is hypocellular and composed of spindle and stellate-shaped cells embedded in an abundant myxoid stroma. A few inconspicuous vessels are present, while nuclear atypia, mitoses, and necrosis are absent. The overall features are those of an intramuscular myxoma.

Intramuscular myxomas are benign mesenchymal neoplasms that most commonly occur in middle-aged females and present as a slow-growing and painless mass. They often affect the extremities, preferentially the quadriceps muscle. The tumors have characteristic MRI findings (high signal intensity on T2 and low signal intensity on T1) that assist in their preoperative recognition. Surgical resection is the treatment of choice, and recurrences are rare if completely excised. Malignant transformation has not been described.

On gross examination, the tumors show a gelatinous and lobulated cut surface, and cystic changes can be appreciated. Most intramuscular myxomas shows the aforementioned histological features, and their Immunohistochemical (IHC) profile is characterized by variable CD34 positivity, rare smooth muscle actin (SMA) reactivity, and negativity for MUC4, desmin, and S100. A subset of tumors referred to as cellular myxomas can show hypercellular areas and have increased vascularity; these still show bland cytomorphology and behave in a benign fashion.

Most (> 90%) intramuscular myxomas, including cellular variants, harbor activating point mutations in exon 8 or 9 of GNAS. Assessing the GNAS mutation status of a myxoid tumor in small biopsies or diagnostically challenging cases is a useful tool that separates intramuscular myxoma from its mimickers. GNAS mutations are also involved in the pathogenesis of fibrous dysplasia, and the association of intramuscular myxomas and fibrous dysplasia is known as Mazabraud syndrome. Patients with this syndrome tend to have multiple intramuscular myxomas and the polyostotic form of fibrous dysplasia. The onset of bone lesions precedes the appearance of the intramuscular myxomas, which usually present in the 5th or 6th decade.

Deep (aggressive) angiomyxoma occurs in the deep soft tissues of the pelvis and perineal region, including the vulvovaginal area in women and the inguinoscrotal soft tissue in men. The tumor cells show spindled morphology and are embedded in a myxoid stroma characterized by a prominent vascular component composed of medium-sized to large vessels. Desmin is typically positive in the spindle cells. HMGA2 gene rearrangements are present in a significant percentage of tumors; however, HMGA2 IHC is not a specific marker despite good sensitivity (90% sensitivity and 80% specific).

Low-grade fibromyxoid sarcoma shows alternating fibrous and myxoid areas and exhibits bland spindle cells arranged in whorls or short fascicles. One-third of cases contain hyalinized collagen nodules surrounded by a cuff of epithelioid tumor cells, so-called collagen rosettes. MUC4 is a highly sensitive and specific IHC marker for this tumor, and it harbors either FUS::CREB3L2 or FUS::CREB3L1 gene fusions.

Myxofibrosarcoma shows a multinodular infiltrative growth, incomplete fibrous septa, variable pleomorphism, and variable myxoid stroma containing a network of elongated curvilinear blood vessels. Low-grade myxofibrosarcoma is relatively hypocellular due to prominent areas of myxoid matrix and contains hyperchromatic and pleomorphic tumor cells. In contrast, high-grade myxofibrosarcoma is more cellular and shows sheets and fascicles composed of spindle and pleomorphic tumor cells with marked atypia. Myxofibrosarcoma does not have a specific IHC profile, and no definable/recurrent molecular events have been described.

Myxoid liposarcoma is composed of bland round to ovoid cells embedded in a myxoid stroma characterized by branching capillary vasculature. Variable numbers of small lipoblasts are identified. The tumor harbors FUS::DDIT3 or EWSR1::DDIT3 fusion genes, and the identification of DDIT3 gene rearrangement by fluorescence in-situ hybridization is diagnostic.

1. Which molecular event is commonly present in intramuscular myxomas?
    
   1. DDIT3 gene rearrangement
   2. FUS::CREB3L1 gene fusion
   3. FUS::CREB3L2 gene fusion
   4. GNAS mutation
   5. HMGA2 gene rearrangement 
       
2. Which myxoid mesenchymal neoplasm is most likely to be positive for MUC4?
    
   1. Deep (aggressive) angiomyxoma
   2. Intramuscular myxoma
   3. Low-grade fibromyxoid sarcoma
   4. Myxofibrosarcoma
   5. Myxoid liposarcoma  
       
3. The association of intramuscular myxomas and fibrous dysplasia is known as
    
   1. Carney syndrome
   2. Li–Fraumeni syndrome
   3. Mazabraud syndrome
   4. McCune–Albright syndrome
   5. Rothmund–Thomson syndrome

1. Nielsen GP, O'Connell JX, Rosenberg AE. Intramuscular myxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular variants. Am J Surg Pathol. 1998;22(10):1222-1227.
2. van Roggen JF, McMenamin ME, Fletcher CD. Cellular myxoma of soft tissue: a clinicopathological study of 38 cases confirming indolent clinical behaviour. Histopathology. 2001;39(3):287-297.
3. Reiter A, Trumm K, Ballhause TM, et al. Diagnostic and Therapeutic Pathways of Intramuscular Myxoma. Diagnostics (Basel). 2022;12(7):1573.  doi: 10.3390/diagnostics12071573.
4. Schwartz HS, Walker R. Recognizable magnetic resonance imaging characteristics of intramuscular myxoma. Orthopedics. 1997;20(5):431-435.
5. Sunitsch S, Gilg MM, Kashofer K, Gollowitsch F, Leithner A, Liegl-Atzwanger B. Detection of GNAS mutations in intramuscular / cellular myxomas as diagnostic tool in the classification of myxoid soft tissue tumors. Diagn Pathol. 2018;13(1):52.
6. Vescini F, Falchetti A, Tonelli V, et al. Mazabraud's Syndrome: A Case Report and Up-To-Date Literature Review. Endocr Metab Immune Disord Drug Targets. 2019;19(6):885-893. 

1. D- GNAS mutation
2. C - Low-grade fibromyxoid sarcoma
3. C - Mazabraud syndrome