Clinicopathological and Genetic Findings of Infantile Nodular Fasciitis

Nodular fasciitis (NF) is a rapidly growing benign soft tissue tumor characterized by fibroblastic/myofibroblastic proliferation. It predominantly affects adults aged 20 to 40 years, with the upper extremities being the most common site of involvement. Due to its rapid growth rate, high cellularity, and brisk mitosis, NF is often mistaken for soft tissue sarcomas during the diagnostic process. Recent studies have identified recurrent gene rearrangements of ubiquitin-specific protease 6 (USP6), located at 17p13.2, as a key molecular feature of NF. USP6 rearrangements are found in approximately 90% of NF cases, with over 65% of these cases harboring myosin heavy chain 9 (MYH9)-USP6 fusions, typically in type I (exon 1–exon 1) or type II (exon 1–exon 2) patterns. These findings have established USP6 rearrangements as a valuable diagnostic biomarker for distinguishing NF from its histologic mimics. While NF is common in adults, it is exceedingly rare in infants. This study aims to elucidate the clinical, pathological, and genetic features of infantile NF to better understand the tumorigenesis mechanism underlying this entity.

Clinical Characteristics

This study was conducted at West China Hospital, Sichuan University, and involved a retrospective review of surgical pathology files from January 2008 to August 2020. Out of 604 NF cases identified, 12 were infantile cases. Eleven cases (patients under 2 years old) were included in the study, while one previously published case was excluded. The cohort comprised seven male and four female patients. The most common presentation was a firm, round, and solid soft tissue mass, observed in 10 out of 11 cases. The duration of symptoms ranged from 0.5 to 12.0 months, with a median of 3 months. Notably, spontaneous resolution was not observed in any of the cases, and none of the patients had a history of trauma. Birth histories were available for nine patients, with three delivered by cesarean section and six delivered naturally.

The anatomical distribution of the lesions was predominantly in the head and neck region (54.5%), including the neck (n = 3), ear (n = 2), and parotid gland (n = 1). The trunk was involved in 36.4% of cases, and the extremities in 9.1%. The age at diagnosis ranged from 4 to 23 months, with a median of 11 months. Imaging data, including ultrasound and computed tomography, were available for four cases, with unclear boundaries observed in three of these cases (75%). All patients underwent surgical excision, with resected tumors measuring 1.4 to 4.0 cm in the largest dimension (median 1.5 cm). The lesions were located in the subcutis (n = 5), muscle (n = 4), parotid gland connective tissue (n = 1), and one case lacked detailed information. Most specimens exhibited an ill-defined, firm nodule with a gray-white appearance.

Pathological Findings

Histological examination revealed muscular invasion in five of the 11 patients. All tumors were primarily composed of spindle cells arranged in a fascicular pattern. Most cases (7/11) presented with abundant fat spindle cells and a small amount of lymphocyte infiltration, while some lesions showed spindle cells with medium density and apparent inflammatory cell infiltration. Microcystic changes were observed in most cases (7/11), and red blood cell extravasation was not prominent in the majority (9/11). Scattered osteoclastic giant cells were identified in five of the 11 patients (45.5%). Mitotic figures ranged from 1 to 13 per 10 high-power fields (HPFs), with no atypia observed.

Immunohistochemical staining was performed, and all cases with available data were positive for smooth muscle actin (SMA) and negative for desmin. The MIB-1 index, available in nine cases, ranged from 8% to 25%. These findings are detailed in Supplementary Table 1.

Genetic Findings

Fluorescence in situ hybridization (FISH) was conducted to detect USP6 gene rearrangements. Nine of the 11 cases (81.8%) showed positivity for USP6 rearrangement, with the percentage of split red-green signals ranging from 15% to 78%. Among these cases, eight exhibited balanced rearrangement with a one-fusion (1F), one-green (1G), and one-red (1R) signal pattern. One case showed an unbalanced rearrangement, with 55% of cells displaying a one-fusion and one-red (1F + 1R) signal pattern. Two cases were negative for USP6 rearrangement.

Reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing were performed on retrievable tissues from seven cases with USP6 rearrangement. The RT-PCR primers for detecting common fusion types of USP6 are listed in Supplementary Table 2. The results indicated that only one case was positive for MYH9-USP6 fusion, with both type I and type II patterns observed. The remaining six cases were negative for MYH9-USP6 fusion in either type I or type II pattern. These findings are summarized in Supplementary Table 3.

Treatment and Follow-Up

All patients underwent surgical excision, and no additional treatment was provided. Follow-up information was available for 81.8% (9/11) of the patients, with a median follow-up duration of 51 months (range: 5–121). Among these nine patients, two developed local recurrence within 5 months postoperatively. One patient underwent re-excision and remained disease-free for 19 months after the second operation, while the other patient was alive with a relapsed tumor at 3 months post-recurrence. The remaining seven patients were disease-free after surgery.

Discussion

This study presents a comprehensive analysis of infantile NF, highlighting its clinical, pathological, and genetic features. Although NF is well-documented in adults and older children, it is exceptionally rare in infants. The findings from this study contribute to a deeper understanding of this entity, particularly in the context of its unique characteristics in the infantile population.

The clinical presentation of infantile NF differs from that of adults, with a higher prevalence of lesions in the head and neck region. This contrasts with the typical involvement of the upper extremities in adult cases. The absence of spontaneous resolution and the lack of a trauma history in all cases suggest that the pathogenesis of infantile NF may differ from that of adult NF.

Histologically, infantile NF shares many features with adult NF, including the presence of spindle cells arranged in a fascicular pattern and the absence of atypia. However, infantile NF exhibits some distinct characteristics, such as a higher prevalence of microcystic changes and a lower frequency of myxoid changes and red blood cell extravasation. The mitotic activity in infantile NF is comparable to that in adult cases, with no atypia observed.

The genetic findings in this study are particularly noteworthy. USP6 rearrangements were identified in 81.8% of cases, a rate similar to that reported in adult NF. However, the detection of MYH9-USP6 fusion via RT-PCR was significantly lower in infantile NF (14.2%) compared to adult cases (65%–75%). This discrepancy may be attributed to the limitations of traditional RT-PCR methods, such as primer design and detection sensitivity. Future studies utilizing next-generation sequencing technologies may uncover additional or novel genetic alterations in infantile NF.

The identification of an unbalanced USP6 rearrangement in one case is a novel finding. This case exhibited higher cellularity and more brisk mitoses (13/10 HPF) compared to cases with balanced rearrangements. A review of the literature revealed only three previously reported cases of NF with unbalanced USP6 rearrangements. Further research with larger cohorts is needed to elucidate the clinical significance of atypical USP6 rearrangements in NF.

Accurate histopathologic diagnosis is crucial in the management of NF, as misdiagnosis can lead to aggressive or excessive treatment. The differential diagnosis for infantile NF includes cellular fibrous histiocytoma, fibromatosis, inflammatory myofibroblastic tumor, and spindle cell sarcomas such as infantile fibrosarcoma, spindle cell rhabdomyosarcoma, and myxofibrosarcoma. The presence of USP6 rearrangements in infantile NF, but not in these histologic mimics, underscores the diagnostic utility of USP6 status in distinguishing NF from other soft tissue lesions.

Surgical resection remains the mainstay of treatment for NF, with recurrences being rare. However, in this cohort, two patients experienced local recurrence within 5 months postoperatively. Both recurrences occurred in lesions located in the auricle of the ear, suggesting that complete surgical excision may be challenging in this anatomical region. The authors recommend complete surgical excision as the optimal treatment for infantile NF, whenever feasible.

Conclusion

This study provides a detailed characterization of infantile NF, highlighting its unique clinical, pathological, and genetic features. The identification of USP6 rearrangements and MYH9-USP6 fusion in a series of infantile cases contributes to our understanding of the molecular pathogenesis of this rare entity. The findings underscore the importance of accurate histopathologic diagnosis and the role of USP6 status in distinguishing NF from its histologic mimics. Further research with larger cohorts is needed to fully elucidate the characteristics of infantile NF and to explore potential therapeutic targets.

doi.org/10.1097/CM9.0000000000001727

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