Infantile Cranial Fasciitis: A Clinicopathologic Evaluation

Objective:

To investigate the clinicopathologic features, immunophenotype, molecular genetic changes, and differential diagnosis of cranial fasciitis (CF).

Methods:

The clinical manifestations, imaging, surgical technique, pathologic characteristics, special staining, and immunophenotype, as well as break-apart fluorescence in situ hybridization assay for USP6 of 19 CF cases were analyzed, retrospectively.

Results:

The patients were 11 boys and 8 girls, aged 5 to 144 months, with a median age of 29 months. There were 5 cases (26.31%) in the temporal bone, 4 cases (21.05%) in the parietal bone, 3 cases (15.78%) in the occipital bone, 3 cases (15.78%) in the frontotemporal bone, 2 cases (10.52%) in the frontal bone, 1 case (5.26%) in the mastoid of middle ear, and 1 case (5.26%) in the external auditory canal. The main clinical manifestations were painless, with the presentation of masses that grew rapidly and frequently eroded the skull. There was no recurrence and no metastasis after the operation. Histologically, the lesion consists of spindle fibroblasts/myofibroblasts arranged in bundles, braided or atypical spokes. Mitotic figures could be seen, but not atypical forms. Immunohistochemical studies showed diffuse strong positive SMA and Vimentin in all CFs. These cells were negative for Calponin, Desmin, β-catenin, S-100, and CD34. The ki-67 proliferation index was 5% to 10%. Ocin blue-PH2.5 staining showed blue-stained mucinous features in the stroma. The positive rate of USP6 gene rearrangement detected by fluorescence in situ hybridization assay was about 10.52%, and the positive rate was not related to age. All patients were observed for 2 to 124 months and showed no signs of recurrence or metastasis.

Conclusions:

In summary, CF was a benign pseudosarcomatous fasciitis that occurs in the skull of infants. Preoperative diagnosis and differential diagnosis were difficult. Computed tomography typing might be beneficial for imaging diagnosis, and pathologic examination might be the most reliable way to diagnose CF.

Cranial fasciitis (CF) is a rare disease characterized by the proliferation of cranial fibroblasts and myofibroblasts in infants and belongs to a special subtype of nodular fasciitis (NF). There are many diseases that require a differential diagnosis of cranial mass in infants. Because of the local invasiveness of CF, it is difficult to distinguish from malignant tumors such as sarcoma, which are prone to misdiagnosis and mistreatment in clinicopathologic diagnosis. Therefore, there have been no prospective studies of CF from multiple perspectives to date, and that the limited clinical literature on CF consists mainly of case reports, the associated true morbidity, genetic risk factors, prognosis, and long-term follow-up questions remain unanswered. The clinical, surgical, radiologic, pathologic, molecular genetic features, and differential diagnosis of 19 cases of CF were retrospectively analyzed to improve the understanding of the disease by clinical and pathologists.

INSTRUMENTS AND METHODS

Patient

Nineteen children diagnosed with CF by pathologic biopsy were collected in Shenzhen Children’s Hospital from January 2011 to March 2022. Clinical data were obtained from electronic medical records (Table 1, Supplemental Digital Content 1, http://links.lww.com/SCS/E844), in all cases, a complete surgical resection was performed. The telephone follow-up was conducted until March 2022.

Computed tomography (CT) and magnetic resonance imaging (MRI)

Before scanning by GE (General Electric), Lightspeed 64 Slice CT (United States) and Siemens Magnetom Skyra 3.0 T MRI scanner (Germany), the children were unable to cooperate oral sedation or rectal enema with 10% chloral hydration solution (Qingdao, China) at a dose of 0.5 mL/kg. The total amount of the medicine should not exceed 10 mL, and the scan should be performed after the children have fallen asleep. Computed tomography plain scan and 3-dimensional (3D) were reconstructed in a supine position. The MRI scan sequence includes T₁WI, T₂WI, partial DWI and enhanced T₁WI. Twelve children were examined by CT and 2 by MRI (Table 2, Supplemental Digital Content 2, http://links.lww.com/SCS/E845).

Ultrasonic Diagnosis

High-frequency line-array probes of the Philipsi U22 ultrasonic instrument (PHILIPS, Netherlands) were used, and the shallow frequency range was 5 to 12 MHz. Convex array probes are sometimes used at frequencies of 3.5 to 5.0 MHz. Automatic biopsy guns (BARDMAGNKM, United States) and 18G biopsy needles were used. Patients choose the appropriate position (normally supine). The location, shape, boundary, size, internal echo, peripheral, and internal blood flow signals of the mass and the adjacent relationship with surrounding blood vessels and organs were observed. According to the principle of sampling, a puncture biopsy was conducted under the guidance of ultrasound, and then tissues were taken and sent for pathologic examination. Five children underwent preoperative puncture biopsy with B-ultrasound (Table 2, Supplemental Digital Content 2, http://links.lww.com/SCS/E845).

Operative Technique

In short, the child was placed in a supine or appropriate position and a coronal incision was made on the leading edge of the cranial mass. The incision should be long enough to expose the mass. After blunt separation with curved forceps, partial masses could be sent for pathologic cryoscopy. Bipolar electrocoagulation assisted mass anatomy and rigorous hemostasis. Some CFs lesions invaded and damaged the dura mater, which was repaired with absorbable sutures. The mass was completely removed from front to back, the diseased bone was removed with a milling cutter and forceps, and bone wax was used to stop the bleeding. Small bone window (skull defect area <30 cm²) could directly close the incision layer by layer with absorbable suture. Large bone window (skull defect area 30–100 cm²) needed to use the biomimetic bone materials (nano-phase hydroxyapatite/collagen composite bone) after personalized computer 3D printing before cranioplasty in children. The latest approach to cranioplasty was autologous granular bone repair, which was filled with autologous blood.

Hematoxylin-Eosin (HE) Staining, Immunohistochemistry and Special Staining

The specimens were fixed with 10% neutral formalin, paraffin embedded, sliced 4 μm thick, and stained with HE. The HE sections of all cases were reviewed by 2 senior pathologists. AB-PH2.5 staining kit (NO: MST-8039) was purchased from Maixin Biotechnology Co., LTD. (Fuzhou, China). Immunohistochemical staining was performed by the MaxVision method. Antibodies including SMA, Vimentin, CD34, S-100, Desmin, ki-67, Calponin, and β-catenin were purchased from Maixin Biotechnology Co., LTD. (Fuzhou, China). Antibody concentration was a ready-to-use reagent. For all specimens, negative and positive controls were set. Staining was performed by automatic immunohistochemistry (Roche Benchmark XT, Switzerland). All of the above operations were carried out in strict accordance with the product instructions.

Fluorescence in situ hybridization assay Detection

Fluorescence in situ hybridization assay was used to detect the USP6 gene break in tumor tissues. The USP6 (17P13.2) gene break probe reagent was purchased from Jinyu Biotechnology Co., LTD. (Guangzhou, China). The specific operation steps were carried out according to the kit instructions. Judgment criteria: When observing the signals of tumor cells, select the nuclei with clear nuclear boundaries, isolated and non-overlapping nuclei, and clear hybridization signals. The criteria for positive results: 200 cells were randomly selected and the percentage of isolated signal cells was calculated. Two fusion signals indicated the negative expression of the gene break. A red, a green and a fusion signal indicated the positive expression of the gene break. Positive expression in ≥10% of tumor cells was considered to represent gene rearrangement.

RESULTS

Clinical Characteristics

The patients were 11 boys and 8 girls, aged 5 to 144 months, with a median age of (35.74±24.04) and median age of 29 months. There were 5 cases (26.31%) in the temporal bone, 4 cases (21.05%) in the parietal bone, 3 cases (15.78%) in the occipital bone,3 cases (15.78%) in the frontotemporal bone, 2 cases (10.52%) in the frontal bone, 1 case (5.26%) in the mastoid of middle ear, and 1 case (5.26%) in the external auditory canal. The clinical and imaging data were obtained from electronic medical records (Table 1, Supplemental Digital Content 1, http://links.lww.com/SCS/E844); A complete surgical resection was performed in all cases. The telephone follow-up was conducted until March 2022.

Operative Technique

Illustrated here is an incision to remove the diseased scalp. During surgery, a gray mass was found on the outer plate of the skull. The periosteum attached to the lesion was resected and a frozen section demonstrated the proliferation of spindle cells. The outer dura was excised along with the cranial mass and the entire cranial mass was histologically assessed. There seemed to be no abnormal tissue in the inner dura and hemostasis was performed with bipolar cauterization (Fig. 1). In the study, 15 children had their surgical incisions directly sutured layer by layer with absorbable sutures. Three children underwent cranioplasty with bionic bone materials (nano-phase hydroxyapatite / collagen composite bone) after computer 3D printing, which better solved the problem of growth and development of children after cranioplasty. Only 1 patient was treated with advanced autologous granular bone repair to repair skull defects.

FIGURE 1.

(A) Preoperative 3-dimensional volume rendering of the computed tomography imaging. Imaging showed the lytic lesion (cranial fasciitis) involving the inner and outer tables of the parietal bone with associated overlying soft tissue swelling. (B–C) Intraoperative pictures showing preresection and postresection of the lesion.

Imaging Features

Only one case had 2 lesions, others had a single lesion. Computed tomography examination of 12 children indicated three main types of skull destruction, type I was cranial dilatation bone destruction, type II was cranial compression thinning, type III was lytic bone destruction. The plain scan showed an isodensity or slightly high-density mass in cross-section, presenting single or multiple bone destruction in the skull with clear boundary, which could occur in any part of the skull, and maybe 3 to 60 mm in size. Magnetic resonance imaging examination in 2 cases demonstrated equal signs on T₁WI and DWI and equal or slightly higher signal intensity on T₂WI in the substantial part of the CF mass. In the other case, low signal intensity on T₁WI and high signal intensity on T₂WI showed obvious uneven enhancement in the solid part of the mass, with visible necrosis inside, which may involve the meninges of the brain. B-ultrasound examination of 5 children displayed hypoechoic mass with clear boundary, regular shape, uneven internal echo, cord-like hypersignal echo, no posterior acoustic shadow, no liquid dark area echo, deep skull depression, and no visible communication between mass and intracranial (Fig. 2).

FIGURE 2.

(A) An irregular shaped abnormal density shadow was observed in the right auricle, with an unclear boundary. Part of the lesions extended inward to the level of the external auditory canal, and no bone damage was observed in the adjacent bone (CT enhanced scanning). (B) New organism of the right external auditory canal (3-dimensional reconstruction). The subcutaneous soft tissue thickening of the left occipital region corresponds to cranial dilatation bone destruction (Type I, CT scanning). (C) Multiple irregular bone lesions in the left frontal bone and right temporal bone. Cranial compression thinning in the right temporal region (Type II, CT scanning). (D) Lytic bone destruction of the left temporal bone, a few small bone slices and soft tissue density shadow fill in the damaged region (Type III, CT scanning). (E) Hypoechoic mass was found in the subcutaneous soft tissue of the right posterior occipital, with clear boundary and an irregular shape. The internal echo was uniform, and the deep bone echo showed no obvious abnormality. CDFI: low-echoic mass indicating a branching blood flow signal (B-mode ultrasonography). CT indicates computed tomography.

Histologic Features

The lesions, which originated from the deep fascia of the scalp, were composed of fusiform or stellate fibroblasts / myofibroblasts arranged in loose cords, bundles or irregular patterns. The cells lack nuclear hyperchromasia or pleomorphism. Mitotic figures can be seen, but atypical forms are not observed. These cells are present in a background composed of myxoid or fibromyxoid stroma, rich in thin-walled vessels, with focal fissure or microcapsule formation and no obvious erythrocyte extravasation. Similar to the so-called “mucinous” nodular fasciitis. Osseous metaplasia is occasionally observed in CF (Fig. 3).

FIGURE 3.

(A) The mass consists of fusiform or stellate fibroblasts/myofibroblasts arranged in loose cords, bundles or irregular patterns [Hematoxylin and eosin (H&E) ×10, original magnification]. (B) Interstitial mucinous or fibrous mucinous (H&E ×10, original magnification). (C) Focal fissure or microcapsule formation (H&E ×10, original magnification). (D) Rich in thin-walled blood vessels and oozing erythrocyte (H&E ×20, original magnification). (E) Focal lymphocyte aggregation (H&E ×10, original magnification). (F) Focal areas may be associated with ossification (H&E ×10, original magnification).

Immunophenotype, Special Staining and fluorescence in situ hybridization assay Detections

Automatic immunohistochemical detection was performed in all 19 cases, which showed diffuse strong positive SMA and vimentin in neoplastic cells. Calponin, Desmin, β-catenin, S-100, and CD34 were negative, and the ki-67 proliferation index was 5% to 10%. Ocin blue staining for one child revealed blue-stained mucinous material in the stroma. Fluorescence in situ hybridization assay tests were performed on all cases, of which 2 were positive for the USP6 gene and 17 were negative (Fig. 4).

FIGURE 4.

(A) SMA showed diffuse and strong cytoplasmic expression in tumor cells (MaxVision ×10). (B)Vimentin showed strong positive staining in spindle cells (MaxVision ×10). (C) β-catenin showed negative nuclear expression of tumor cells (MaxVision ×10). (D) The positive rate of immunohistochemical staining of Ki-67 was about 5% to 10% (MaxVision ×10). (E) Special staining shows blue mucus in the tumor stroma [Ocin blue (AB) -PH2.5 ×10]. (F) FISH was positive for the USP6(17P13.2) gene break probe. In tumor cells, a yellow signal was shown as a fusion signal, whereas a red signal and a green signal were USP6(17P13.2) gene break signal ( ×10). FISH indicates fluorescence in situ hybridization assay.

Follow-Up

The results showed that nineteen patients in this group had a favorable prognosis and no recurrence or metastasis was found during 2 to 124 months of follow-up.

DISCUSSION

Cranial fascitis is a rare non-neoplastic disease characterized by fibroblast/ myofibroblast hyperplasia, with ˂80 cases reported at present.1 Unlike NF, CF is generally confined to the soft tissues of the scalp or skull and most often occurs in infants and young children. The ratio of males to females was close to 1.5:1.2,3 The typical clinical manifestations of CFs were isolated, rapidly growing, solid and painless masses on the scalp, with a diameter typically no more than 2 to 3 cm². Among 19 typical CF cases in Shenzhen Children’s Hospital, we found that the youngest patient was 5 months old. Intracranial mass was found at birth and progressively enlarged with age. 78.94% of cases were ˂4 years old. The oldest child was 12 years old. Patients over 5 years of age were comparatively uncommon, presumably due to careful parental care and surgical resection. Cranial fascitis presents a painless and swelling mass with rapid enlargement of the temporal, parietal, occipital, frontal bone, and middle ear mastoid. The average diameter was 2.5 cm. The volume and location of the mass were consistent with those reported in the literature. The child feels no discomfort and generally ignores it until it became relatively large. Cranial fascitis was an easily misdiagnosed primary cranial mass. It frequently eroded the outer plate of the skull, penetrates the inner plate and infiltrates the meninges and even the pia mater. Because of the osteolytic defect of the skull with soft tissue mass, it could be misdiagnosed as Langerhans cell histiocytosis or bone tuberculosis. Because of its rare occurrence, it was not usually considered in the differential diagnosis of primary cranial lesions. The rare occurrence of CF might be related to obstetric trauma, but most cases did not have a history of trauma.

Currently, it was generally believed that CF may originate from capsuloaponeurosis, the loose connective tissue beneath the aponeurosis, the deep and superficial fascia layer, and the periosteum or fibrous membrane covering the surface of the bone suture or fontanelle.4 The mass frequently involved the cortex of the skull, occasionally the dura mater and tympanum.5 The characteristics of local invasion and rapid growth of CF might be misjudged as a malignant tumor. In fact, CF could be regarded as a special type of NF with a favorable prognosis. The mass expanded rapidly in the first 2 months, after which the size tended to be stable. It was generally not easy to relapse after surgical resection.6 As for the etiology of CF, some people had proposed a hypothesis that fibroblast/myofibroblast reactive proliferation could be promoted after local trauma or brain tumor radiotherapy, thus leading to the formation of CF.7 Currently, some patients had a history of trauma or birth injury in the reported literature, but most patients had not a history of trauma.8 Other studies had proposed the abnormal regulation mechanism of Wnt/β-catenin pathway,9 and CF was divided into 2 subtypes according to the presence or absence of abnormal staining of the β-catenin nucleus. Those without abnormal staining of the β-catenin nucleus might be caused by the mutation of the β-catenin downstream gene in the Wnt/β-catenin pathway. The 19 cases of β-catenin in this paper were all nuclear negative, so they might belong to this category. In another CF subtype, abnormal nuclear staining of β-catenin might actually be early desmofibroma. Cutaneous wound healing studies in mice show that β-catenin signaling was indeed activated in fibroblasts imposes a healing phenotype by promoting fibroblast proliferation, migration and local invasion.10 Consequently, in all cases with clinicopathologic features of CF, β-catenin immunohistochemistry should be performed. In contrast, negative nuclear expression of β-catenin in CF supports fewer invasive fibroblast/myofibroblast proliferation and better prognosis than positive nuclear expression of β-catenin.

Cranial fascitis penetrated the skull and invaded the meninges, causing a series of clinical symptoms related to the invasion site. Invasion and eye socket cause eye protrusion and tears; invasion of the tympanum caused earache, otorrhea and hearing loss.11 If the mass was too large, it could also cause cerebral hernia, epilepsy, hemiplegia, and other neuro-related symptoms.12 In this study, 2 children presenting symptoms, whereas the other seventeen children did not. One child had a crooked mouth caused by facial nerve damage. The other showed increased periauricular swelling and obvious pain in the external auditory canal.

Computed tomography manifestations in this study were divided into 3 types: Type I was dominated by cranial expansive bone destruction accompanied by soft tissue mass, accounting for about 33.33%. Type II was mainly characterized by thinning and depression of internal and external skull plates, accompanied by scalp soft tissue masses, accounting for about 33.33%. Type III was mainly osteolytic destruction of the skull with soft tissue mass of the scalp, accounting for about 16.67%. Type I and type III bone damage was obvious, penetrating the inner and outer plates of the skull and involving the dura mater. Cranial fascitis might be peripheral sclerosis, calcification was rare, and residual bone fragments could be observed in the damaged area. The other cases without cranial lesions (such as external auditory canal) accounted for about 16.67%. Radiologists should master the characteristics of CT for accurate preoperative diagnosis of CFs. Magnetic resonance imaging of 2 children showed low to moderate signal intensity on T1-weighted imaging, which could be accompanied by enhancement, and medium to high signal intensity on T2-weighted imaging. B-type ultrasound of all 5 children showed hypoechoic mass with clear boundary, homogeneous or uneven internal echo, slightly enhanced peripheral soft tissue echo, and no obvious abnormality in deep bone echo.

Cranial fascitis was often presented in histopathology as a well-defined, unencapsulated mass. The pathologic morphology of 19 cases in this research was mainly composed of spindle cells, with slightly basophilic cytoplasm, elongated to oval nuclei, dense chromatin, obscure nucleoli, and no atypia or pathologic mitosis. Spindle cells might be arranged randomly or in a matte pattern, accompanied by mucinous or gelatinous stroma, scattered histocytes, multinucleated cells, osteoclast giant cells, and reactive osteogenic formation, as well as spot bleeding and inflammatory cell infiltration. The histological features of CF and NF were similar, and the location and molecular genetics were the most important basis for differential diagnosis. Nodular fasciitis was nodular myofibroblastic hyperplasia, which occured subcutaneously or in the superficial fascia. It generally formed a local mass in soft tissue, but not in the skull. About 60% to 70% of NF had the fusion gene USP6-MYH9.

Cranial fascitis cells demonstrated characteristics of fibroblast / myofibroblast differentiation in immunohistochemistry. In this study, SMA and Vimentin were all positive, whereas desmin, CD34, S-100, Calponin, and β-catenin were negative, and the ki-67 proliferation index was 5% to 10%. One child underwent ocin blue (AB) staining and showed blue-stained mucus in the tumor stroma. Ubiquitin-specific Protease 6 (USP6) gene rearrangement was a common genetic alteration of NF and plays an important role in the diagnosis of NF. In our case, however, the USP6 gene rearrangement test was positive in only 2 cases and negative in 17 cases. Cranial fascitis was a special subtype of NF, and only about 10.52% of USP6 gene rearrangement occured in CF. The molecular pathologic results were evidently favorable to NF and could only serve as an auxiliary diagnosis for CF. The immunohistochemical expression of CF and NF was similar, but the fusiform fibroblasts of NF were positive for CD10 and Calponin, whereas CF was negative.

Cranial fascitis was differentiated from other types of reactive lesions or tumors that occur in the scalp or skull of infants. (1) Proliferative fasciitis or proliferative myositis in children:13 Similar to CF, it had rapid growth in a short period and mucinous matrix in histologic morphology, and many large polygonal cells like ganglion cells were scattered in the differential characteristics. Immunohistochemistry showed that spindle cells mainly expressed Vimentin and SMA. The ganglion-like large cells were weakly positive for actin, but not for desmin and myogenin. (2) Infantile fibrohamartoma14 : A benign tumor formed by hyperplastic fibrous tissue occurring in infants, mostly located in the axilla, upper arm, and shoulder blade. Infantile fibrohamartoma was distinguished by a mixture of three components: interlaced fibrous tissue, vortex-like primitive mesenchymal tissue (rich in mucus matrix and capillaries), and mature adipose tissue. Vimentin was expressed in mature fibrous tissue and immature mesenchymal tissue, and actin was also expressed in mature fibrous tissue. (3) Myofibromatosis:15 A benign mesenchymal tumor that usually occured in neonates and infants (under 2 y of age). The histologic morphology was single or multiple nodules. The peripheral area with slight staining was composed of myofibroblasts, and the central area with deep staining was composed of primitive mesenchymal cells arranged like hemangiopericoma. Vimentin and SMA were expressed in both myofibroblasts and primitive mesenchymal cells, but desmin and S-100 were not. (4) Juvenile hyaline fibromatosis16 was a rare nodular lesion occurring in children’s head skin, which was composed of fibroblast and amorphous substance positive for Periodic Acid-Schiff (PAS) staining. The boundary between the mass and surrounding tissue was unclear, and it could invade surrounding soft tissues, and the local recurrence rate after resection was high. Spindle cells expressed Vimentin, but not actin and S-100. Collagen in the interstitium expressed type I and type III collagen, but not type II and type IV collagen. (5) Langerhans cell histiocytosis (LCH):17 A malignant tumor that occurs in children with clonal proliferation of Langerhans cells of the skull, ribs and femur, and was often marked by eosinophilic infiltration. Langerhans cells were rich in cytoplasm and had clear nuclear furrows. Langerin and CD1α were expressed by immunohistochemistry, which were easy to distinguish from CF. Nevertheless, in terms of CT and MRI, LCH showed osteolytic and penetrating bone destruction, which was very similar to the lytic bone destruction of CF. In this study, 2 CF imaging cases were misdiagnosed as LCH. Langerhans cell histiocytosis showed an iso-hyposignal on T₁WI, a slightly higher signal on T₂WI, and a low signal on DWI. However, CF showed isodensity and isosignals, whereas DWI showed isosignals, which could be distinguished between the two.

Surgical resection was frequently used to treat CF because of bone invasion, so subcranial curettage might be necessitated. If the skull defect was large after surgery, cranial reconstruction was also required.3 In this study, the advanced biomimetic bone materials (nano-phase hydroxyapatite/collagen composite bone) were used to repair skull defects after computer 3D printing and autologous granular bone repair. Follow-up over 12 months showed a favorable prognosis. The most common complications of autologous cranioplasty were infection and absorption of the skull bone flap. Postoperative seizures, pain-induced changes in cerebral blood flow, diffuse cerebral edema, cerebral parenchyma hemorrhage, ventricular hemorrhage, and extensive hemorrhagic infarction were unusual complications of autologous cranioplasty. In addition, flap collapse syndrome and sudden postoperative death were rare complications. Children who did not require skull reconstruction generally had a favorable prognosis after surgery, and even if the tumor was not completely removed, the recurrence rate after surgery was low because damage to vital surrounding structures was avoided.10 In this research, the tympanum of the middle ear of 1 patient, who had skull penetration and dura mater invasion was surgically removed and treated. The 6-year follow-up showed that the patient had good prognosis with no signs of recurrence. Consequently, even if CF exhibits locally aggressive biological behavior, overtreatment should be avoided.

CONCLUSION

Cranial fascitis was a rare pseudosarcomatous fasciitis that occurs in the skull of infants and young children. Preoperative diagnosis and differential diagnosis were difficult. Computed tomography typing might be helpful for imaging diagnosis and pathologic examination might be the most reliable way to diagnose CF, and immunohistochemical β-catenin nuclear negative expression indicated a comparatively favorable prognosis for the tumor.

Supplementary Material

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