General clinical and demographic features of the total cohort
After eliminating the cases of duplication and failure in detection, 94 cases of spindle cell lesions were retrieved, including 40 cases of NF, 44 cases of benign or intermediate lesions and 10 cases of malignant tumors histologically similar to NF. The cohort consisted of 52 males (55.3%) and 42 females (44.7%), ranging in age from 1 to 70 years (median, 30 years). The patient's clinico-pathological information is shown in Table 1 and Table 2.
Table 1
Clinico-pathological features of nodular fasciitis cases
Case no.
|
Age
|
Sex
|
Site
|
Duration time before diagnosis
|
Size(cm)
|
previous diagnosis
|
USP6 gene rearrangement by FISH
|
1
|
33
|
M
|
Right neck
|
10 days
|
2.5
|
In-house case
|
Positive
|
2
|
42
|
M
|
Subcutis of right forearm
|
1 week
|
2
|
In-house case
|
Positive
|
3
|
42
|
F
|
Right thigh
|
1 month
|
2.3
|
In-house case
|
Positive
|
4
|
26
|
F
|
Right lower abdominal wall
|
NA
|
1.3
|
In-house case
|
Positive
|
5
|
44
|
F
|
Left hip
|
NA
|
1.7
|
In-house case
|
Positive
|
6
|
57
|
M
|
Right sternoclavicular joint
|
NA
|
4.0
|
In-house case
|
Positive
|
7
|
27
|
F
|
Right thigh
|
NA
|
2.2
|
In-house case
|
Positive
|
8
|
46
|
F
|
Lower left clavicle
|
6 months
|
3.2
|
In-house case
|
Positive
|
9
|
13
|
F
|
Right thigh root intramuscular
|
1 year
|
6.2
|
In-house case
|
Positive
|
10
|
60
|
M
|
Left chest wall
|
half a month
|
2.0
|
Spindle cell tumor
|
Positive
|
11
|
26
|
M
|
Left upper arm
|
NA
|
NA
|
Dermatofibroma
|
Positive
|
12
|
4
|
M
|
Waist back
|
1 day
|
4.8
|
Desmoid-type fibromatosis
|
Positive
|
13
|
50
|
M
|
Right cheek
|
4 months
|
NA
|
Inflammatory myofibroblastic tumor
|
Positive
|
14
|
30
|
M
|
Left cheek
|
2 weeks
|
NA
|
Nodular fasciitis
|
Positive
|
15
|
5
|
M
|
Eyelid
|
NA
|
1.0
|
Spindle cell tumor, borderline tumor is considered
|
Positive
|
16
|
7
|
M
|
Left waist
|
half a year
|
1
|
Nodular fasciitis
|
Positive
|
17
|
45
|
F
|
Right thumb
|
NA
|
1.5
|
Soft tissue tumor
|
Positive
|
18
|
34
|
M
|
Nose Root
|
half a month
|
NA
|
Desmoid-type fibromatosis
|
Positive
|
19
|
57
|
M
|
Right eye orbit
|
1 month
|
1.0
|
Haemangioendothelioma
|
Positive
|
20
|
32
|
F
|
Left cheek
|
2 months
|
NA
|
NA
|
Positive
|
21
|
3
|
M
|
Left forehead
|
half a year
|
1.2
|
Soft tissue tumor
|
Positive
|
22
|
29
|
M
|
Side of Cervical spine
|
4 months
|
3.0
|
Myofibroblastic tumor
|
Positive
|
23
|
30
|
F
|
Left back
|
1 week
|
2.5
|
Nodular fasciitis
|
Positive
|
24
|
7
|
M
|
Right temporal
|
5 months
|
1
|
Inflammatory myofibroblastic tumor
|
Positive
|
25
|
53
|
F
|
Left biceps
|
1 month
|
2.4
|
leiomyosarcoma
|
Positive
|
26
|
54
|
M
|
Left hand
|
1 year
|
NA
|
Synovial sarcoma
|
Positive
|
27
|
4
|
M
|
Right parotid region
|
1 month
|
1.7
|
Infantile fibrosarcoma
|
Positive
|
28
|
48
|
M
|
Waist
|
NA
|
NA
|
Dermatofibrosarcoma protuberans
|
Positive
|
29
|
11
|
M
|
Posterior neck
|
3 months
|
3.0
|
Dermatofibrosarcoma protuberans
|
Positive
|
30
|
36
|
F
|
Left forearm
|
3 weeks
|
3.5
|
Low-grade fibromyxoid sarcoma
|
Positive
|
31
|
15
|
M
|
Right neck
|
3 months
|
3.0
|
Low-grade fibromyxoid sarcoma
|
Positive
|
32
|
22
|
M
|
Buccal
|
NA
|
1.0
|
Low-grade fibromyxoid sarcoma
|
Positive
|
33
|
44
|
F
|
Right hip
|
3 months
|
2.8
|
Low-grade fibromyxoid sarcoma
|
Positive
|
34
|
34
|
M
|
Right thigh
|
10 days
|
4.0
|
Myxofibrosarcoma / Low-grade fibromyxoid sarcoma
|
Positive
|
35
|
35
|
M
|
Extrathyroid soft tissue nodule
|
NA
|
NA
|
Postoperative thyroid cancer
|
Negative
|
36
|
36
|
F
|
Right thigh
|
> 2 years
|
1.4
|
NA
|
Negative
|
37
|
31
|
F
|
Subcutis of right upper arm
|
NA
|
1.2
|
In the course of breast cancer treatment
|
Negative
|
38
|
25
|
M
|
Right chest wall
|
NA
|
NA
|
NA
|
Negative
|
39
|
48
|
M
|
Right thigh
|
1 week
|
2.0
|
Nodular fasciitis
|
Negative
|
40
|
5
|
F
|
Subcutaneous back
|
> 5 months
|
NA
|
NA
|
Negative
|
NA: not available |
Table 2
clinico-pathological features of lesions mimicking NF
Case no.
|
Tumor
|
Age
|
Sex
|
Site
|
USP6 gene rearrangement by FISH
|
1
|
Desmoid-type fibromatosis
|
31
|
M
|
Cervical vertebra
|
Negative
|
2
|
Desmoid-type fibromatosis
|
34
|
F
|
the left lower abdominal wall
|
Negative
|
3
|
Desmoid-type fibromatosis
|
23
|
F
|
Left neck
|
Negative
|
4
|
Desmoid-type fibromatosis
|
65
|
M
|
Right abdominal paraaortic
|
Negative
|
5
|
Desmoid-type fibromatosis
|
48
|
M
|
Left neck
|
Negative
|
6
|
Desmoid-type fibromatosis
|
42
|
F
|
Deep fasciatus
|
Negative
|
7
|
Desmoid-type fibromatosis
|
61
|
M
|
Right shoulder
|
Negative
|
8
|
Desmoid-type fibromatosis
|
30
|
F
|
Left rectus abdominis
|
Negative
|
9
|
Desmoid-type fibromatosis
|
22
|
F
|
Left breast
|
Negative
|
10
|
Desmoid-type fibromatosis
|
20
|
M
|
Right upper arm
|
Negative
|
11
|
Desmoid-type fibromatosis
|
15
|
F
|
Left abdominal wall
|
Negative
|
12
|
Desmoid-type fibromatosis
|
29
|
F
|
Groin
|
Negative
|
13
|
Desmoid-type fibromatosis
|
18
|
F
|
Left upper arm
|
Negative
|
14
|
Desmoid-type fibromatosis
|
33
|
F
|
Right upper jaw
|
Negative
|
15
|
Desmoid-type fibromatosis
|
53
|
F
|
Left abdominal wall
|
Negative
|
16
|
Desmoid-type fibromatosis
|
67
|
F
|
Right chest wall
|
Negative
|
17
|
Desmoid-type fibromatosis
|
28
|
F
|
abdominal cavity
|
Negative
|
18
|
Desmoid-type fibromatosis
|
25
|
F
|
NA
|
Negative
|
19
|
Reactive/myofibroblast proliferative lesions
|
24
|
M
|
Neck shoulder
|
Negative
|
20
|
Reactive/myofibroblast proliferative lesions
|
46
|
M
|
Right thigh
|
Negative
|
21
|
Reactive/myofibroblast proliferative lesions
|
16
|
M
|
Right tibia
|
Negative
|
22
|
Reactive/myofibroblast proliferative lesions
|
47
|
M
|
Left upper arm intermuscular
|
Negative
|
23
|
Reactive/myofibroblast proliferative lesions
|
28
|
M
|
Face
|
Negative
|
24
|
Reactive/myofibroblast proliferative lesions
|
54
|
F
|
Thyroid
|
Negative
|
25
|
Reactive/myofibroblast proliferative lesions
|
29
|
F
|
Right neck
|
Negative
|
26
|
Cellular fibrous histiocytoma
|
14
|
M
|
Left arm
|
Negative
|
27
|
Cellular fibrous histiocytoma
|
15
|
M
|
Left abdominal wall
|
Negative
|
28
|
Solitary fibrous tumor
|
32
|
F
|
Abdominal wall
|
Negative
|
29
|
Solitary fibrous tumor
|
46
|
M
|
Right nasal cavity
|
Negative
|
30
|
Myositis ossificans
|
70
|
F
|
Right calf
|
Negative
|
31
|
Myositis ossificans
|
20
|
M
|
Left axillary fossa
|
Negative
|
32
|
Inflammatory myofibroblast tumor
|
55
|
F
|
Left mandibular gingiva
|
Negative
|
33
|
Deep benign fibrous histiocytoma
|
50
|
M
|
NA
|
Negative
|
34
|
Fibrohistiocytoma
|
19
|
F
|
Right upper arm
|
Negative
|
35
|
Proliferative myositis
|
50
|
F
|
Right thigh
|
Negative
|
36
|
Schwannoma
|
37
|
M
|
Left thigh
|
Negative
|
37
|
perineurioma
|
42
|
M
|
Skin of left ankle
|
Negative
|
38
|
Dermatofibroma
|
41
|
M
|
left waistwaist
|
Negative
|
39
|
Benign myofibroblastic tumor
|
26
|
F
|
Left forearm
|
Negative
|
40
|
Benign myofibroblastic tumor
|
20
|
F
|
Subcutaneous of right waist
|
Negative
|
41
|
Benign or intermediate tumor
|
1
|
M
|
Left hip
|
Negative
|
42
|
Fibrous dysplasia of bone
|
25
|
M
|
Left femoral neck
|
Negative
|
43
|
Chondroblastoma
|
20
|
M
|
Upper right femur
|
Negative
|
44
|
Chondroblastoma
|
11
|
F
|
Upper left tibia
|
Negative
|
45
|
Low-grade myofibroblast sarcoma
|
28
|
M
|
Right neck
|
negative
|
46
|
Low-grade myofibroblast sarcoma
|
16
|
M
|
Left thigh
|
negative
|
47
|
Low-grade myofibroblast sarcoma
|
26
|
M
|
Right neck
|
negative
|
48
|
Low grade myxoid fibrosarcoma
|
57
|
F
|
Left knee
|
negative
|
49
|
Pleomorphic undifferentiated sarcoma
|
43
|
M
|
Right supraclavicle
|
negative
|
50
|
Synovial sarcoma
|
24
|
F
|
Right sole
|
negative
|
51
|
osteosarcoma
|
24
|
F
|
Right upper jaw
|
negative
|
52
|
osteosarcoma
|
36
|
M
|
Left distal femur
|
negative
|
53
|
Low-grade malignant mesenchymal tumors
|
29
|
M
|
Subcutaneous back
|
negative
|
54
|
Spindle cell rhabdomyosarcoma
|
21
|
M
|
Anterior maxillary region
|
negative
|
Of the NF group, 9 were in-house cases and 31 were consult cases, with the latter being the majority. The most common site affected is head and neck (n = 15, 37.5%), followed by the trunk (n = 10, 25.0%), upper extremities (n = 7, 17.5%), and lower extremities (n = 8, 20.0%). Tumor size ranged from 1.0 to 6.2 cm (median, 2.0 cm). Tumor size of 30 cases was recorded, with 21 (73.3%) cases smaller than 3 cm. Median age was 32.5 years (ranging, 1–60 years). Twenty-five (25/40, 62.5%) patients were in their second to fifth decades, and 10 (10/40, 25.0%) patients were children and adolescents (age ≤ 15 years). The preoperative duration of 28 cases of patients were obtained, ranged from 1 day to > 2 years, 53.6% (15/28) of which were less than 3 months, while 28.6% (22/28) were less than 6 months. Thirty-one cases of NF were consult cases, and the initial submitted diagnoses and the reason for external consultation for 27 cases were recorded. Some of them were given definite diagnosis by the referring pathologists, while others with indefinite diagnosis were given assessment of potential biological behavior (e.g., favoring a sarcoma or sarcomatoid neoplasm). Of these 27 cases with diagnostic opinions, only 4 cases were correctly diagnosed as NF, while 9(9/27, 33.3%) cases were initially diagnosed as malignant tumors, including low-grade malignant fibromyxoid sarcoma, myxoid fibrosarcoma, myxoid liposarcoma, synovial sarcoma, etc. Others were named as desmoid fibromatosis, inflammatory myofibroblast tumor and other benign or intermediate lesions.
Microscopically, our cases had a wide variety of morphologic features: many cases had abundant myxoid matrix, and a few cases had a higher cellularity, while some lesions was characterized by increased collagen production, sometimes with deposition of keloid-like collagen fibers. All the cases were composed of plump, immature-appearing fibroblasts and myofibroblasts that arranged in short intersecting fascicles. In the area with obvious mucoid degeneration, those cells were arranged in a haphazard fashion, often called “tissue culture appearance” or “feathery pattern”, usually accompanied extravasated erythrocytes and scattered lymphocytes. Mitotic figures are fairly common, but cytological pleomorphism and nuclear atypia were absent. Most lesions were well circumscribed but unencapsulated, whereas a minority of cases had poorly defined borders with infiltration into the surrounding skeletal muscle, adipose tissue, and entrapped nerve fascicles. The stroma was at least focally myxoid in all cases and there were frequent cystic spaces in these myxoid areas. In some cases, the cells were abundant and dense, with more mitotic images and similar morphology to malignant tumors (Fig. 1). Mitotic figures are fairly common, but atypical mitoses are virtually never seen. Possibly related to the duration of the lesion, there are three major subtypes of NF: mucinous, cellular and fibrous.
Due to its variable morphologic features, nodular fasciitis were easily misdiagnosed as other benign of even malignant lesions with mucinous appearance, of with proliferation of fibroblasts and myofibroblasts, such as low-grade myofibroblast sarcoma, desmoid-type fibromatosis, cellular fibrous histiocytoma, solitary fibrous tumor, myositis ossificans, inflammatory myofibroblast tumor, et al.
Clinic-pathological features of 54 cases of spindle cell lesions mimicking NF were summarized in Table 2. Some of the cases displayed proliferation of fibroblast or myofibroblast features, some showed mucinous stroma, some showed proliferation of collagen fiber, and some showed dense spindle cellularity. All these features were mimicking different periods of NF, which have been described as mucinous, cellular and fibrous subtypes (Fig. 2).
Frequency of USP6 translocation in NF and in NF-like lesions
The results of FISH analysis of USP6 translocation was shown in Table 3. Of these 98 cases, 35 (35/98, 37.6%) were positive. Within the 40 cases of NF, 35 (35/40, 85.0%) of them were positive. All of other 58 cases that mimic NF were negativet. It is worth noting that all 9 cases that initially diagnosed as malignant tumors by the submitting pathologist were all positive for USP6 gene rearrangement. The microscopic images and FISH results of representative cases showed in Fig. 3.
Table 3
The frequency of USP6 Gene Rearrangement by FISH Analysis in nodular fasciitis and histological mimics
Lesions
|
cases (n)
|
USP6 gene rearrangement (n, %)
|
Nodular fasciitis
|
40
|
34 (85.0)
|
Begnin or intermediate tumor
|
45
|
0/45(0)
|
Fibromatosis
|
17
|
0/17
|
Reactive/reparative myofibroblastic lesion
|
7
|
0/7
|
Myositis ossificans
|
2
|
0/2
|
Chondroblastoma
|
2
|
0/2
|
Others
|
17
|
0/17
|
Malignant tumor
|
10
|
0/10
|
Total
|
95
|
34/95(35.8)
|