sarcoma (4 cases), malignant peripheral nerve sheath tumor differentiation. In practice, all of the tumors classified as
(5 cases), and leiomyosarcoma (11 cases) were obtained MFH were worked up using a full immunohistochemical
from the surgical pathology files of the Vancouver General panel (not including h-caldesmon) at the time of original
Hospital, Vancouver, British Columbia. Cases of infiltrating diagnosis, and, in addition, ultrastructural examination was
breast carcinoma with surrounding desmoplastic stroma (5 performed in 16 of the tumors. This workup failed to show
cases) and acute cholecystitis with a reactive myofibroblastic any features of smooth muscle differentiation in any of these
response (5 cases) were similarly obtained. The diagnostic tumors. This group of tumors was extremely variable in its
criteria used for each of the tumors and tumor-like lesions architecture, and tissue blocks demonstrating at least a focal
are as follows: fascicular growth pattern were chosen for the immunohisto-
1. Fibromatosis: a soft tissue tumor deep to the fascia chemical staining in this study Image 4.
composed of intersecting fascicles of spindle cells embedded 5. Leiomyosarcoma: a cutaneous, subcutaneous, or
in a richly collagenized background. The fascicles demon- deeply located soft tissue neoplasm composed of intersecting
strate numerous thin-walled capillaries. Individual cells have fascicles of plump spindle cells with abundant eosinophilic
uniform elongate spindled nuclei with vesicular chromatin cytoplasm. The cells demonstrate considerable variation in
and readily visible small nucleoli. Mitotic figures are infre- nuclear size, shape, and morphologic features; however, the
quent Image 1. majority exhibit hyperchromatic nuclei. The neoplastic cells
2. Nodular fasciitis: a cellular soft tissue tumor contain abundant eosinophilic cytoplasm that shows focal
present within the subcutaneous tissue. The mass is focally irregular intracytoplasmic vacuoles. Distinct linear fibrillarity
well circumscribed and associated with an organized is present within the cytoplasm of many of the cells. Cell
collagenous (fascial) layer. There is architectural variability membranes typically are seen readily. Mitotic figures are
with cells arranged as sheets, fascicles, and storiform arrays present, including atypical forms. In general, the tumors
and, at least focally, a haphazard distribution within a capil- classified as leiomyosarcomas exhibited less architectural
lary-rich ground substance (tissue culturelike). Cytologi- variability than the MFHs. Ultrastructural examination,
cally, the lesional cells exhibit plump oval to spindled nuclei, which could be performed in 4 of 11 cases, confirmed
vesicular chromatin, and, frequently, large nucleoli. The cells features of smooth muscle cells Image 5.
have readily visible eosinophilic cytoplasm. Mitotic figures 6. Synovial sarcoma: a monophasic or biphasic
are seen readily Image 2. spindle and/or epithelioid cell sarcoma. The lesional spindle
3. Cellular cutaneous fibrous histiocytoma: a dermal- cells demonstrate relatively uniform nuclei and a scant
based cellular spindle cell tumor measuring less than 2.0 cm tapering cytoplasmic process. The lesional cells are arranged
with or without focal extension into the subcutaneous fat. as sheets and fascicles and commonly are associated with
The tumor cells are arranged as sheets, storiform arrays, and dense eosinophilic collagen. Marked nuclear pleomorphism
intersecting fascicles. At the center of the tumor, the dermal is not a feature of these tumors. Biphasic neoplasms have, in
collagen pattern is obliterated. The lateral edges of the mass addition to the characteristics of synovial sarcomas, true
are poorly defined and contain hyalinized collagen bundles. glands and tubules, often with eosinophilic luminal contents.
The lesional cells are plump spindle cells with eosinophilic 7. Malignant peripheral nerve sheath tumor: a vari-
cytoplasm and elongate nuclei with stippled chromatin and ably cellular spindle cell sarcoma composed of sheets and
focally visible nucleoli. Occasional mitotic figures are fascicles of spindle cells with hyperchromatic wavy nuclei.
present Image 3. Mitoses are found readily, and these tumors typically demon-
4. MFH, storiform pleomorphic variant: a cellular strate varying cellularity and nuclear pleomorphism. In prac-
spindle and epithelioid cell neoplasm occurring within tice, at the time of diagnosis these tumors demonstrated
subcutaneous or deep soft tissue. These tumors are character- origin from a peripheral nerve, occurred in patients with
ized by marked architectural variability. Lesional cells may neurofibromatosis, or both.
be arranged as sheets, fascicles, and storiform arrays. Indi- Reactive myofibroblastic proliferations representing the
vidual cells demonstrate considerable variation in size, supporting stroma in conventional infiltrating ductal carci-
shape, and nuclear morphologic features. Markedly irregular noma of the breast and the subserosal spindle cell prolifera-
hyperchromatic nuclei are found readily. Cytoplasm varies tion on the surface of acutely inflamed gallbladders also
from scant to abundant and is predominantly eosinophilic. were examined.
Distinct linear striations are not present. Mitotic figures,
including atypical forms, are readily present. Of importance, Immunohistochemical Methods
in this group of neoplasms, no definite lineage differentiation Immunohistochemical stains were performed with an
is present. Specifically, there is no light microscopic avidin-biotin-peroxidase complex and a Ventana ES auto-
evidence of adipose, endothelial, peripheral nerve, or myoid mated immunostainer (Ventana Medical Systems, Tucson,
Image 1 Fascicles of cellular collagen-rich fibromatosis Image 2 Cellular focus of nodular fasciitis demonstrating
(H&E, 200). poorly formed storiform arrays (H&E, 200).
Image 3 The deep aspect of a cellular cutaneous fibrous Image 4 High-grade malignant fibrous histiocytoma
histiocytoma demonstrating the intense cellularity, mild demonstrating storiform growth and focal tumor giant cells
atypia and focal fascicular growth (H&E, 200). (H&E, 200).
Table 2
Summary of Staining Results
AntiSmooth
Diagnosis Case No. Antih-Caldesmon Desmin Anti-Muscle Actin Muscle Actin
Leiomyosarcoma 1 3+ 3+ 3+ 3+
2 3+ 3+ 3+ 3+
3 3+ 3+ 3+ 3+
4 3+ 3+ 3+ 3+
5 3+ 3+ 3+ 3+
6 3+ 2+ 3+ 3+
7 1+ 2+ 1+ 2+
8 3+ 3+ 3+ 3+
9 3+ 3+ 3+ 3+
10* 3+ 3+ 3+ 3+
11* 3+ 3+ 3+ 3+
MFH 1 0 0 0 0
2 0 0 0 VF
3 0 0 0 0
4 0 0 0 0
5 VF 0 0 2+
6 0 0 0 0
7 VF 0 0 0
8 0 0 0 0
9 0 0 0 1+
10 0 1+ 0 0
11 0 0 0 0
12 0 0 0 0
13 0 0 0 0
14 0 0 0 1+
15 0 0 0 0
16 0 0 0 0
17 0 0 0 0
18 0 0 0 0
19 0 0 1+ 2+
20 0 0 0 0
21 0 1+ 1+ 1+
22 VF 1+ 0 1+
23 0 0 0 0
24 0 VF 1+ 1+
25 0 0 0 1+
26 0 1+ 0 1+
Synovial sarcoma 1 0 0 0 0
2 0 0 0 0
3 0 0 0 0
4 0 0 0 0
MPNST 1 0 0 VF 1+
2 0 0 VF 1+
3 0 0 0 0
4 0 0 0 0
5 0 0 0 0
Fibromatosis 1 0 1+ 0 1+
2 0 1+ 1+ 1+
3 0 1+ 1+ 2+
4 0 1+ 1+ 2+
5 0 1+ 1+ 1+
6 0 1+ 1+ 1+
7 0 0 0 1+
8 0 1+ 1+ 1+
9 0 0 1+ 1+
10 0 1+ 0 1+
11 0 0 1+ 2+
Nodular fasciitis 1 0 0 2+ 3+
2 0 0 0 3+
3 0 0 0 2+
4 0 0 1+ 3+
CCFH 1 0 0 0 1+
2 0 1+ 1+ 1+
3 0 0 0 0
4 0 0 0 0
5 0 1+ 0 1+
6 0 0 0 0
7 VF 0 0 1+
8 0 0 0 0
9 0 0 0 1+
10 0 1+ 0 0
11 0 0 0 1+
Desmoplastic stroma 1 0 0 1+ 3+
2 0 0 2+ 3+
3 0 0 0 2+
4 0 0 1+ 2+
5 0 0 1+ 3+
Myofibroblastic reaction 1 0 0 2+ 3+
2 0 0 1+ 1+
3 0 0 1+ 2+
4 0 0 1+ 2+
5 0 0 0 1+
CCFH, cellular cutaneous fibrous histiocytoma; MFH, malignant fibrous histiocytoma; MPNST, malignant peripheral nerve sheath tumor; VF, very focal staining involving <1%
of the tumor cells; 0, no staining; 1+, <25% of cells; 2+, 25%-75% of cells; 3+, >75% of cells.
* Dedifferentiated leiomyosarcoma; positive staining in conventional areas only.
Desmoplastic stroma surrounding invasive breast carcinoma.
Myofibroblastic reaction occurring on the surface of the gallbladder in acute cholecystitis.
of cellular contraction.8-11 High- and low-molecular-weight myofibroblastic tumors, desmoid tumors, and a variety of
forms of the protein occur.8,9 The high-molecular-weight myoepithelial-type neoplasms were consistently negative.4
form is thought to be restricted to smooth muscle and These investigators noted extensive staining in all tumors
myoepithelial cells.5 There have been few studies of the tested for antibodies directed against actin (HHF35) and
expression of h-caldesmon in soft tissue tumors. Watanabe et smooth muscle actin,4 as we did. Two of 8 gastrointestinal
al4 demonstrated that h-caldesmon expression was limited to stromal tumors tested also exhibited positive staining for h-
soft tissue neoplasms demonstrating smooth muscle differen- caldesmon. Watanabe et al4 concluded . . . that h-caldesmon
tiation. Leiomyomas, angioleiomyomas, leiomyosarcomas, can be used as a specific marker of smooth muscle cells and
and glomus tumors were consistently diffusely and strongly tumors originating from smooth muscle cells.
positive for antih-caldesmon, whereas MFHs, inflammatory Miettinen et al5 reported very similar results, demon-
strating h-caldesmon staining in 96% of 90 examined
visceral and soft tissue tumors demonstrating smooth muscle
differentiation. Four of 31 retroperitoneal leiomyosarcomas
were the only smooth muscle tumors that failed to stain posi-
tively.5 On the other hand, 6 cases of nodular fasciitis and 10
desmoid tumors failed to demonstrate positive staining.5
Miettinen et al5 recorded focal staining involving less than
10% of tumor cells in 11 of 15 tumors classified as MFH and
in the dedifferentiated regions of dedifferentiated liposar-
coma in 6 of 10 tumors. In contrast, these investigators noted
that positive staining for h-caldesmon was restricted to the
well-differentiated component of several examined uterine
leiomyosarcomas.5 Overall, these results are rather similar to
our own. As both of these groups of investigators have
described, antih-caldesmon typically stains the vast
majority of cells in smooth muscle tumors.4,5
We also noted focal positive staining in fewer than 1%
of tumor cells in 3 of 26 MFHs and in 1 of 11 cellular cuta-
Image 6 Diffuse cytoplasmic staining for h-caldesmon in neous fibrous histiocytomas in our study group. Although we
virtually every cell of this leiomyosarcoma (200). found diffuse positive staining in 10 of 11 tumors classified
A B
Image 7 A, Section of one of the tumors we classified as a dedifferentiated leiomyosarcoma. The well-differentiated
leiomyosarcoma is present in the lower half of the image. The upper half consists of an undifferentiated malignant fibrous
histiocytomalike pleomorphic sarcoma (H&E, 100). B, h-Caldesmon staining of the region of the tumor shown in Image 7A.
Note the staining is confined to the well-differentiated component of the tumor (100).
Image 8 Rare h-caldesmonstained cells in one of the Image 9 Nodular fasciitis demonstrating diffuse intense
tumors classified as malignant fibrous histiocytoma. This staining (smooth muscle actin, 200).
was the field with the greatest number of positively stained
cells. Most cells in this tumor were not stained by antih-
caldesmon (200).
Image 10 Fibromatosis with strong staining (smooth Image 11 Cellular cutaneous fibrous histiocytoma showing
muscle actin, 200). intense positive staining in a proportion of the tumor cells
(desmin, 200).
as conventional leiomyosarcoma, in 2 of the tumors in our in practical terms, MFH is a diagnosis of exclusion.12,13 To
series, there was an abrupt transition between conventional this end, the more histogenetically apt designations of
leiomyosarcoma and undifferentiated MFH-like sarcoma undifferentiated spindle cell sarcoma or sarcoma not
(tumors that we classified as dedifferentiated leiomyosar- otherwise specified may be more appropriate for these
comas). In these tumors, positive staining was restricted to tumors. The percentage of high-grade sarcomas classified as
the morphologically typical leiomyosarcoma. MFH seems to be inversely proportional to the effort with
It has become increasingly clear that MFH, despite its which alternative lines of differentiation are sought. Our
name, typically lacks definite histiocytic differentiation and, experience with high-grade soft tissue sarcomas of adult-