BONE AND SOFT TISSUE PATHOLOGY
Case 1 -
hox Inflammatory Myofibroblastic Tumor/Inflammatory Fibrosarcoma Tumor Family
John R. Goldblum
Click on each slide thumbnail image for an enlarged view
An 8-year-old Caucasian female had a recent history of a 15-pound weight loss, nausea, vomiting and
diarrhea. Upon evaluation, the patient was found to have a 9-cm pelvic mass, which was excised.
The tumor is composed of a cellular proliferation of elongated spindled cells that are arranged into short
fascicles or storiform growth pattern. There is a fairly prominent inflammatory component composed
predominantly of lymphocytes and plasma cells, which are intermingled amidst the neoplastic cells. The
cells have slight cytoplasmic eosinophilia and slightly irregular nuclei with variably sized nucleoli.
Scattered mitotic figures are seen but are not atypical.
Case 1 - Figure 1 - Inflammatory myofibroblastic tumor. This low-magnification view shows a cellular proliferation of spindled cells arranged into short fascicles.
Case 1 - Figure 2 - Inflammatory myofibroblastic tumor. This high-magnification view shows slightly atypical cells with distinct cytoplasmic eosinophilia. Chronic inflammatory cells are scattered amidst the neoplastic cells.
Case 1 - Figure 3 - (Immunostain for ALK) Diffuse cytoplasmic ALK-1 immunoreactivity in an inflammatory myofibroblastic tumor.
Immunohistochemical analysis revealed that the tumor cells were strongly positive for vimentin and ALK-1,
the latter showing diffuse cytoplasmic staining. The tumor cells also showed focal staining for smooth
muscle actin, but immunostains for desmin, cytokeratins (AE1/AE3), epithelial membrane antigen, S-100
protein, CD34, KIT (CD117), CD21, CD30 and CD35 were negative.
There are several topics in the field of soft tissue pathology that remain controversial and difficult to
understand, no matter how much experience one may have in this field. Perhaps no other term in the field of
soft tissue pathology causes as much confusion as inflammatory pseudotumor, since it seems to mean different
things to different people. For a superb evaluation on this topic, I would suggest turning to Dr. John
Chan's review published in Advances in Anatomic Pathology in 1996.1
Inflammatory pseudotumor is a term that has been applied to diverse entities of differing etiologies
(including reparative pseudosarcomatous lesions of the lower genitourinary tract),2-6 infectious lesions,
including those secondary to mycobacterium avium intracellulare infection,7,8 and Epstein-Barr
virus-associated follicular dendritic cell tumors usually found in the liver or spleen.9-11 The focus of
this discussion will be on what appears to be a neoplastic form of inflammatory pseudotumor, heretofore
referred to as inflammatory myofibroblastic tumor (IMT) or inflammatory fibrosarcoma (IFS). The latter have
been described in virtually every anatomic location in patients of any age and have been called by many
names, including plasma cell granuloma, plasma cell pseudotumor, inflammatory myofibrohistiocytic
proliferation, inflammatory fibromyxoid tumor, and omental-mesenteric myxoid hamartoma.
IMT/IFS have been reported in virtually every anatomic site. Pulmonary IMT is the most common pulmonary
tumor of childhood.12 However, for extrapulmonary IMT/IFS, most arise in the retroperitoneum, abdomen or
mesenteric region.13 For example, of the 84 cases of extrapulmonary IMT reported by Coffin et al,13 61 (73%)
arose in the abdomen, retroperitoneum or pelvis. Other reported sites of involvement include the head and
neck, upper respiratory tract, trunk and extremities. Although the age range is broad, extrapulmonary
tumors show a predilection for children with a mean age of approximately 10 years. Females are affected
slightly more commonly than males.
The presenting symptoms depend upon the site of primary tumor involvement. Patients with intra-abdominal
tumors most commonly complain of abdominal pain or present with an abdominal mass with increased girth,
sometimes with signs and symptoms of gastrointestinal obstruction. Some patients have prominent type-B
systemic manifestations including fever, weight loss, night sweats and malaise. Laboratory abnormalities
including an elevated erythrocyte sedimentation rate, anemia, thrombocytosis and polyclonal
hypergammaglobulinemia may be present. Both these type-B symptoms and laboratory abnormalities tend to
quickly resolve upon tumor excision, and recur with tumor recrudescence.12-13
Grossly, most IMT/IFS are lobular, multinodular or bosselated tumors with a hard or rubbery cut surface that
varies from white, gray to tan-yellow. Those tumors that are extensively hyalinized or calcified may cut
with a gritty sensation. Although most of these tumors are solitary, in some cases patients may have
multiple tumor nodules that are restricted to the same anatomic location.13-15 Most are between 5 and 10 cm
in greatest dimension at the time of excision.
This family of tumors is characterized by a variety of histologic patterns, and, in fact, different patterns
may be found in different areas within the same tumor. Some tumors are composed predominantly of
cytologically bland spindled or stellate-shaped cells that are loosely arranged in a myxoid or hyaline
stroma with scattered inflammatory cells, thereby somewhat resembling nodular fasciitis or other reactive
pseudosarcomatous processes. Others (as in the current case) are composed of a compact proliferation of
spindled cells arranged in fascicles or a storiform growth pattern. The nuclei tend to be elongated, and
most lack significant nuclear hyperchromasia or cytologic atypia. However, scattered atypical cells are
commonly seen. Mitotic figures are variable but are not atypical. These cellular zones are usually
associated with a prominent infiltrate composed of plasma cells and/or lymphocytes, occasionally with the
formation of germinal centers. Some tumors show pronounced cytologic atypia and are composed of cells with
large nuclei and prominent nucleoli.15 Some have large histiocytoid cells resembling ganglion cells or even
Immunohistochemical and Ultrastructural Findings
The tumor cells stain strongly for vimentin and variably with myoid markers including smooth muscle actin,
muscle specific actin and desmin. In the study by Meis and Enzinger,15 smooth muscle actin and muscle
specific actin marked 90% and 83% of the cases, respectively. On the other hand, there was equivocal desmin
staining in only 1 of 11 (9%) cases. In the study by Coffin et al,13 there was staining for smooth muscle
actin, muscle specific actin and desmin in 92%, 89% and 69% of cases, respectively. Focal cytokeratin
immunoreactivity was noted in 36% of the cases in the study by Coffin et al,13 and 77% of the cases in the
study by Meis and Enzinger,15 predominantly in portions of the tumor that were in a submesothelial location.
KP1 (CD68) staining is found in up to 25% of cases.13,15 As discussed below, some but not all members of the
IMT/IFS tumor family stain for ALK (using antibodies ALK-1 or p80).
Ultrastructurally, most of the constituent cells have fibroblastic features with a well-developed Golgi
apparatus, abundant rough endoplasmic reticulum and extracellular collagen. However, some cells show
evidence of myofibroblastic differentiation with intracytoplasmic thin filaments and dense bodies.13-15
The differential diagnosis in any given case depends upon the clinicopathologic setting (patient age,
gender, tumor location and number of lesions) as well as the predominant histologic pattern. Hypocellular
or myxoid variants elicit completely different diagnostic considerations than those composed of highly
cellular spindled cells. Diagnostic considerations might include inflammatory malignant fibrous
histiocytoma, inflammatory leiomyosarcoma, lymphoma and follicular dendritic cell tumors. Predominantly
sclerosing variants of IMT/IFS must be distinguished from the group of inflammatory fibrosclerosing lesions,
which include sclerosing mediastinitis, idiopathic retroperitoneal fibrosis, Reidel's thyroiditis and
orbital inflammatory pseudotumor. The latter tend to occur in older patients and, although mass-forming,
are usually ill-defined with entrapment of the surrounding normal tissues. They tend to have more prominent
sclerosis and phlebitis than the typical IMT/IFS. Other diagnostic considerations might include solitary
fibrous tumor, nodular fasciitis and other pseudosarcomatous proliferations, fibromatosis, infantile
fibrosarcoma and myofibrosarcoma. In most cases, clinicopathologic setting, histologic and
immunohistochemical features can distinguish among these entities.
Molecular Genetic Findings
There is considerable evidence to suggest that inflammatory myofibroblastic tumor is in fact a neoplastic
process. There are rare examples of overt sarcomatous transformation with the development of metastatic
disease.17-19 In addition, a number of IMT have been studied cytogenetically and have been found to harbor
clonal cytogenetic aberrations, especially at 2p22-24.20-23 The anaplastic lymphoma kinase (ALK) gene,
located on 2p23, has been implicated in the pathogenesis of this lesion. This gene codes for a tyrosine
kinase receptor that is a member of the insulin growth factor receptor superfamily. ALK rearrangements
result in constitutive expression and activation of this gene with abnormal phosphorylation of cellular
substrates. Fusion partners that appear to be important in the oncogenesis of at least some IMT include
tropomyosin 3 (TPM3-ALK) and tropomyosin 4 (TPM4-ALK).24 In the study by Lawrence et al, other
non-tropomyosin ALK oncoproteins resulting in cytoplasmic or nuclear ALK immunoreactivity were also
implicated in the pathogenesis of some IMT. In fact, there is evidence to suggest that different fusion
partners result in different patterns of ALK immunoreactivity, including diffuse cytoplasmic, granular
cytoplasmic, nuclear membranous and nuclear patterns of staining.24-27 Overall, between 36 and 60% of IMT
stain for ALK using ALK-1 or p80.25-27
Inflammatory Myofibroblastic Tumor versus Inflammatory Fibrosarcoma
Some of the controversy and confusion regarding this subject pertains to nomenclature. In my opinion, it is
not possible to make histologic distinctions between lesions reported by some authors as inflammatory
fibrosarcoma and by others as inflammatory myofibroblastic tumor. In fact, there is some overlap in case
material reported in the studies by Coffin et al13 and Meis et al.15 It is clear that tumors that arise in
the abdomen or retroperitoneum have a propensity for more aggressive clinical behavior than their
extra-abdominal counterparts, with recurrence rates ranging from 23 to 37%.13-15 Another issue relates to
the metastatic potential of these lesions since it may be difficult, if not impossible, to distinguish a
metastasis from multifocal disease. In the study by Coffin et al of 53 cases of "inflammatory
myofibroblastic tumor" with follow-up, there were no instances of metastasis, whereas 3 of 27 patients with
"inflammatory fibrosarcoma" reported by Meis and Enzinger developed metastases to lung and brain. In at
least one of the cases reported by Meis and Enzinger (Case 26),15 the simultaneous presentation of
histologically bland mediastinal and cerebral lesions with no evidence of disease nearly four years after
surgery raises the possibility that these lesions are multifocal, as opposed to necessarily representing a
metastasis. There are also some reports of inflammatory myofibroblastic tumors merging into frankly
The mainstay of therapy is surgical resection with re-excision of recurrent tumors. There is no proven
benefit of chemotherapy and/or radiation therapy. Cellularity, mitotic counts and extent of inflammation do
not appear to be prognostic markers. Cytologic atypia, the presence of ganglion-like cells, p53
immunoreactivity and DNA aneuploidy have been reported to be potentially useful for identifying tumors that
are more likely to pursue an aggressive clinical course.30
- Chan JKC. Inflammatory pseudotumor: a family of lesions of diverse nature and etiologies. Adv Anat
- Albores-Saavedra J, Manivel JC, Essenfeld H, et al. Pseudosarcomatous myofibroblastic proliferations
in the urinary bladder of children. Cancer 1990;66:1234-1241.
- Hojo H, Newton WA, Hamoudi AB, et al. Pseudosarcomatous myofibroblastic tumor of the urinary bladder
in children: a study of 11 cases with review of the literature - a Intergroup Rhabdomyosarcoma Study.
Am J Surg Pathol 1995;19:1224-1236.
- Jones EC, Clement PB, Young RH. Inflammatory pseudotumor of the urinary bladder: a
clinicopathological, immunohistochemical, ultrastructural and flow cytometric study of 13 cases. Am J
Surg Pathol 1993;17:264-274.
- Proppe KH, Scully RE, Rosai J. Postoperative spindle cell nodules of genitourinary tract resembling
sarcomas: a report of eight cases. Am J Surg Pathol 1984;8:101-108.
- Ro JY, El-Naggar AK, Amin MB, et al. Pseudosarcomatous fibromyxoid tumor of the urinary bladder and
prostate: immunohistochemical, ultrastructural and DNA flow cytometric analysis of nine cases. Hum
- Umlas J, Federman M, Crawford C, et al. A spindle cell pseudotumor due to mycobacterium
avium-intracellulare in patients with acquired immunodeficiency syndrome (AIDS). Am J Surg Pathol
- Wood C, Nickoloff BJ, Todes-Taylor NR. Pseudotumor resulting from atypical mycobacterial infection:
a "histoid" variety of mycobacteria avium-intracellulare complex infection. Am J Clin Pathol
- Arbor DA, Kamel OW, van de Rijn M, et al. Frequent presence of the Epstein-Barr virus in
inflammatory pseudotumor. Hum Pathol 1995;26:1093-1098.
- Selves J, Meggetto F, Brousset P, et al. Inflammatory pseudotumor of the liver: evidence for
follicular dendritic cell proliferation associated with clonal Epstein-Barr virus. Am J Surg Pathol
- Shek TWH, Ho FCS, Ng IOL, et al. Follicular dendritic cell tumor of the liver: evidence for an
Epstein-Barr virus-related clonal proliferation of follicular dendritic cells. Am J Surg Pathol
- Hancock BJ, DiLorenzo M, Youssef S, et al. Childhood primary pulmonary neoplasms. J Pediatr Surg
- Coffin CM, Watterson J, Priest JR, et al. Extrapulmonary inflammatory myofibroblastic tumor
(inflammatory pseudotumor): a clinicopathologic and immunohistochemical study of 84 cases. Am J Surg
- Meis-Kindblom JM, Kjellstrom C, Kindblom L-G. Inflammatory fibrosarcoma: update, reappraisal, and
perspective on its place in the spectrum of inflammatory myofibroblastic tumors. Semin Diagn Pathol
- Meis JM, Enzinger FM. Inflammatory fibrosarcoma of the mesentery and retroperitoneum: a tumor
closely simulating inflammatory pseudotumor. Am J Surg Pathol 1991;15:1146-1156.
- Mirra M, Falconieri G ,Zanconati F, et al. Inflammatory fibrosarcoma: another imitator of Hodgkin's
disease? Pathol Res Pract 1996;192:474-478.
- Spencer H. The pulmonary plasma cell/histiocytoma complex. Histopathology 1984;8:903-916.
- Pettinato G, Manivel JC, DeRosa N, et al. Inflammatory myofibroblastic tumor (plasma cell
granuloma): clinicopathologic study of 20 cases with immunohistochemical and ultrastructural
observations. Am J Clin Pathol 1990;94:538-546.
- Maier HC, Sommers SC. Recurrent and metastatic pulmonary fibrous histiocytoma/plasma cell granuloma
in a child. Cancer 1987;60:1073-1076.
- Griffin CA, Hawkins AL, Dvorak C, et al. Recurrent involvement of 2p23 inflammatory myofibroblastic
tumors. Cancer Res 1999;59:2776-2780.
- Snyder CS, Dell'Aquila M, Haghighi P, et al. Clonal changes in inflammatory pseudotumor of the lung:
a case report. Cancer 1995;76:1545-1549.
- Su LD, Perez-Atayde A, Sheldon S, et al. Inflammatory myofibroblastic tumor: cytogenetic evidence
supporting clonal origin. Mod Pathol 1998;11:364-368.
- Treissman SP, Gillis DA, Lee CL, et al. Omental-mesenteric inflammatory pseudotumor. Cancer
- Lawrence B, Perez-Atayde A, Hibbard MK, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory
myofibroblastic tumors. Am J Pathol 2000;157:377-384.
- Chan JKC, Cheuk W, Shimizu M. Anaplastic lymphoma kinase expression in inflammatory pseudotumors. Am
J Surg Pathol 2001;25:761-768.
- Cessna MH, Zhou H, Sanger WG, et al. Expression of ALK-1 and p80 in inflammatory myofibroblastic
tumor and its mesenchymal mimics: a study of 135 cases. Mod Pathol 2002;15:931-938.
- Cook JR, Dehner LP, Collins M, et al. Anaplastic lymphoma kinase (ALK) expression in the
inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol
- Donner LR, Trompler RA, White RR. Progression of inflammatory myofibroblastic tumor (inflammatory
pseudotumor) of soft tissue into sarcoma after several recurrences. Hum Pathol 1996;27:1095-1098.
- Zavaglia C, Barberis M, Gelosa F, et al. Inflammatory pseudotumor of the liver with malignant
transformation: report of two cases. Ital J Gastroenterol 1996;28:152-159.
- Hussong JW, Brown M, Perkins SL, et al. Comparison of DNA ploidy, histologic, and
immunohistochemical findings with clinical outcome in inflammatory myofibroblastic tumors. Mod Pathol