—  SPECIALTY CONFERENCE  —

BONE AND SOFT TISSUE PATHOLOGY

Case 1 - hox Inflammatory Myofibroblastic Tumor/Inflammatory Fibrosarcoma Tumor Family

John R. Goldblum
Cleveland Clinic
Cleveland, Ohio


Click on each slide thumbnail image for an enlarged view
Clinical History:
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.

Microscopic Description
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.

Ancillary Data
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.

Discussion
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 

General Information
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.

Clinical Findings
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 

Gross Findings
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.

Microscopic Findings
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 Reed-Sternberg cells.16 

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 

Differential Diagnosis
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 malignant-appearing neoplasms.13,28,29 

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 

References

  1. Chan JKC. Inflammatory pseudotumor: a family of lesions of diverse nature and etiologies. Adv Anat Pathol 1996;3:156-171.
  2. Albores-Saavedra J, Manivel JC, Essenfeld H, et al. Pseudosarcomatous myofibroblastic proliferations in the urinary bladder of children. Cancer 1990;66:1234-1241.
  3. 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.
  4. 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.
  5. 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.
  6. 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 Pathol 1993;24:1203-1210.
  7. 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 1991;15:1181-1187.
  8. 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 1985;83:524-527.
  9. 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.
  10. 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 1996;20:747-753.
  11. 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 1996;20:313-324.
  12. Hancock BJ, DiLorenzo M, Youssef S, et al. Childhood primary pulmonary neoplasms. J Pediatr Surg 1993;28:1133-1136.
  13. 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 Pathol 1995;19:859-872.
  14. 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 1998;15:133-143.
  15. 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.
  16. Mirra M, Falconieri G ,Zanconati F, et al. Inflammatory fibrosarcoma: another imitator of Hodgkin's disease? Pathol Res Pract 1996;192:474-478.
  17. Spencer H. The pulmonary plasma cell/histiocytoma complex. Histopathology 1984;8:903-916.
  18. 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.
  19. Maier HC, Sommers SC. Recurrent and metastatic pulmonary fibrous histiocytoma/plasma cell granuloma in a child. Cancer 1987;60:1073-1076.
  20. Griffin CA, Hawkins AL, Dvorak C, et al. Recurrent involvement of 2p23 inflammatory myofibroblastic tumors. Cancer Res 1999;59:2776-2780.
  21. 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.
  22. Su LD, Perez-Atayde A, Sheldon S, et al. Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin. Mod Pathol 1998;11:364-368.
  23. Treissman SP, Gillis DA, Lee CL, et al. Omental-mesenteric inflammatory pseudotumor. Cancer 1994;73:1433-1437.
  24. 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.
  25. Chan JKC, Cheuk W, Shimizu M. Anaplastic lymphoma kinase expression in inflammatory pseudotumors. Am J Surg Pathol 2001;25:761-768.
  26. 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.
  27. 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 2001;25:1364-1371.
  28. 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.
  29. 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.
  30. 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 1999;12:279-286.