Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Inflammatory Myofibroblastic Tumor of the Breast

  • Gaetano MagroEmail author
  • Lucia Salvatorelli
Living reference work entry

Latest version View entry history

DOI: https://doi.org/10.1007/978-3-319-28845-1_4756-2

Synonyms

Definition

Inflammatory myofibroblastic tumor (IMT) is currently classified by WHO as a soft tissue tumor composed of spindly myofibroblasts admixed with inflammatory cells such as plasma cells, lymphocytes, and eosinophils (Coffin and Fletcher 2013). IMT can occur in adults at several anatomic sites, including the breast. Although initially thought to be an exaggerated inflammatory local response to various stimuli, and thus variably labeled as “inflammatory pseudotumor (IP) or plasma cell granuloma,” there is growing evidence that a subset of these lesions are truly neoplastic in nature with the tendency to recur in up to 25% of the cases and with a slight risk of distant metastasis. This is especially true if IMT typically arises in the lung and abdomen of children/adolescents (Coffin and Fletcher 2013). As future studies are needed to better define the boundaries between a reactive and a neoplastic process, the combined diagnosis of “inflammatory pseudotumor/inflammatory myofibroblastic tumor,” specifying the presence or not of ALK-1 expression (see below), seems actually to be more appropriate for these lesions.

Clinical Features

  • Incidence

    The terms IMT or IP of the breast have been used interchangeably over time, and only 24 cases have been reported in English literature so far (Haj et al. 2003; Vecchio et al. 2011; Zhao et al. 2013; Bosse et al. 2014; Choi et al. 2015; Markopoulos et al. 2015; Talu et al. 2016).

  • Age

    IMT/IP can occur at any age including adolescents (16–86 years), but it is more frequently observed between the third to sixth decades.

  • Sex

    The majority of cases seems to occur spontaneously in women. Only rarely IMT has been described in male patients, following local mechanical trauma (Vecchio et al. 2011).

  • Clinical presentation

    Patients usually present with a painless nodule ranging in size from 1.0 to 8 cm in its greatest diameter, without associated constitutional symptoms (fever, malaise, weight loss) as usually seen in pediatric patients with lung and abdominal tumors.

  • Radiographic findings

    Imaging features (ultrasound; mammography) are non-specific and usually reveal a solitary, less frequently multifocal, round to oval mass which may show either well-circumscribed (Zhao et al. 2013) or ill-defined margins with the suspicion of malignancy (Haj et al. 2003).

  • Treatment

    Complete surgical excision is the adequate treatment. Most cases have an indolent clinical course (Vecchio et al. 2011), but local recurrence can be documented in a minority of cases (15–20% of cases) (Zhao et al. 2013; Choi et al. 2015). Only rarely IMT of the breast may show metastatic potential (Zhao et al. 2013; Choi et al. 2015). However, some tumors labeled as “inflammatory myofibroblastic tumors” are not convincing based on the illustrations provided by the authors, and they could represent low- to intermediate-grade myofibroblastic sarcomas (Choi et al. 2015). Patients with IMT/IP of the breast need a long-term follow-up.

Macroscopy

Grossly, IMT/IP presents as a round to oval mass, sometimes lobulated, with well or often ill-defined margins. The size is variable, ranging from 1.5 to 8.0 cm (average tumor size of 3.1 cm). The cut surface reveals a tumor mass firm in consistency and gray whitish in color. Necrosis and hemorrhage are absent.

Microscopy

IMT/IP shows morphological and immunohistochemical features similar to those reported at other sites (Table 1). At low magnification, a tumor mass with infiltrative margins into the surrounding fibro-fatty breast tissue is observed. It consists of a proliferation of plump, bland-looking spindle cells with the features of myofibroblasts, showing pale to slightly eosinophilic cytoplasm and ovoid to tapering vesicular nuclei with inconspicuous nucleoli (Fig. 1a, b H&E). These cells are usually arranged in interlacing short bundles with focal swirling and/or storiform growth pattern (Fig. 1a, b H&E). Mitotic count is extremely variable, ranging from few (1–2) to 10 mitoses per 10 high power fields. Characteristically the spindle cells are closely admixed with inflammatory cells, especially lymphocytes (Fig. 2a H&E), plasma cells (Fig. 2b H&E), and eosinophils. Cellularity is quite variable and tumor stroma is fibrous to loose. A minority of cases shows extensive hypocellular and hyalinized areas, closely resembling scar-like tissue. Rarely the tumor cells may exhibit moderate/severe cytological atypia consisting of large vesicular or hyperchromatic nuclei (Fig. 2c H&E) with one or two prominent nucleoli. Necrosis and atypical mitoses are absent. Macrophages and a few multinucleated giant cells can be occasionally seen.
Table 1

Clinicopathologic features

Inflammatory myofibroblastic tumor/inflammatory pseudotumor

Clinical features

 Females (only rarely males)

 Age: 16–86 years

 Painless nodule (1–8 cm) arising spontaneously

Imaging

 Nodule with well-circumscribed or ill-defined margins

Gross pathology

 Poorly circumscribed mass

 Firm in consistency

 Gray whitish in color

Histological features

Margins: Well- or poorly circumscribed

Cells: Plump, bland-looking spindle cells admixed with lymphocytes, plasma cells, and eosinophils

Growth pattern: Interlacing short fascicles; focal storiform or swirling pattern

Mitotic count: 0–3 mitoses per 10 high power field

Stroma: Fibrous to focally edematous

Immunohistochemistry

Positive markers: Vimentin and α-smooth muscle actin

Variable expression: Desmin; ALK-1 (40–50% of cases)

Negative markers: Cytokeratins, EMA, CD34, S-100 protein, β-catenin, STAT6

Cytogenetics

FISH analysis: ALK-gene rearrangements/amplification

Fig. 1

(a) Proliferation of bland-looking spindle cells with fascicular and swirling growth patterns. (b) Higher magnification showing the cytological details

Fig. 2

Proliferating spindle cells are closely admixed with lymphocytes (a) and plasma cells (b). In some areas the spindle cells may exhibit moderate nuclear atypia (c). Immunostaining with alpha-smooth muscle actin is a common finding (d)

Immunophenotype

IMT/IP shows a myofibroblastic profile with immunoreactivity for vimentin, α-smooth muscle actin (Fig. 2d Immunostaining with α-smooth muscle actin), and variably with desmin. The expression of ALK-1 protein has been demonstrated in three cases (Zhou et al. 2013; Bosse et al. 2014), proving that, at least, a subset of these lesions could represent true IMT. Occasionally immunostaining for cytokeratins has been described. No immunoreactivity is reported for CD34, CD21, CD35, S100, and estrogen/progesterone receptors (Table 1).

Molecular Features

The role of ALK gene is still unclear in the pathogenesis of IMT. The distinction between IMT and IP still remains arbitrary, especially in the absence of a proven immunohistochemical expression of ALK-1 or rearrangements of ALK gene by means of FISH. Some investigators prefer the diagnosis of IP when dealing with ALK-negative lesions arising at unusual sites, including the breast, of adult patients (Vecchio et al. 2011). Among the cases of IMT/IP of the breast tested by FISH, only four cases have been found to be ALK-rearranged. Notably ALK1 expression and/or ALK gene rearrangement does not seem to predict clinical course. In this regard, only a few cases, regardless of ALK-1 expression and/or ALK rearrangements, develop local recurrence or more rarely distant metastases (Zhao et al. 2013; Bosse et al. 2014; Choi et al. 2015; Markopoulos et al. 2015; Talu et al. 2016).

Differential Diagnosis

The diagnosis of IMT/IP arising in the breast is challenging, especially on a core needle biopsy. The pathologists facing with a bland-looking spindle cell lesion of the breast should keep in mind a wide variety of benign and malignant lesions, including reactive spindle cell nodule, nodular fasciitis, IgG4-related sclerosing mastitis, myofibroblastoma, solitary fibrous tumor, desmoid-type fibromatosis, low-grade (fibromatosis-like) spindle cell carcinoma (Metaplastic Carcinoma), low-grade myofibroblastic sarcoma, and dermatofibrosarcoma protuberans (Table 2). A history of a previous biopsy or fine-needle aspiration (FNA), as well as the recognition of entrapped/displaced epithelial mammary structures, stromal hemosiderin deposition, foamy and hemosiderin-laden macrophages, lymphocytes and plasma cells, fat necrosis, and foreign body giant cell reaction, favors the diagnosis of reactive spindle cell nodule.
Table 2

Differential diagnosis

Differential diagnosis of inflammatory myofibroblastic tumor/inflammatory pseudotumor

Inflammatory myofibroblastic tumor/inflammatory pseudotumor

Imaging features: Well-circumscribed or ill-defined margins

Histology: Interlacing short fascicles of spindle cells, closely intermingling with lymphocytes, plasma cells, and eosinophils

Immunohistochemistry: Staining with vimentin and α-smooth muscle actin; variable staining with desmin and ALK-1; CD34, CD21,CD35, β-catenin, and STAT6 are negative

Reactive spindle cell nodule

Imaging features: Nodule with circumscribed margins, following biopsy or FNAC

Histology: Short fascicles; focal storiform pattern; hemosiderin deposition; foamy and hemosiderin-laden macrophages, lymphocytes, and plasma cells; fat necrosis and foreign body giant cell reaction

Immunohistochemistry: Staining with α-smooth muscle actin; CD34, desmin, β-catenin, and pancytokeratins are negative

Nodular fasciitis

Imaging features: Ill-defined margins, at least focally

Histology: Short, focally intersecting fascicles; foci of extravasated red blood cells and lymphocytes; tissue culture-like appearance

Immunohistochemistry: Staining with α-smooth muscle actin; CD34, desmin, β-catenin, and pancytokeratins are negative

IgG4-related sclerosing mastitis

Imaging features: Multiple nodular masses with ill-defined or circumscribed margins

Histology: Fibro-sclerotic tissue with prominent inflammation of lymphocytes (nodular aggregate of lymphoid cells; lymphoid follicle formation) and plasma cells; variable number of fibroblast-like cells

Immunohistochemistry: IgG4-expressing plasma cells

Myofibroblastoma

Imaging features: Well-circumscribed nodule

Histology: Short, haphazardly intersecting fascicles interrupted by keloid-like collagen fibers

Immunohistochemistry: Staining with desmin, CD34, estrogen, and progesterone receptors; variable expression of α-smooth muscle actin, bcl2, CD10, CD99; pancytokeratins, S100 protein, β-catenin, and STAT6 are negative

Solitary fibrous tumor

Imaging features: Well-circumscribed nodule

Histology: Short fibroblast-like spindle to round/ovoid cells, haphazardly arranged; focal storiform pattern

Immunohistochemistry: Staining with CD34 and STAT6; desmin, α-smooth muscle actin, and pancytokeratins are negative

Desmoid-type fibromatosis

Imaging features: Ill-defined, often infiltrative margins

Histology: Long fascicles, focally intersecting; fibrous stroma

Immunohistochemistry: Staining with α-smooth muscle actin and β-catenin; CD34, desmin, pancytokeratins, and STAT6 are negative

Low-grade (fibromatosis-like) spindle cell carcinoma

Imaging features: Ill-defined or frankly infiltrative margins

Histology: Proliferation of spindle cells with, at least focally, mild to moderate nuclear atypia; scattered clusters of epithelioid to polygonal cells; occasionally small squamous-glandular structures and/or foci of in situ or invasive carcinoma

Immunohistochemistry: Staining with pancytokeratins and p63; variable expression of α-smooth muscle actin and desmin; CD34, β-catenin, and STAT6 are negative

Low-grade myofibroblastic sarcoma

Imaging features: Poorly circumscribed nodule

Histology: Proliferation of spindle cells with fascicular arrangement; low to focally moderate nuclear pleomorphism; occasionally severe nuclear pleomorphism

Immunohistochemistry: Staining with α-actin; desmin, pancytokeratins, β-catenin, CD34, and STAT6 are negative

Dermatofibrosarcoma protuberans

Imaging features: Ill-defined margins

Histology: Proliferation of spindle cells with diffuse storiform pattern; infiltration of adipose tissue in a “honeycomb” pattern

Immunohistochemistry: Staining with CD34 and STAT6; desmin, α-smooth muscle actin, β-catenin, and pancytokeratins are negative

Nodular fasciitis shares with IMT/IP irregular margins, at least focally, and the presence of variable myxoid matrix, mitoses, and inflammatory cells. However lymphocytes and plasma cells in the latter are more prominent and closely intermingling with the spindle cells. Unlike nodular fasciitis, IMT/IP lacks the typical tissue-culture/granulation-like appearance.

Immunoglobulin (IgG)4-related sclerosing mastitis is rare with only a few cases reported in the breast to date (Cheuk et al. 2009). Histologically the breast masses usually contain prominent stromal sclerosis with a variable number of spindle fibroblast-like cells, a dense lymphoplasmacytic infiltrate, and loss of breast lobules (Cheuk et al. 2009). This lesion differs from IMT/IP in that fibrosis and inflammation predominate over the spindle cell component. Diagnostic clue is the presence of numerous (range from 272 to 495 per high power field) IgG4-expressing plasma cells (Cheuk et al. 2009).

Myofibroblastoma, a benign tumor of the mammary stroma which presents as a nodule with well-circumscribed margins, is usually composed of eosinophilic spindle cells arranged in short, haphazardly intersecting fascicles with interspersed keloid-like collagen fibers. Unlike IMT/IP, myofibroblastoma contains mast cells but not lymphocytes, plasma cells, or eosinophils in the stroma. In addition myofibroblastoma usually co-expresses diffusely CD34, desmin, and α-smooth muscle actin, while ALK1 immunoreactivity is absent.

In contrast to IMT/IP, solitary fibrous tumor characteristically shows short fibroblast-like cells haphazardly arranged and medium-sized blood vessels with hyalinized walls and branching configuration. In addition solitary fibrous tumor is diffusely positive for CD34 and STAT6, which are not expressed in IMT/IP.

Desmoid-type fibromatosis usually exhibits extensive infiltrative margins with fingerlike projections into the adjacent fibro-fatty tissue and breast parenchyma. The diagnosis of desmoid-type fibromatosis is based on the presence of long, sweeping fascicles set in a variable fibrous stroma. Spindle cells are aligned parallel and their nuclei are spaced, without overlapping. Inflammatory cells admixed with the proliferating spindle cells are lacking in desmoid-type fibromatosis. Although desmoid-type fibromatosis may share with IMT/IP the immunohistochemical expression of α-smooth muscle actin, the former is typically positive for β-catenin in about 80% of cases.

Low-grade (fibromatosis-like) spindle cell carcinoma is included in the differential diagnosis because neoplastic cells adopt a spindle cell morphology. Detection of epithelioid-polygonal cells arranged in small cohesive clusters, in addition to spindle cell component, and immunoreactivity for cytokeratins and myoepithelial markers, especially p63, supports the diagnosis of carcinoma. Low-grade myofibroblastic sarcoma shares with IMT/IP the expression of α-smooth muscle actin. However, its presentation (nodule with well-circumscribed margins); presence, at least focally, of moderate nuclear atypia; and high mitotic count (from 7 to 35 mitoses per 10 HPF), along with absence of inflammatory cells, favor the diagnosis of low-grade myofibroblastic sarcoma.

Finally, dermatofibrosarcoma protuberans may share with IMT/IP the storiform/swirling growth pattern which can be focally encountered in the latter. Unlike IMT/IP, dermatofibrosarcoma protuberans exhibits a diffuse storiform pattern and is diffusely positive for CD34, while myogenic markers (desmin, α-smooth muscle actin) are absent.

References and Further Reading

  1. Bosse, K., Ott, C., Biegner, T., Fend, F., Siegmann-Luz, K., Wallwiener, D., & Hahn, M. (2014). 23-year-old female with an inflammatory Myofibroblastic tumour of the breast: A case report and a review of the literature. Geburtshilfe und Frauenheilkunde, 74, 167–170.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Cheuk, W., Chan, A. C., Lam, W. L., Chow, S. M., Crowley, P., Lloydd, R., Campbell, I., Thorburn, M., & Chan, J. K. (2009). IgG4-related sclerosing mastitis: Description of a new member of the IgG4-related sclerosing diseases. The American Journal of Surgical Pathology, 33, 1058–1064.CrossRefPubMedGoogle Scholar
  3. Choi, E. J., Jin, G. Y., Chung, M. J., Moon, W. S., & Youn, H. J. (2015). Primary inflammatory myofibroblastic tumors of the breast with metastasis: Radiographic and histopathologic predictive factors. Journal of Breast Cancer, 18, 200–205.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Coffin, C. M., & Fletcher, J. A. (2013). Inflammatory myofibroblastic tumour. In C. D. M. Fletcher, J. A. Bridge, P. C. W. Hogendoorn, & F. Mertens (Eds.), WHO classification of tumours of soft tissue and bone (4th ed., pp. 83–84). Lyon: WHO Press.Google Scholar
  5. Haj, M., Weiss, M., Loberant, N., & Cohen, I. (2003). Inflammatory pseudotumor of the breast: Case report and literature review. The Breast Journal, 9, 423–425.CrossRefPubMedGoogle Scholar
  6. Markopoulos, C., Charalampoudis, P., Karagiannis, E., Antonopoulou, Z., & Mantas, D. (2015). Inflammatory myofibroblastic tumor of the breast. Case Reports in Surgery, 2015, 705127.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Talu, C. K., Çakır, Y., Hacıhasanoğlu, E., Leblebici, C., Aksoy, Ş., & Nazlı, M. A. (2016). Inflammatory myofibroblastic tumor of the breast coexisting with pseudoangiomatous stromal hyperplasia. The Journal of Breast Health, 12, 171–173.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Vecchio, G. M., Amico, P., Grasso, G., Vasquez, E., La Greca, G., & Magro, G. (2011). Post-traumatic inflammatory pseudotumor of the breast with atypical morphological features: A potential diagnostic pitfall. Report of a case and a critical review of the literature. Pathology, Research and Practice, 207, 322–326.CrossRefPubMedGoogle Scholar
  9. Zhao, H. D., Wu, T., Wang, J. Q., Zhang, W. D., He, X. L., Bao, G. Q., Li, Y., Gong, L., & Wang, Q. (2013). Primary inflammatory myofibroblastic tumor of the breast with rapid recurrence and metastasis: A case report. Oncology Letters, 5, 97–100.CrossRefPubMedGoogle Scholar
  10. Zhou, Y., Zhu, J., Zhang, Y., Jiang, J., & Jia, M. (2013). An inflammatory myofibroblastic tumour of the breast with ALK overexpression. BMJ Case Reports, 2013.  https://doi.org/10.1136/bcr-07-2011-4474, pii: bcr0720114474.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Medical and Surgical Sciences and Advanced Technologies, G.F. Ingrassia, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele,” Anatomic Pathology Section, School of MedicineUniversity of CataniaCataniaItaly