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Year : 2014  |  Volume : 57  |  Issue : 2  |  Page : 178-182
Absence of anaplastic lymphoma kinase-1 expression in inflammatory myofibroblastic tumors of the central nervous system: Does it signify a different nosologic entity from its systemic counterpart?

1 Departments of Pathology, Government Medical College, Kozhikode, Kerala, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Mangalore, Karnataka, India
3 Kasturba Medical College, Mangalore, Karnataka, India
4 Department of Neurosurgery, Shri Sathya Sai Institute of Medical Sciences, Bengaluru, Karnataka, India

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Date of Web Publication19-Jun-2014


Background and Aim: Inflammatory myofibroblastic tumors (IMFTs) are uncommon neoplasms of the central nervous system (CNS) of intermediate grade biologic potential. Anaplastic lymphoma kinase (ALK-1), a diagnostic marker of anaplastic large cell lymphoma, is also expressed in a subset of IMFTs and appears to have prognostic significance. Though, few studies have evaluated expression of ALK-1 in IMFTs of the CNS. This retrospective study was undertaken to evaluate the expression of ALK-1 expression in IMFT of CNS by immunohistochemistry and correlate with the clinical, radiological and pathologic features. Materials and Methods: Five cases diagnosed as IMFT/inflammatory pseudotumour/plasma cell granuloma, diagnosed in CNS over 10 year period (1998-2007) were retrieved from the archives of Department of Neuropathology of a tertiary referralcenter. The clinical profile and imaging features were collected from the case records. Hematoxylin and eosin stained sections were reviewed with immunohistochemistry for smooth muscle actin (SMA), vimentin, desmin, ALK-1, p53, MIB-1, CD68, leukocyte common antigen, CD3, and CD20. Results: All five cases of IMFTs presented as dural-based space occupying or en-plaque lesions. Histologically, four cases had combined plasma cell granuloma-fibrous histiocytoma morphology, and one had fibrous histiocytoma-like morphology. Immunohistochemically, SMA was strongly positive in spindle cell component of the tumors confirming diagnosis. ALK-1 expression could not be detected by immunohistochemistry in any of the cases. Conclusion: Further studies analyzing ALK-1 gene mutation and rearrangements are required to determine pathogenetic role, if any, in CNS IMFTs.

Keywords: Anaplastic lymphoma kinase, central nervous system, inflammatory myofibroblastic tumor, central nervous system, inflammatory myofibroblastic tumor

How to cite this article:
Govindan A, Mahadevan A, Chakraborti S, Furtado S, Krishna S. Absence of anaplastic lymphoma kinase-1 expression in inflammatory myofibroblastic tumors of the central nervous system: Does it signify a different nosologic entity from its systemic counterpart?. Indian J Pathol Microbiol 2014;57:178-82

How to cite this URL:
Govindan A, Mahadevan A, Chakraborti S, Furtado S, Krishna S. Absence of anaplastic lymphoma kinase-1 expression in inflammatory myofibroblastic tumors of the central nervous system: Does it signify a different nosologic entity from its systemic counterpart?. Indian J Pathol Microbiol [serial online] 2014 [cited 2023 Sep 27];57:178-82. Available from:

   Introduction Top

Inflammatory myofibroblastic tumors (IMFT) are uncommon mesenchymal neoplasms of intermediate biologic potential. Primarily a visceral and soft tissue tumor common in children and young adults, it is a distinctive lesion composed of varying proportions of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes and eosinophils, producing a spectrum of histopathological patterns. The exuberant inflammatory component is responsible for the lesion being variously referred to as "inflammatory pseudotumors" or "plasma cell granulomas" suggesting a reactive or inflammatory origin. Prominence of the spindle cell component makes it mimic other spindle cell lesions in soft tissue and viscera. Inflammatory myofibroblastic tumors can occur in any organ system, but has a predilection for lung, mesentery and omentum. Central nervous system (CNS) and spinal cord are extremely rare sites of involvement, [1],[2] where they mimic lymphoplasmacyte-rich meningiomas, plasmacytoma, lymphoma or pachymeningitis. Long considered it to be an inflammatory or reactive process, the recent detection of chromosomal translocations involving chromosome band 2p23, the site of the anaplastic lymphoma kinase (ALK) gene in extra CNS IMFTs, suggests a neoplastic pathogenesis. [3],[4],[5] Overexpression of ALK-1 in IMFTs has also been found to have prognostic significance. Frequently reported in abdominal and pulmonary tumors, presence of ALK-1 is associated with early age of onset and higher frequency of recurrences. [6] In published literature, there are only eight studies that have investigated ALK-1 expression in CNS IMFTs. [1],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[ 13] The findings are variable, with only five of total 27 reported cases revealing ALK-1 over-expression. [1],[7],[10] In this study, we attempt to determine the frequency of ALK-1 expression in cases of CNS IMFTs.

   Materials and methods Top

All the cases diagnosed as IMFT/inflammatory pseudotumor/plasma cell granuloma between 1998 and 2007 (10 years) were retrieved from the archives of Department of Neuropathology of a tertiary referral center that caters exclusively to neurological, neurosurgical and psychiatric disorders. The clinical profile and imaging features were collected from the case records [Table 1]. Hematoxylin and eosin stained sections were reviewed and histopathologically subtyped as plasma cell granuloma-like or fibrous-histiocytoma like IMFT. Periodic acid-Schiff (PAS), Gomori's methenamine silver (GMS) and Ziehl-Neelsen stains were performed to look for fungal elements and acid fast bacilli, respectively. All the cases were histologically confirmed by positivity for smooth muscle actin (SMA, monoclonal, 1:50, Novocastra, UK) in the spindle cell component. The paraffin embedded sections were also subjected to immunohistochemistry with antibodies to vimentin (monoclonal, 1:200, BioGenex, USA), desmin (monoclonal, 1:80, BioGenex, USA), ALK-1 (monoclonal, 1:80, BioGenex, USA), p53 (monoclonal, 1:100, Novocastra, UK), MIB-1 (monoclonal, 1:100, DAKO, Denmark), CD68 (monoclonal, 1:30, BioGenex, USA), leukocyte common antigen (monoclonal, 1:100, DAKO, Denmark), CD3 (monoclonal, 1:100, BioGenex, USA) and CD20 (monoclonal, 1:100, BioGenex, USA), incorporating appropriate positive and negative controls. Five cases of pseudotumor of orbit, two cases of chronic subdural hematoma, one case of chronic pachymeningitis and two cases of granulomatous meningitis, served as biological controls.
Table 1: Summary of clinical, radiological, histopathological and immunohistochemical fi ndings

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   Results Top

Five cases of IMFT of the CNS were reported over last 10 years (1998-2007). All these cases were referred for histopathological review from other hospitals. The clinical and radiologic features are summarized in [Table 1]. All the subjects involved were adults (age range: 26-50 years; mean 37.2 years; male:female = 3:2). The most common presenting symptoms were headache, vomiting, and seizures. Radiologically, all the five were dural-based lesions, three presenting as mass and two as en-plaque lesions. One of the dural-based mass lesions had both an intra- and extra-axial component. One case each involved frontal region, parietal convexity, parasagittal in the occipital region with extension into the sagittal and straight sinuses, temporal lobe and base of the brain. On imaging, the lesions were of varying intensity and showed minimal to moderate contrast enhancement, one of them showing perilesional edema [Figure 1]. No followup was available in any of the cases.
Figure 1: Axial magnetic resonance images show a lesion in the parasagitial region on either side of superior sagitial sinus, close to posterior occipital cortex, isointense on T1-weighted (a) and T2-weighted (b), uniform contrast enhancement (T1-contrast; c). The lesion is compressing posterior occipital cortex and eff acing the sulci, with perilesional edema in occipital and posterior parietal white matier (b). Involvement of superior sagitial sinus (c and d) and straight sinuses (coronal T1-contrast; d), with partial loss of fl ow void in the superior sagitial sinus (a) is noted, without any skull hyperostosis or lesional necrosis

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Microscopically, depending on the predominant histologic features, the cases were classified as plasma cell granuloma-type or fibrous histiocytoma-type [Table 1]. Histologically, four had combined plasma cell granuloma-like/fibrous histiocytoma-like morphology [Figure 2]a and b], and one had fibrous histiocytoma-like morphology [Figure 2]c]. None of the cases in the study either revealed any fungal elements on PAS, GMS stains or acid fast bacilli on ZN stain. Fibrous histiocytic component of the tumor in all the cases had myofibroblastic spindle cells with oval to elongated nuclei, arranged in fascicles [Figure 2]a] the interspersed collagen [Figure 2]c], being intensely labeled with vimentin [Figure 2]d] and SMA [Figure 2]e and f]. Desmin immunolabeling was negative in all cases, except in the mass in parasagittal occipital region (Case 3), which demonstrated focal positivity for desmin. Lymphohistiocytic infiltrate varied from mild to moderate, and labeled with CD68 and LCA. The lymphocytic infiltrate was composed predominantly of CD3 positive T-cells, than CD20 positive B-cells. Scattered mature plasma cells with occasional binucleate forms were seen in all cases. In four cases, nodular aggregates of plasma cells were noted, in a background of fibrous histiocytoma-like morphology and mild to moderate lymphohistiocytic infiltrate, hence annotated as combined plasma cell granuloma- and fibrous histiocytoma-like IMFT. ALK-1 was uniformly negative in all the cases irrespective of histological subtype [Figure 2]f]. Mutant p53 protein was detected immunohistochemically in one case (Case 5) and was absent in the rest. MIB-1 labeling index was <1% in four cases and 15-20% in Case 5 [Figure 2]f]. It was noteworthy that Case 5 with high MIB-1 labeling index also had concurrent p53 mutation. Among the controls, interestingly, three out of the five cases of pseudotumor of the orbit demonstrated focal positivity for SMA, while one case each of chronic subdural membrane, granulomatous pachymeningitis, and chronic pachymeningitis showed scattered SMA positive spindle cells. All cases failed to demonstrate ALK-1 positivity.
Figure 2: Spindle shaped tumor cells are arranged in fascicles and vague whorls with dense inflammatory infiltrate (a) (H and E, ×80), composed of predominantly lymphocytes interspersed with plasma cells (b) (H and E, ×160). Spindle cell nuclei are oval to elongated with fine chromatin (c) (H and E, ×300) and the cells are positive for vimentin (d) (×200), smooth muscle actin (e) (×120, (f) (×200),
and negative for anaplastic lymphoma kinase-1 (g) (×180, inset: Positive control (×180). Case 5 showed increased MIB-1 (h) (×120) labeling of 15-20%

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   Discussion Top

Inflammatory myofibroblastic tumor was earlier considered an inflammatory lesion because of its resemblance to nonneoplastic fibroblastic proliferation and overwhelming inflammatory response. Recent demonstration of chromosomal rearrangements involving 2p23 in a subset of IMFTs gave strength to the assumption that they are neoplastic in character. [3],[4],[5] Immunohistochemically, this is detectable as the expression of ALK-1 and p80 in tissues. [4] In the extra-CNS IMFTs, expression of ALK-1 is found to be a favorable prognostic indicator, as it is associated with local recurrences, but not distant metastasis. [6] Total excision is the treatment of choice. Radiotherapy and chemotherapy have been tried in recurrent cases. [1],[7]

Hausler et al. (2003) reviewed 57 cases of intracranial IMFTs. In two-thirds of cases, they presented as dural-based masses, while intraparenchymal lesions were less frequent (12%). The remainder were mixed intraparenchymatous/meningeal (7%), intraventicular in 12% and extending from intracerebral to extracerebral sites in 9% cases. [1] In a review of 38 cases, Buccoliero et al. (2005) found that 82% were single intracranial lesions, 3% were solitary spinal and 16% were multifocal lesions. They noted a male preponderance in contrast to our study, though the mean age of presentation was similar (mean 32 years, age range of 5-76 years). The lesions involved cerebral, cerebellar, brainstem and spinal leptomeninges. [14] In a study of 10 dural-based IMFTs by Jeon et al., (2005) male predilection and most common presentation in the fifth decade was seen. [8] ALK-1 expression was not studied in any of these large series that predated the discovery of this gene in IMFT.

In this study, the dural-based intracranial IMFTs were either exophytic mass-forming or en-plaque lesions. There was no gender predilection and the mean age of presentation was 37.2 years. Imaging revealed heterointense lesions with or without contrast enhancement.

Histologically, varying admixture of the three components of the tumor - the spindled myofibroblasts, fibroblasts and inflammatory cells, produce the three basic histological patterns - nodular fasciitis-like, fibrous histiocytoma-like and desmoid-fibromatosis type. [15] Extra-pulmonary IMFTs fit into either of these three patterns. [16] In this study, we have used the classification proposed by Jeon et al., (2005) of plasma cell granuloma-type and fibrous histiocytoma-type, which is more appropriate for intracranial subset of IMFTs. The former, has a prominent inflammatory cell component in comparison to the predominant myofibroblastic component in the later. An intermediate pattern combining these two types may also exist. [8]

Intracranial IMFTs closely mimic intracranial plasmacytomas, lymphoproliferative disorders, idiopathic hypertrophic pachymeningitis and lymphoplasmacytic variant of meningioma. The diagnosis requires demonstration of SMA positivity in the spindle cell component confirming their myofibroblastic origin. The inflammatory infiltrate is polyclonal confirmed by immunohistochemical or molecular studies that help to differentiate IMFTs from plasmacytomas and other lymphoproliferative disorders.

Given the varied histopathological spectrum, it is not surprising that IMFTs are also genetically heterogeneous. In children and young adults clonal rearrangements that activate the ALK receptor tyrosine kinase gene in chromosome band 2p23 have been detected in the extra CNS IMFTs. [16] The resultant ALK-1 protein over-expression is detectable by immunochemistry in the myofibroblasts, the neoplastic component, and not in the inflammatory component. In contrast, the cytogenetic rearrangements and ALK-1 over-expression was not found in adults over 40 years age. [16] There are only eight published reports that have investigated ALK-1 over-expression in a total of CNS IMFTs. [1],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[13] The findings are variable, with only five out of the 27 cases (18.5%) being immunopositive for ALK-1. [1],[7],[10] Of these, two cases of intracranial IMFT with ALK-1 over-expression, [1],[7] recurred suggesting that ALK-1 over-expression may have the same prognostic significance in CNS lesions as its extracranial counterpart. However, recurrence was also noted in two cases that were ALK-1 negative. [8]

Jeon et al., who reviewed a large series of 10 cases of CNS IMFTs, failed to detect ALK-1 overexpression in any of their cases, [8] similar to this study. It is possible that these tumors demonstrate chromosomal rearrangements at the molecular level that may not be demonstrable in tissue at the protein level by immunohistochemitry. This requires further investigation in larger group of patients.

   Conclusion Top

The CNS IMFTs do not consistently express ALK-1 and recurrences have occurred in both ALK-1 positive and negative tumors, suggesting that they maybe a different biologic entity as compared to their extra-CNS counterparts and follow a different biologic pathway. The biology of these uncommon CNS IMFTs needs to be further characterized with more studies.

   Acknowledgment Top

Our kind acknowledgments to Dr. Clementina Rama Rao, Professor of Pathology and Prashanth Kumar, Junior Technician, Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore for performing immunohistochemsitry for ALK-1 on the cases.

We thank Dr. A Raja of Department of Neurosurgery, Kasturba Medical College, Manipal, Karnataka, Dr. T G Bindu of Indoamerican Hospital, Vaikom, Kerala and Dr. M S Bhaskar of Ramans Medical Services, Mysore, Karnataka, for referring the cases for review.

Technical assistance of Mr. K Manjunath, Mrs. Rajyasakti, Human Brain Tissue Repository (Brain Bank), Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India, for assistance with photographic illustrations and histopathology preparation is also acknowledged.

   References Top

1.Häusler M, Schaade L, Ramaekers VT, Doenges M, Heimann G, Sellhaus B. Inflammatory pseudotumors of the central nervous system: Report of 3 cases and a literature review. Hum Pathol 2003;34:253-62.  Back to cited text no. 1
2.Makino K, Murakami M, Kitano I, Ushio Y. Primary intracranial plasma-cell granuloma: A case report and review of the literature. Surg Neurol 1995;43:374-8.  Back to cited text no. 2
3.Cook JR, Dehner LP, Collins MH, Ma Z, Morris SW, Coffin CM, et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: A comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364-71.  Back to cited text no. 3
4.Coffin CM, Patel A, Perkins S, Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 2001;14:569-76.  Back to cited text no. 4
5.Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 1999;59:2776-80.  Back to cited text no. 5
6.Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: Comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 2007;31:509-20.  Back to cited text no. 6
7.Lacoste-Collin L, Roux FE, Gomez-Brouchet A, Despeyroux ML, Uro-Coste E, Coindre JM, et al. Inflammatory myofibroblastic tumor: A spinal case with aggressive clinical course and ALK overexpression. Case report. J Neurosurg 2003;98:218-21.  Back to cited text no. 7
8.Jeon YK, Chang KH, Suh YL, Jung HW, Park SH. Inflammatory myofibroblastic tumor of the central nervous system: Clinicopathologic analysis of 10 cases. J Neuropathol Exp Neurol 2005;64:254-9.  Back to cited text no. 8
9.Suri V, Shukla B, Garg A, Singh M, Rishi A, Sharma MC, et al. Intracranial inflammatory pseudotumor: Report of a rare case. Neuropathology 2008;28:444-7.  Back to cited text no. 9
10.Swain RS, Tihan T, Horvai AE, Di Vizio D, Loda M, Burger PC, et al. Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor. Hum Pathol 2008;39:410-9.  Back to cited text no. 10
11.Kato K, Moteki Y, Nakagawa M, Kadoyama S, Ujiie H. Inflammatory myofibroblastic tumor of the cerebellar hemisphere - Case report. Neurol Med Chir (Tokyo) 2011;51:79-81.  Back to cited text no. 11
12.Yavuzer D, Dalbayrak S, Oz B, Yilmaz M, Akansel G. Intracranial inflammatory pseudotumor: Case report and review of the literature. Clin Neuropathol 2010;29:151-5.  Back to cited text no. 12
13.Lui PC, Fan YS, Wong SS, Chan AN, Wong G, Chau TK, et al. Inflammatory pseudotumors of the central nervous system. Hum Pathol 2009;40:1611-7.  Back to cited text no. 13
14.Buccoliero AM, Caldarella A, Santucci M, Ammannati F, Mennonna P, Taddei A, et al. Plasma cell granuloma - An enigmatic lesion: Description of an extensive intracranial case and review of the literature. Arch Pathol Lab Med 2003;127:e220-3.  Back to cited text no. 14
15.Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 2000;157:377-84.  Back to cited text no. 15
16.Fletcher CD, Unni KK, Mertem F. Pathology and Genetics of Tumors of Soft Tissue and Bone. Lyon: International Agency for Research on Cancer; 2002.  Back to cited text no. 16

Correspondence Address:
Anita Mahadevan
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.134658

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