Inflammatory myofibroblastic tumor of the central nervous system and ...

Human Pathology (2008) 39, 410–419

www.elsevier.com/locate/humpath

Original contribution

Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor Rebecca S. Swain MD a , Tarik Tihan MD, PhD a,⁎, Andrew E. Horvai MD, PhD a , Dolores Di Vizio MD, PhD b , Massimo Loda MD b , Peter C. Burger MD c , Bernd W. Scheithauer MD d , Grace E. Kim MD a a

Department of Pathology, Neuropathology, University of California, San Francisco, CA 94143-0102, USA Dana-Farber Cancer Institute, Boston, MA 02115, USA c Johns Hopkins University, Baltimore, MD 21287, USA d Mayo Clinic, Rochester, MN 55905, USA b

Received 17 May 2007; revised 20 July 2007; accepted 25 July 2007

Keywords: Inflammatory myofibroplastic tumor; Inflammatory pseudotumor; Central nervous system; Plasma cell granuloma

Summary Inflammatory myofibroblastic tumor (IMT) is a distinctive spindle cell lesion and occurs primarily in soft tissue. Recent evidence suggests a neoplastic nature, although historically, both neoplastic and nonneoplastic processes were combined in this category. Originally described as a nonneoplastic process, the term inflammatory pseudotumor (IP) has been used synonymously with IMT. IMTs have been linked to ALK gene (2p23) rearrangements, and some have suggested an association with the human herpesvirus 8 (HHV-8). IMT in the central nervous system (CNS) is rare, its characteristics are poorly defined, and its relation to similar tumors at other sites is unclear. To better characterize IMT within the CNS, we studied clinicopathologic features of 6 IMTs and compared them with 18 nonneoplastic lesions originally classified as IP. The IMT group consisted of 2 male and 4 female patients with a median age of 29 years. Of the six IMTs, 5 occurred within the cerebral hemispheres, and one was in the posterior fossa. All tumors were composed of neoplastic spindle cells and a variable amount of inflammatory infiltrate. Eighteen IPs included in this study consisted of predominantly inflammatory masses occasionally seen in the setting of systemic diseases. Only 1 IMT and none of the IPs recurred during the follow-up period. Four IMTs had either ALK protein overexpression or 2p23 rearrangement, and 1 case demonstrated both. None of the IPs were positive for ALK. Neither IMT nor IP cases demonstrated HHV-8 expression. We suggest that IMT in the CNS is distinct from the nonneoplastic IP, and distinguishing IMT from nonneoplastic lesions should enable better decisions for patient management. © 2008 Elsevier Inc. All rights reserved.

⁎ Corresponding author. E-mail address: [email protected] (T. Tihan). 0046-8177/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2007.07.012

IMT of the central nervous system

1. Introduction Inflammatory myofibroblastic tumor (IMT) is a recently recognized spindle cell neoplasm, and its nature and origin are still controversial. IMTs primarily affect children and young adults but can occur at many sites and over a wide age range [1]. Initial publications on “IMT” considered this entity synonymous with the inflammatory pseudotumor (IP) [2]. This loose nosologic association has continued in numerous publications to date [3]. In the 2002 World Health Organization classification scheme, IMT is defined as a “distinctive lesion composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils” [4]. Recent studies provided evidence that some IMTs have clonal rearrangements of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene located on 2p23, as well as immunohistochemical expression of ALK protein [5-7]. Some suggested that IMT and inflammatory fibrosarcoma were histogenetically related, and if they were separate entities, they were differentiated more by relative degrees than absolutes [1,8]. These and other studies have clearly identified a group of neoplasms consisting of a clonal spindle cell population with a potential to recur and metastasize, quite distinct from the inflammatory/nonneoplastic lesions historically recognized as IP [9]. Nonetheless, many reports of IMTs and IPs included a heterogeneous group of neoplastic and nonneoplastic lesions that appear histologically similar [10-15]. Microscopically, 3 growth patterns of IMT have been described and recognized by the current World Health Organization classification scheme [4]: the nodular fasciitis– like variant, the fibromatosis/fibrohistiocytic type, and the desmoid type. The spindle cells frequently show positive staining with antibodies against ALK-1 protein and vimentin and, variably, with antibodies against smooth muscle antigens. Fluorescence in situ hybridization (FISH) with a probe flanking the ALK gene at 2p23 typically demonstrates a rearrangement [7], an apparently distinct genetic alteration for IMT [16]. While the tumors with ALK gene rearrangements are readily considered a unique neoplastic category, histologically similar neoplastic lesions may lack this genetic alteration. It is also not clear whether nonneoplastic, nonclonal lesions lacking ALK rearrangement should be included in this category [17]. Some authors suggest that ALK kinase–deficient lesions classified as IP are biologically distinct from the IMT, at least in some tissues [18]. A recent study proposed a link between IMT and herpesvirus based on the observation of human herpesvirus–8 (HHV-8) sequences in the genome of 5 ALK-1– negative lesions classified as IMT [19]. Subsequent series failed to detect such an association [20,21]. It is still unclear whether HHV-8 is detected in IMT or in the nonneoplastic examples misplaced in the IMT category. Central nervous system (CNS) involvement by IMT is extremely rare, and its characterization is confounded by the lack of clear distinction between neoplastic and nonneoplas-

411 tic processes. Until recently, almost all cases reported in the CNS have been considered IP, or “plasma cell granuloma,” with references to their inflammatory nature [22]. Similar to the soft tissue literature, some neuropathological studies used the terms IMT and IP interchangeably [23-25]. A recent study on IMTs in the CNS included 10 cases [25], none of which demonstrated ALK protein expression. The authors of this report acknowledged that their cases included both neoplastic and reactive entities. However, other case studies on IMTs involving the CNS have demonstrated ALK abnormalities [26,27]. Since a clear designation of the true nature of IMT was typically overlooked or avoided, earlier reports likely included an indiscriminate mixture of neoplastic and nonneoplastic processes. Yet, it is important to recognize the distinction between neoplastic and nonneoplastic lesions to provide a more realistic guide for treatment and outcome. A recent study further outlines the importance of segregating the neoplasms diagnosed as IMT based on their genetic alterations. Our study aims to distinguish neoplastic lesions considered as IMT from nonneoplastic lesions better designated as IPs to provide a biologically more meaningful approach to these lesions.

2. Materials and methods We obtained 6 cases of IMTs in the CNS from the consultation files of 3 of the authors (P.C.B., B.W.S., T.T.). An additional 18 cases of IP were retrieved from the archives of Johns Hopkins Medical Center, Baltimore, MD, and the consultation files of one of the authors (P.C.B.). Clinical information was obtained from referring physicians and institutional medical records. Appropriate permissions were obtained from the institutional review boards. Formalinfixed, paraffin-embedded tissue was used for histologic review and routine histologic and immunohistochemical studies.

2.1. Immunohistochemistry Antibodies were obtained form the following sources: polyclonal ALK (Zymed Laboratories, South San Francisco, CA), mLANA (Advanced Biotechnologies, Inc, Columbia, MD), pLANA (Dr Don Ganem, University of California, San Francisco, CA), and vIL-6 (Dr Yuan Chang, University of Pittsburgh, Pittsburgh, PA). All sections for immunohistochemistry (IHC) were deparaffinized and rehydrated. Endogenous peroxidase blockage was performed with 3% hydrogen peroxide in phosphate-buffered saline 10 minutes before antigen retrieval except for ALK, which was performed post antigen retrieval in 3% hydrogen peroxide in calcium magnesium-free (CMF)/phosphate-buffered saline + 0.05% Tween20 + 0.1% sodium azide. Antigen retrieval was achieved by microwaving for 10 minutes in 10 mmol/L citrate buffer (pLANA, mLANA) or PASCAL pressure

412 cooker with DAKO target retrieval solution pH 6.0 (ALK; Dako, Carpinteria, CA). Nonspecific binding blockade was performed by incubating the sections with goat or rabbit serum for 30 minutes for mLANA (rat), pLANA (rabbit), and vIL-6 (rabbit). Primary antibody incubation was 30 minutes for ALK (dilution = 1:100) and 60 minutes for mLANA (1:500), pLANA (1:2000), and vIL-6 (1:500) at the indicated concentrations. After washing, secondary biotinylated antibody incubation for 30 minutes was performed using the DAKO Envision+ system for ALK, goat antirabbit for pLANA, and vIL-6, and rabbit antirat for mLANA.

2.2. Fluorescence in situ hybridization Fluorescence in situ hybridization for ALK translocation was performed at The Dana Farber Cancer Institute (Boston, MA) using the Vysis LSI ALK Dual Color BreakApart Rearrangement probe (Des Plaines, IL). The probe set contains a 250-kb probe for the telomeric side of the 2p23 breakpoint labeled with spectrum orange and a 300-kb probe for the centromeric side of the breakpoint with spectrum green. A total of 50 interphase cells with tumor cell morphology (spindled) were scored in each case. A positive result was defined by the presence of 2p23 rearrangement, as indicated by the separation of at least 1 orange and 1 green probe signal (a distance of at least 1 probe width) in more than 2% of tumor cells. A negative result was defined by the presence of 2 normal signals (either immediately adjacent orange and green signals or fused yellow signals) in a cell or the presence of ALK rearrangement in less than 2% of tumor cells. A normal threshold has not been established for this probe in the literature, whereas a normal range of 0% to 2% has been used clinically for the presence of ALK translocation in the diagnosis of anaplastic large cell lymphomas (Dr K. Reddy, Genzyme Genetics, personal communication). An anaplastic large-cell lymphoma sample and a uterine/cervical IMT previously verified to have the ALK gene abnormality were used as positive controls.

3. Results

R. S. Swain et al. Table 1

Clinical features of patients in IMT and IP groups

Median age (y) Sex (M/F) Recurrence Mean follow-up (mo) Concurrent systemic disease or fever Prior surgery on the same site Reduction of tumor size after steroid treatment

CNS IMT

CNS IP

29 2/4 1/6 80 0/6 0/6 0/2

46 8/10 0/12 57 7/18 3/18 2/5

underwent a gross total resection. Pathologic evaluation revealed a spindle cell neoplasm. Immunohistochemical studies performed at the original institution demonstrated no staining for neuronal, glial, vascular, embryonal and smooth muscle markers, and positive staining only with vimentin and with NSE antibodies. The original diagnosis was that of a low grade sarcoma with a significant inflammatory infiltrate. The patient received postoperative chemotherapy. He remained symptom-free for 68 months, at which time he developed a mass in the contralateral hemisphere. The tumor was resected, and found to show similar histologic and immunohistochemical features as the original tumor. No further adjuvant therapy was given. The patient was alive without recurrence 15 months after surgical resection of the recurrence, and was lost to follow-up.

3.3. Patient 2 A 28-year-old female presented with several-month history of seizures. Imaging revealed an enhancing, sharply circumscribed, frontal extraaxial tumor attached to falx cerebri. The clinical impression was meningioma, and a near gross total resection was achieved. The mass was easily separated from the brain by a plane of arachnoid tissue. Pathologic examination revealed a spindle cell neoplasm with a desmoid-like pattern and focal cellular pleomorphism. Original immunohistochemical studies demonstrated no staining with antibodies against epithelial membrane antigen, CD34, bcl-2, glial fibrillary acidic protein (GFAP), Cam5.2, or S-100. She is currently alive 51 months after the initial surgery.

3.1. Clinical features 3.4. Patient 3 A brief outline of patient characteristics is presented in Table 1. Short histories are presented for 6 patients with IMT, along with a summary of clinical features of the patients in the IP category.

3.2. Patient 1 An 8-year-old boy presented with a several-month history of headaches and recent onset of drowsiness. Magnetic resonance imaging revealed a large cystic lesion with an enhancing nodule in the right frontal lobe. The patient

A 30-year-old man presented with headaches, and an extradural mass was discovered in the posterior fossa. The clinical impression was meningioma, and he underwent a subtotal resection. Pathologic evaluation in the original institution revealed fibrous tumor with diffuse strong actin and desmin immunopositivity. The tumor was negative for CD68, progesterone receptor, S-100, epithelial membrane antigen and keratin. He was scheduled for a radiation therapy when he was lost to follow-up. He was alive 63 months after initial surgery, but his recurrence status was unknown.


3.5. Patient 4 A 31-year-old woman presented with a 1-month history of headache. Imaging revealed a dura-based supraorbital right frontal mass with surrounding edema. A gross total resection of the tumor was achieved. Pathologic examination at the original

413 institution demonstrated a spindle cell tumor. The tumor cells were strongly immunopositive for smooth muscle actin and focally positive for p53 protein, with a high Ki-67 labeling index. She was followed up for 7 months without a recurrence and was lost to follow-up. She was known to be alive 73 months following initial surgery, but no information was available on tumor recurrence.

Fig. 1 Radiologic features in IMTs. A, and B, Axial computed tomographic scan appearance of tumor in patient 6. C, Axial T2-weighted magnetic resonance image of the tumor. D, Surgical specimen.

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3.6. Patient 5 A 74-year-old woman presented with headache and partial complex seizures. She had a history of infiltrating duct carcinoma treated surgically 3 years ago. Imaging revealed a 3.8-cm right hemispheric mass at the temporoparietal junction, and the initial impression was a meningioma. Intraoperatively, the tumor was not associated with either the ventricles or dura mater, and a gross total resection was achieved. Original pathologic evaluation revealed a fibromatosis-like spindle cell tumor, expressing smooth muscle actin and with a low Ki-67 labeling index. A battery of stains including bcl-2, p53, CD34, desmin, HAM56, clathrin, neuron-specific enolase (NSE), and CD68 was negative. She was discharged with no further treatment and has been free of disease at 77 months after resection.

3.7. Patient 6 A 10-month-old girl presented with failure to thrive and seizures. Neuroimaging showed a large extra-axial, durabased mass occupying the anterior two thirds of the temporal fossa and extending beyond the posterior temporal region to the parietal lobe (Fig. 1A-C). A gross total resection was achieved (Fig. 1D). Original pathologic examination reported a spindle cell tumor with a fibromatosis-like growth pattern with sufficient mitoses to suggest a low-grade malignancy. Immunohistochemistry demonstrated no evidence of desmin or smooth muscle actin, S-100, or GFAP expression. She was discharged home without further treatment. The patient suffered

R. S. Swain et al. occasional seizures during the first 2 years after surgery but had no focal neurologic deficits. She is currently free of seizures or tumor 123 months after initial surgery and is performing above average in her class.

3.8. Inflammatory pseudotumors The 18 cases of IP were retrieved from the archives of Johns Hopkins Pathology Department over a period of 9 years (1991-1999). There were 10 women and 8 men with a mean age of 41 years (range, 5-87 years). Presenting symptoms included seizures and headaches. The lesions were either solitary, extra-axial, dura-based masses (13 cases) or consisted of local thickening and/or radiologic enhancement of the dura mater (5 cases). The lesions were located in the cerebral hemispheres (9 cases), spinal cord (4 cases), skull base/cavernous sinus (3 cases), and sellar region (2 cases). Radiologically, all demonstrated contrast enhancement (Fig. 2), little or no mass effect, and little or no peritumoral edema. Seven of the patients (39%) had coexisting systemic inflammatory/infectious disorders such as lupus erythematosus, syphilis, neutropenia, or fever of unknown origin. Three patients had undergone prior surgery adjacent to the site of the lesions. One patient had an adjacent meningioma, and the other 2 were treated for inflammatory processes within the paranasal sinuses (7 months and 1 year before discovery of the IPs, respectively). One of the IPs occurred in an adult man with a history of febrile episodes, but no other symptoms. One patient had an unknown systemic disease originally thought to be neurofibromatosis type I, and another had a concurrent prostatic adenocarcinoma. The remaining 5 patients had no evidence of a

Fig. 2 Radiologic features of patients with IP. A, Coronal T1-weighted contrast-enhanced image of a parasellar mass in a 51-year-old woman. B, Coronal T1-weighted, contrast-enhanced image of a dura-based mass in a 16-year-old female.


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Fig. 3 Histologic appearance of IMTs in the CNS. A, Case 1. B, Case 2. C, Case 3. D, Case 4. E, Case 5. F, Case 6. Original magnification ×200.

Fig. 4 Studies on ALK-1 expression in IMTs. A and B, Immunohistochemical staining with the ALK-1 antibody; cases 5 and 6 (original magnification ×200). C, control sample. D, Case 5 showing ALK gene rearrangement by fluorescence in situ hybridization with the Vysis LSI ALK Dual Color BreakApart Rearrangement probe. The long arrows highlight the overlapping green and orange probes indicating the intact gene, whereas the arrowheads identify a separate green and an orange signal confirming the rearrangements.

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R. S. Swain et al.

Table 2

Analysis of ALK expression by FISH and IHC in IMT patients

Patient

Age (y)

Sex

Location

Pattern

IHC

FISH

Recurrent

Case Case Case Case Case Case

8 28 30 31 74 0.8

M F M F F F

R frontal R frontal Cerebellar R frontal R parietal L parietal

Fibromatosis Desmoid-like Fibromatosis Fibromatosis Fibromatosis NF-like

N/A Positive Negative N/A Positive Positive

N/A Negative Positive N/A Positive N/A

Yes No No No No No

1 2 3 4 5 6

Abbreviations: R, right. L, left. N/A, not applicable; NF, nodular fasciitis.

systemic disease or history of tumor. Of these 5 patients, 2 showed radiologic and clinical improvement after steroid treatment, and this information was not available for the remaining 3 patients. None of the patients in the IP group experienced recurrence during the follow-up period that ranged from 2 to 143 months. At the end of the follow-up period, 12 of the 18 patients had no evidence of disease with only minor symptoms related to their CNS lesions. Six patients were lost to follow-up.

3.9. Pathologic features 3.9.1. Inflammatory myofibroblastic tumors The IMTs in the CNS were morphologically similar to those described in soft tissues [4]. The growth patterns were predominantly fibromatosis-like in 4 of 6 cases (Fig. 3A-E). The tumor in patient 2 had a desmoid pattern (Fig. 3B), and

the tumor in patient 6 had a nodular fasciitis pattern (Fig. 3F). In rare foci, spindle cells appeared to aggregate around vascular structures without creating a specific pattern. Cell density ranged from relatively low to focally moderate, with the exception of 1 markedly hypercellular neoplasm. The spindled cells were cytologically bland with delicate chromatin and inconspicuous nucleoli. Mitotic figures, including atypical mitoses, were occasionally observed. The Ki-67 proliferation index was similarly low at or below 5%. The inflammatory cells were most frequently composed of a mixture of lymphocytes, plasma cells with only rare neutrophils, and eosinophils. Calcification and psammomatous bodies were seen in 1 case. Immunohistochemically, all tumors were positive for vimentin, and 5 tumors were positive for antibodies against smooth muscle actin. Desmin staining was negative in 4 and positive in 1 of the cases where the staining was available.

Fig. 5 Histologic findings in CNS IPs. A-C, Low-power magnification demonstrating a prominent inflammatory infiltrate with macrophages and focal fibroblastic proliferation in 3 different patients in the IP category. D, High-power magnification of the same lesion as in (A) showing cellular components. E and F, Immunohistochemical staining in (A) and (C) with CD3 demonstrating a predominantly T-cell infiltrate. All 3 of these lesions were negative for ALK, smooth muscle antigen, and other stromal markers.

IMT of the central nervous system Material was available in 4 of the cases for ALK IHC. Three of these lesions demonstrated focal (case 2) or diffuse (cases 5 and 6) strong cytoplasmic ALK expression (Fig. 4A, B), and 1 was negative. Table 2 presents the findings of ALK analysis in IMT patients. 3.9.2. Inflammatory pseudotumors The18 IPs were composed of inflammatory cells with well-formed lymphoid aggregates (Fig. 5). The inflammatory cells were mainly lymphocytes and plasma cells. A significant third cell type was the histiocyte or macrophage that occasionally appeared to cluster into poorly formed microgranulomas, but a true granulomatous inflammation was evident in only 1 case. In all cases, extensive immunohistochemical and flow cytometric analysis failed to disclose a lymphoproliferative disorder or a hematologic malignancy. In rare cases, background cellularity included a fibroblastic proliferation that resembled a fibrotic reaction rather than a neoplasm. Half of the cases were focally composed of dense connective tissue with a polyclonal plasma cell infiltrate. Four of the cases included giant cells, reminiscent of a foreign body response. Special stains for bacteria, spirochetes, acid-fast bacilli, and fungi were negative in all cases where the studies were performed (n = 15). Immunohistochemically, most of the lesions demonstrated a mixture of CD3- (n = 12) and CD20- (n = 12) positive lymphocytes with a significant histiocytic component showing MAC 387 (n = 3) or CD68 (n = 13) expression and focal S-100 positivity (n = 11). Staining for smooth muscle actin highlighted vessels but was otherwise negative as CD34 and desmin. A battery of lymphocytic cell surface markers applied variably in IHC, or flow cytometry also failed to demonstrate a specific lymphoproliferative disorder. None of the 4 IPs with available material demonstrated ALK expression. No immunohistochemical evidence of HHV8 infection was present in the 6 cases studied for mLANA, pLANA, or vIL-6.

3.10. Fluorescence in situ hybridization Sufficient tissue was available from 3 IMTs and 3 IPs. Attempts to obtain material for hybridization from the remaining paraffin material were unsuccessful. Of 3 IMTs, 2 demonstrated a translocation involving the ALK region— 2p23. Case 3 demonstrated evidence of ALK rearrangement in 4% of tumor cells and case 5 in 18% of tumor cells by FISH (see Fig. 4). None of the IPs demonstrated ALK rearrangement by FISH (0/3).

4. Discussion The 2 major challenges in the classification of lesions diagnosed as IMT or IP are whether we are referring to a single entity or 2 distinct entities and whether we could

417 group neoplastic and nonneoplastic processes in the same nosologic category [17]. IMT has historically suffered such a conundrum: many elaborate reports characterized lesions attributed to this category but avoided addressing the nosologic challenges [2]. In addition, some studies included ALK-negative, probably nonneoplastic entities as well as neoplastic, ALK-positive tumors under IPs, further confounding the issue as to whether IP as well as IMT included both neoplastic and nonneoplastic lesions [15]. The evidence that IMT is a neoplastic process initially emerged more than 15 years ago [28]. More recent studies equated IMT more with the inflammatory fibrosarcoma rather than the nonneoplastic lesions such as IP or plasma cell granuloma [1,4]. Further evidence of neoplastic nature was presented by demonstrating a clonal population harboring the abnormal ALK receptor tyrosine kinase expression due to aberrations in 2p23 [6,7,29]. Although this genetic abnormality was considered typical, a subgroup of neoplasms classified as IMT lacked this genetic aberration. A recent study also highlighted differences between ALK-positive and ALK-negative neoplasms classified as IMTs. Yet, all of these studies agreed on the neoplastic nature of the entity. These advances are partially obscured by numerous earlier reports that report such lesions under one entity, blurring the boundary of neoplastic and nonneoplastic processes. Our study was prompted by the observation that many old and recent studies reported the lesions in question in a hybrid category (IMT/IP) without referring to their neoplastic or reactive nature, and some of these reports were from the CNS [24,30,31]. Furthermore, a study of 10 IMTs in the CNS reported no ALK staining and suggested that this genetic aberration is distinctly rare in IMT of the CNS [25]. Because the lesions in the aforementioned report could not be distinguished from the nonneoplastic processes such as the so-called “plasma cell granuloma,” it was difficult to generalize their conclusion for IMTs in the CNS. In contrast, 2 other case studies reported IMTs in the CNS similar to those described in soft tissue with ALK overexpression [26,27]. In concordance with these two case reports, our analysis of 6 examples showed that IMTs were indeed indistinguishable from their soft tissue counterparts. Furthermore, most of these 6 neoplastic lesions demonstrated ALK protein expression and/or chromosomal translocations of 2p23, providing evidence of their neoplastic nature. These observations led us to conclude that IMT in the CNS shares the same features as those in soft tissue or lung. In contrast, the group of 18 nonneoplastic processes we report as IP highlights a diverse group of lesions and show that reactive/nonneoplastic lesions may have overlapping features with IMT. It may also be possible to further segregate lesions in the IP based on clinical and possible molecular terms because they seem to represent a heterogeneous group of lesions with little common features except for histologic appearance. The combination

418 of a neoplastic spindle cell population with ALK expression was reassuring in establishing the diagnosis of IMT, but it may be difficult to categorize a lesion that lacks characteristic morphological features or ALK expression. It is not clear whether the lack of ALK expression in a morphologically typical lesion precludes the diagnosis of IMT. It is equally unclear whether a lesion with ambiguous morphological features and with ALK staining may be sufficient. There are additional challenges in distinguishing IMT from an IP on clinical grounds. None of the IMTs in our study had associated systemic diseases, although a significant number of the nonneoplastic lesion presented with associated symptoms, such as fever, systemic disease or another tumor. Furthermore, in 2 of the 6 patients without an obvious associated disease, there was a reported reduction in tumor size after steroid treatment. No such regression was recorded in 2 of the patients with a radiologically defined residual mass and subsequent steroid treatment. It is tempting to suggest that patients in the IP category typically have an associated condition that may account for the lesions. However, 6 patients (6 of 18) in this category lacked any associated problems, highlighting the heterogeneity of this group. Furthermore, there is no evidence that the associated conditions are directly responsible from the CNS lesions in these patients. It remains to be seen whether one can distinguish IPs associated with systemic disease from those without. We were unable to confirm the presence of HHV-8 in our samples. None of the immunohistochemical markers were positive for HHV-8 related transcripts in any of the samples tested. In addition, a set of 3 IMTs from the respiratory tract were also negative by both IHC and reverse transcriptase– polymerase chain reaction (data not shown) for HHV-8– related transcripts (vIL-6, v-Bcl-2, v–cyclin D1, v-FLIP). These results are also consistent with those recently reported by 2 other groups [20,21]. Although it is quite possible that some nonneoplastic lesions classified as IP may be associated with HHV-8 infection, we believe that IMT is probably not in this category. This is further supported by the fact that all lesions found to harbor HHV-8 were also ALKnegative and, thus, better classified as IP. It is still possible that a small subset of IMTs may demonstrate such an association, unlike that of CNS leiomyosarcoma and Epstein-Barr virus. In summary, we believe there is sufficient evidence to suggest that IMT in the CNS is a neoplasm similar to its soft tissue counterpart and should be distinguished from the histologically similar, nonneoplastic IP. Such a distinction avoids combining neoplastic and nonneoplastic processes under the same name. It may also provide the opportunity to develop different and specific modalities to treat the neoplastic and nonneoplastic lesions and achieve better patient management. We find little justification for considering IMT as a mere subgroup of IP category.

R. S. Swain et al.

Acknowledgments We are greatly indebted to our colleagues, Dr Collin Smith, Dr David Hunt, Dr Richard Eisen, Dr Gary Pearl, Dr Douglas Dressler, and Dr David McGee who have provided us with the critical clinical information. We thank Patricia Goldthwaite for a thorough search of clinical and pathology databases and for her technical assistance.

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