Plasma Cell Granuloma: an Entity Within the Spectrum of Igg4-Related Disease

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Available online at www.annclinlabsci.org 340 Annals of Clinical & Laboratory Science, vol. 45, no. 3, 2015 Plasma Cell Granuloma: An Entity within the Spectrum of IgG4-Related Disease

Jessica Forcucci1, Shannon Butler-Williams1, Nicole Miller2, and John Lazarchick1

1Medical University of South Carolina, Department of Pathology and Laboratory Medicine, Charleston, SC and 2Atlanticare Regional Medical Center, Department of Pathology, Pomona, NJ, USA

Abstract. Plasma cell granuloma (PCG) is a relatively rare, mass-forming lesion comprised of polyclonal plasma cells set in a background of storiform fibrosis and spindle cell proliferation. While uncommon, this lesion may occur within any site and should be included in the list of differential diagnoses for plasma cell neoplasms. As this entity can be mistaken for a plasma cell neoplasm, surgical pathologists should consider ancillary studies to assess clonality of plasma cell proliferations, especially during intraoperative consultation.

Although the etiology of these lesions is unclear, recent literature and immunohistochemical stains performed on our own cases suggest that PCG falls within the spectrum of IgG4 related diseases, which would have significant clinical significance impacting treatment and the potential for associated disease atdistant body sites. We present two cases of head and neck PCG encountered at a tertiary academic medical center with immunohistochemical staining demonstrating increased IgG4-secreting plasma cells.

Key words: plasma cell granuloma, inflammatory pseudotumor, IgG4

Introduction The patient underwent a subtotal endonasal resection of the mass for diagnosis and symptom amelioration. Plasma cell granuloma, often referred to as inflam- Intraoperative consultation was requested by the sur- matory pseudotumor, is a relatively rare inflamma- geon. Frozen sections and squash preps were performed tory lesion of unknown etiology. They are com- and reported as “mixed inflammation with plasma cells and fibrous tissue, defer to permanents”. The surgeon prised of a polyclonal plasma cell infiltrate occurring felt that the lesion was consistent with plasmacytoma in a background of fibrosis and spindle cell prolif- and elected to partially resect the remainder of the lesion eration. While relatively benign, these tumors may given the high risk of neurovascular injury with further simulate malignancy, become symptomatic second- dissection and radiosensitivity of plasmacytomas. ary to size or location, and present a diagnostic Additional fresh tissue was received in pathology for tu- challenge to pathologists and radiologists. We pres- mor banking; however, no tissue was directed for flow ent two cases of plasma cell granulomas encoun- cytometry. An MRI done post-operatively showed com- tered at a tertiary medical center, which we believe plete resection of the tumor. Although his immediate support the premise that plasma cell granuloma postoperative course was complicated by sinusitis, he falls within the spectrum of IgG4- related disease. was discharged no longer having visual problems or headaches. The patient was lost to follow-up.

Case Reports Case Two. A 55 year old female with a five month history of severe left ear pain with bloody discharge and Case One. A 52 year old male was referred for further drainage unresponsive to medical treatment was referred evaluation of a two month history of sharp, constant for evaluation. Prior imaging demonstrated an ill-de- head pain and blurry vision. Imaging demonstrated an fined 3.2 x 2.2 cm soft tissue mass centered in theleft expansile 3 cm mass within the clivus. The clinical and nasopharynx extending into the carotid space with os- radiographic differential diagnosis included chordoma, teolytic destruction of the middle ear and inner left ex- metastatic disease, lymphoma, and plasmacytoma. ternal auditory canal. Given the patient’s smoking and alcohol use, nasopharyngeal squamous cell carcinoma Address correspondence to John Lazarchick, MD; MUSC, Department of Pathology and Laboratory Medicine, 171 Ashley with extension into the middle ear was a primary con- Avenue, MSC 908, Charleston, SC 29425; phone: 843 792 3107; fax: cern. Outside physicians undertook two separate biop- 843 792 8974; e mail: [email protected] sies of the nasopharyngeal lesion. The first biopsy was

Figure 1. A. H&E at 200x magnification of skull base tumor demonstrating a diffuse population of morphologically unremarkable plasma cells with scattered intermingled lymphocytes set in a storiform pattern of fibrotic connective tissue. B. CD138 at 100x magnification of skull base tumor highlights a diffuse population of plasma cells. C. Kappa in-situ hybridization at 100x magnification of skull base tumor highlights the majority of plasma cell population. D. Lambda in-situ hybridization at 100x magnification of skull base tumor highlights the minority of plasma cell population. E. IgG immunostaining at 400x magnification of skull base tumor. F. IgG4 immunostaining at 400x magnification of skull base tumor. non-diagnostic revealing respiratory mucosa with lym- lymphocytes set in a storiform pattern of fibrotic phoid hyperplasia. A second biopsy was similar in ap- connective tissue (Figure 1 A). No evidence of vas- pearance; however, IgH and TCR gene rearrangements, culitis was present. Kappa/lambda in- situ hybrid- immunohistochemical stains, and flow cytometry were ization studies were performed to further character- performed. A limited flow cytometric analysis demon- ize the lesion, and demonstrated a diffuse population strated a polyclonal B cell population. Gene rearrange- of CD138 positive polyclonal plasma cells (Figures ment studies were negative. It was felt that the biopsied lesion was most consistent with chronic inflammation. 1 B, C, and D). In the absence of plasma cell Upon referral, physical exam revealed a bloody drainage monoclonality, the diagnosis of plasmacytoma was within the external auditory canal. A large polyp within excluded in favor of plasma cell granuloma. the external auditory canal became visible with Valsalva Microscopic evaluation of Case Two revealed a mo- maneuver, and was excised in clinic. A CT and MRI of notonous infiltrate of plasma cells with an inter- the neck showed a mass in the left nasopharynx extend- mingled, scattered lymphohistiocytic infiltrate set ing laterally into the carotid and para-pharyngeal spaces. in a background of loose fibrovascular tissue with- Given the compromising location, the patient was re- out vasculitis (Figures 2 A and B). Scattered eo- ferred for radiation therapy without further surgical re- sinophils were also present. Kappa/lambda in-situ section. She elected to have her radiation therapy at a hybridization (ISH) studies demonstrated a poly- hospital closer to her home. Further follow-up was not available. clonal population of plasma cells most consistent with plasma cell granuloma (Figures 2 C and D). Results Given recent evidence that suggests plasma cell Microscopic evaluation of sections of Case One re- granuloma association with IgG4 related disease, vealed a diffuse population of morphologically un- IgG and IgG4 immunohistochemical stains were remarkable plasma cells with scattered intermingled performed on each case. Case One revealed an 342 Annals of Clinical & Laboratory Science, vol. 45, no. 3, 2015

Figure 2. A. H&E at 100x magnification of auditory canal polyp biopsy demonstrating a monotonous infiltrate of plasma cells with an intermingled, scattered lymphohistiocytic and eosinophilic infiltrate set in a background of loose fibrovascular tissue. B. H&E at 400x magnification of auditory canal polyp biopsy demonstrating monotonous infiltrate of plasma cells. C. Kappa in-situ hybridization at 100xshighlights the majority of the plasma cell population. D. Lambda in-situ hybridization at 100x highlights the minority of the plasma cell population. E. IgG immunostaining at 400x. F. IgG4 immunostaining at 400x.

IgG4:IgG ratio of 64% with approximately 116 inflammatory aortic aneurysms, retroperitoneal fi- IgG4 and 180 IgG positive plasma cells per high brosis, and others [5]. While IgG4 constitutes the power field, respectively (Figures 1 E and F). Case smallest percentage of the IgG subclasses, and has Two revealed an IgG4:IgG ratio of 45% with ap- chemical properties that more frequently place it proximately 28 IgG4 and 62 IgG positive plasma with anti-inflammatory mediators activated by the cells per high power field, respectively (Figures 2 E Th2 pathway, its involvement in this spectrum of and F). disorders is baffling, but unmistakable [6,7].

Discussion Unlike in other organ systems, where the manifes- tations of IgG4-related disease may be an inciden- Plasma cell granulomas are rare lesions that are in- tal radiological finding or physiologic disruption of creasingly recognized as part of the spectrum of the affected organ, plasma cell granulomas inthe IgG4-related disease [1]. The phrasing of “inflam- head and neck most frequently present due to local matory pseudotumor” is slowly being abandoned destruction of the surrounding tissue [8,9]. Their in favor of more precise diagnostic terminologies to ability to erode into and infiltrate bone leads to separate lesions that likely represent different etiol- them easily being misclassified as malignant upon ogies [2-4]. IgG4-related disease was first identified early assessment. Frequently, they are mistaken for in association with autoimmune pancreatitis, and plasmacytomas or lymphomas [10]. Plasma cell since then, the histopathological similarity of le- polyclonality is the most important factor in distin- sions, increased local IgG4 positive plasma cells, guishing plasma cell granulomas from plasmacyto- and increased serum IgG4 has linked disorders in mas. Flow cytometry and/or kappa/lambda in- every major organ system to this mechanism, and situ hybridization studies are needed to demonstrate encompasses conditions such as Riedel’s thyroiditis, plasma cell clonality. Plasma cell granuloma 343

The histopathological features most specific for to correspond with or predict the severity of the le- IgG4-related disease are lymphoplasmacytic infil- sion, the likelihood of recurrence, or the presence trates, storiform fibrosis, and venulitis. The pre- of metachronous lesions [5]. While helpful when dominance of each of these patterns may vary based performed, a failure to obtain serum IgG4 levels on the involved organ. Lesions in the head and does not exclude the spectrum of IgG4-related neck, such as plasma cell granulomas of the man- disease. dibular gland (Kuttner’s tumor) are less commonly affiliated with venulitis than corresponding lesions Conclusion. We present two cases of plasma cell in the thoracic and abdominal organs. Once at granuloma with morphologic and immunohisto- least two of the three morphological criteria have chemical evidence to suggest their inclusion within been met, immunohistological staining of the cells the IgG4 related disease spectrum. The primary is extremely useful for solidly classifying these le- therapy of plasma cell granulomas is surgical exci- sions within the IgG4-related diseases, most specifi- sion with complete reversal of symptoms typical. cally by evaluating both the quantitative number of In those cases where surgery is contraindicated be- IgG4 positive plasma cells and by evaluating the cause of location of the lesions, the lesions can be ratio of IgG4 positive cells to the overall number of treated with radiation therapy and/or glucosteroids. IgG secreting cells in the lesion. Numerous cutoffs Recurrences are unusual but have been reported. have been proposed, depending on tissue type, ranging from an absolute value of anywhere from References over 10 to over 50 IgG4 positive plasma cells per 1. Stone JH, Zen Y, and Deshpande V. IgG4-Related Disease. high power field. Regardless of site, the IgG4:IgG New England Journal of Medicine. 2012;366:539-551. ratio must be greater than 40%, signifying a dispro- 2. 2. Swain RS, Tihan T, Horvai AE, et al. Inflammatory myofibroblastic tumor of the central nervous system and its rela- portionate increase in IgG4 secreting plasma cells tionship to inflammatory pseudotumor. Hum Pathol. 2008; [5]. Despite the clinical utility of serum levels, his- 39: 410-419. topathological study remains the most specific way 3. O’Malley DP, Poulos C, Czader M, Sanger WG, Orazi A. Intraocular inflammatory myofibroblastic tumor with ALK of characterizing these lesions. overexpression. Arch Pathol Lab Med. 2004; 128: e5-e7. 4. Gleason BC, Hornick JL. Inflammatory myofibroblastic tu- With respect to the presented patients, Case One mors: where are we now?J Clin Pathol. 2008; 61: 428-437. 5. Deshpande V, Zen Y, Chan JKCC et al. Consensus statement demonstrated an IgG4:IgG ratio of 64%, while on the pathology of IgG4-related disease. Modern Pathology. Case Two demonstrate an IgG4:IgG ratio of 45%. 2012; 25:1181-1192. 6. Shiino S, Kojima M, Arisawa T, Nakazato Y, Masawa N, Both presented cases had a marked lymphoplasma- Nakamura N. Presence of Immunoglobulin Heavy Chain cytic infiltrate and storiform fibrosis, though nei- Rearrangement in So-Called IgG4-Related Plasma Cell ther had predominant venulitis. It is possible that Granuloma of the Eyelid.J Clin Exp Hematopathol. 2012; 52:141-143. due to the size and location of the lesions, restricted 7. Buccoliero AM, Caldarella A, Santucci M, et al. Plasma Cell sampling obscured venulitis. Granuloma—An Enigmatic Lesion: Description of an Extensive Intracranial Case and Review of the Literature. Arch Pathol Lab Med. 2003; 127:e220-e223 While neither of the presented cases had corre- 8. CoffinCM, Watterson J, PriestJR, DehnerLP. Extrapulmonary sponding serum IgG4 drawn, it is a useful criterion inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of for increasing the specificity of the diagnosis if ini- 84 cases. Am J Surg Pathol. 1995;19(8):859-872. tially drawn at the time of diagnostic evaluation. It 9. Ajibade DV, Tanaka IK, Paghda KV et al. Inflammatory pseu- is important to note; however, that serum IgG4 is dotumor (plasma cell granuloma) of the temporal bone. ENT: Ear, Nose, & Throat Journal. 2010; 89; 7:e1-e13. widely variable, and is found to be within normal 10. Gandhi RH, Li L, Qian J, Kuo YH. Intraventricular inflam- levels in up to 40% of patients with morphologi- matory pseudotumor: report of two cases and review of the cally and immunohistochemically confirmed plas- literature. Neuropathology. 2011; 31:446-454. ma cell granuloma. The serum levels do not appear