liver failure during interferon beta treatment of multiple sclero- sis. Neurology 2001; 56; 1416. Uveal MALT lymphoma with extensive. AL-type amyloid production ...
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3. Durelli L, Bongioanni MR, Ferrero B, Oggero A, Marzano A, Rizzetto M. Interferon treatment for multiple sclerosis: autoimmune complications may be lethal. Neurology 1998; 50; 570–571. 4. Pietrosi G, Mandala L, Vizzini GB et al. Fulminant hepatic failure and autoimmune disorders in patient with multiple sclerosis on interferon beta 1a: a fatal combination? Transpl. Int. 2008; 21; 502–504. 5. Wallack EM, Callon R. Liver injury associated with the beta-interferons for MS. Neurology 2004; 63; 1142–1143. 6. Yoshida EM, Rasmussen SL, Steinbrecher UP et al. Fulminant liver failure during interferon beta treatment of multiple sclerosis. Neurology 2001; 56; 1416.
Uveal MALT lymphoma with extensive AL-type amyloid production mimicking uveal melanoma
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DOI: 10.1111/his.12465 © 2014 John Wiley & Sons Ltd
Sir: A 52-year-old white Caucasian male patient was referred to the ocular oncology clinic complaining of a 2-week history of deterioration of vision in the left eye. At presentation his acuity was recorded at 6/5 right eye, 6/36 left eye. He was systemically well and gave no significant past medical history. On examination, both eyes were white and quiet, and the right eye showed no abnormality. Fundoscopy of the left eye revealed a variably pigmented choroidal mass encircling the optic disc with a small amount of overlying subretinal fluid (Figure 1A). Fluorescein and ICG angiography were non-contributory, while B-scan ultrasonography demonstrated a hypoechoic choroidal lesion with an associated retrobulbar hypoechoic mass, indicating extraocular extension (Figure 1B, C). Further investigations showed no evidence of systemic malignancy. The working diagnosis was an atypical choroidal melanoma with extraocular extension. A choroidal biopsy was planned but declined by the patient, and after a discussion of the treatment options for melanoma, namely stereotactic radiosurgery, proton beam therapy or enucleation, the patient elected to undergo a left enucleation. During the enucleation an extraocular nodule of pink tumour was noted adjacent to the optic nerve. Histopathological examination demonstrated a diffuse mass in the postero-nasal choroid accompanied by an extraocular mass, adjacent to the optic nerve (Figure 2A). Among the choroidal lymphoid mass were extensive perivascular and interstitial nodular deposits of hyaline eosinophilic material, confirmed Histopathology, 66, 603–612.
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Figure 1. A, Fundus photograph of the left eye demonstrating the atypical choroidal mass at the posterior pole (arrows). B, B-scan ultrasound demonstrating the acoustically hollow choroidal lesion with overlying subretinal fluid (small arrow) and the area of extraocular extension (large arrow). C, Standardized A-scan showing low internal reflectivity of the lesion.
by Congo Red positivity and apple green birefringence to be amyloid. Foreign body-type giant cells were identified around some of the intraocular and extraocular amyloid deposits (Figure 2B–E). Immunohistochemical staining of the amyloid deposits using monospecific antibodies reactive with serum A protein (SAA), transthyretin (TTR) and with kappa and lambda immunoglobulin chains revealed that the amyloid deposits stained with antibodies to lambda light chains, confirming this to be AL-type amyloid (lambda subtype, Figure 2F).
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Figure 2. A, Low-power haematoxylin and eosin (H&E)-stained section showing the globe with a posterior diffuse choroidal mass (thin arrow), with an extraocular component (thicker arrow). B, Higher-power H&E showing lymphocytes surrounding eosinophilic perivascular and interstitial material. C, H&E showing a foreign body response to the eosinophilic material. D, Congo Red staining of the eosinophilic material. E, Apple green birefringence of the Congo Red-positive material, confirming amyloid. F, The amyloid deposits are immunohistochemically positive for lambda light chains, in keeping with AL subtype amyloid (brown staining is positive). G, Higher-power H&E showing mostly small lymphocytes. H, CD20 immunohistochemistry showing positive staining of the lymphocytes, leaving the amyloid deposits unstained (in negative profile). I, Higher power of H showing neat membranous CD20 staining. J, CD21 staining shows follicular dendritic cells (black arrows). K, Mum-1 positive lymphoplasmacytoid cells at the edges of the lymphocytic infiltrate, concentrated under Bruch’s membrane (at bottom of figure). L, Biorad-2 polymerase PCR assay for IgH gene rearrangement showing a single monoclonal peak in FR1 (top), FR2 (middle) and FR3 (bottom), confirming the unequivocal monoclonal nature of the B cell infiltrate.
The lymphoid population comprised small lymphocytes, centrocyte-like cells, some larger blast-type cells scattered among the smaller lymphocytes (Figure 2G), and plasmacytoid cells, especially peripherally beneath Bruch’s membrane. The lymphocytes were positive for CD20, indicating a B cell phenotype (Figure 2H, I), and negative for CD5, CD10, CD23 and cyclin D1. Follicular dendritic cell clusters were seen, being effaced by the abnormal CD20-positive B cell lymphoid infiltrate (Figure 2J). Mum-1 positive plasmacytoid cells were seen, especially at the edges of the B cell lymphoid infiltrate, beneath Bruch’s membrane (Figure 2K). IgH PCR showed an unequivocal B cell monoclone in the three frames examined (BioRad2 assay, Figure 2L). The morphology, immunohistochemical profile and molecular features were of extranodal marginal zone lymphoma of MALT type (MALToma) diffusely affecting the choroid, with an extraocular component. In view of the lymphoma and amyloid deposits, the patient underwent lymphoma staging and assessment to rule out systemic amyloid deposition. These revealed no evidence of systemic lymphoma or amyloid and the patient remains disease free 10 months post-enucleation. Uveal MALT lymphoma is rare. The largest series to date documents 13 enucleated cases, age range 33–81 years, with a male predominance (10 of 13).1 Eleven of 13 cases exhibited extraocular extension and 12 of 13 were primary uveal MALT lymphomas. Two of these primary cases showed systemic involvement 3 and 7 years after the diagnosis of uveal MALT lymphoma. However, none of the cases in the above series displayed amyloid deposition. Localized AL amyloidosis is due to production of amyloidogenic light chains by localized proliferation of clonal B cell/plasma cells, and accounts for 12% of patients seen at the UK National Amyloidosis centre.2 In a series of 616 patients with localized AL amyloidosis, eye and its adnexa accounted for 2% of all cases,2 but none had intraocular amyloid deposits. Amyloid deposition in ocular tissues is usually of AL type. Histopathology, 66, 603–612.
Amyloidosis associated with MALT lymphoma is rare, but well recognized. In most cases of localized AL amyloidosis it is difficult to document clonality or clearly define the nature of the underlying condition. Lymphoma-associated amyloid has been recorded in the orbit3 and conjunctiva.4 This has often been reported in the context of Sj€ ogren’s syndrome. The most comprehensive clinicopathological series identified 20 patients with amyloid-producing MALT lymphomas from diverse sites (including three from the ocular adnexa but no intraocular cases).5 The amyloid deposits were perivascular and interstitial, often present in the same biopsy. Amyloid deposits predominated in amount over the lymphoma component in 12 of 20 cases. Foreign bodytype giant cells were identified around the amyloid deposits, as in our case. In cases where amyloid typing was possible, all revealed localized AL amyloid (lambda subtype), due to amyloidogenic light chains produced by the neoplastic plasma cells in the MALT lymphoma. At follow-up, relapsed lymphoma often contained amyloid deposits. None of the cases showed any evidence of systemic amyloid deposition, and there appeared to be no prognostic difference between amyloid-producing and conventional MALT lymphomas. Intraocular amyloidosis that mimics tumours is very rare. Char et al.6 described the first case of intraocular amyloid deposition, mimicking an intraocular tumour in the ciliary body of a 35-year-old female with systemic lupus erythematosus. The clinical interpretation was of a leiomyoma, given its slow growth pattern and amelanotic appearance. Following local resection, histology showed a plasmacytoma with massive amyloid deposition, constituting the main bulk of the mass. The amyloid stained for kappa chains, rather than lambda. In our case, the clinical presentation was highly suggestive of a diffuse uveal melanoma with extraocular spread, albeit with atypical fundal appearances. A biopsy in this circumstance would have permitted a distinction between lymphoma and melanoma that
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could have led to eye-sparing radiotherapy/chemotherapy, to which uveal MALT lymphoma is very sensitive. However, given the extensive amyloid deposits, a biopsy may well have simply sampled amyloid alone, necessitating further biopsies to confirm the diagnosis. We hypothesize that the extensive amyloid deposits altered the imaging and clinical findings of the lymphoma, mimicking a diffuse choroidal melanoma with posterior extraocular extension. Imran Haq1 Paul A Rundle1 Janet A Gilbertson2 Ashutosh D Wechalekar2 Hardeep S Mudhar3 1
Ocular Oncology Clinic, Royal Hallamshire Hospital, Sheffield, UK, 2National Amyloidosis Centre, University College London Medical School (Royal Free Campus), London, UK, and 3National Specialist Ophthalmic Pathology Service, Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK 1. Coupland SE, Foss HD, Hidayat AA et al. Extranodal marginal zone B cell lymphomas of the uvea: an analysis of 13 cases. J. Pathol. 2002; 197; 333–340. 2. Mahmood S, Sachchithanantham S, Bridoux F et al. Risk of progression of localised amyloidosis to systemic disease in 606 patients over 30 years. Blood 2013; 122; 3143. 3. Knowles DM II, Jokobiec FA, Rosen M, Howard G. Amyloidosis of the orbit and adnexae. Surv. Ophthalmol. 1975; 19; 367–384. 4. Marsh WM, Streeten BW, Hoepner JA, Zhang W, Davey FR. Localised conjunctival amyloidosis associated with extranodal lymphoma. Ophthalmology 1987; 94; 61–64. 5. Ryan RJH, Sloan MJ, Collins AB et al. Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue with amyloid deposition. Am. J. Clin. Pathol. 2012; 137; 51–64. 6. Char DH, Crawford JB, Howes E, Carolan JA. Amyloid mass of the ciliary body. Arch. Ophthalmol. 2006; 124; 908–910.
Adult-onset inflammatory myofibroblastic tumour of the stomach with a TFG–ROS1 fusion DOI: 10.1111/his.12575 © 2014 John Wiley & Sons Ltd
Sir: Inflammatory myofibroblastic tumours (IMTs) are rare mesenchymal neoplasms of borderline malignancy that generally affect children and young adults.1 IMTs most commonly occur in the lung, mesentery, and retroperitoneum.1 Gastric IMTs are extremely rare,
with 90%) of the lesion was composed of hypocellular sclerosis (Figure 1C). However, the yellow nodule showed hypercellular proliferation of spindle cells in fascicles, associated with a mild lymphoplasmacytic infiltrate (Figure 1D). There was no mitosis or necrosis. Immunohistochemically, the spindle cells were focally positive for desmin but were negative for smooth muscle actin, h-caldesmon, myogenin, and pan-cytokeratin. Overall, the histological findings were consistent with an IMT; however, a sensitive immunohistochemistry test for ALK gave a negative result. Suspecting the presence of alternative kinase fusions, based on a recent study,4 we performed immunohistochemistry for ROS1 according to a method that we previously showed to be useful for identifying ROS1-rearranged lung cancers.5 The test showed weak but diffuse cytoplasmic immunoreactivity, with additional intracytoplasmic punctate staining (Figure 2A). Fluorescence in-situ hybridization by use of custom ROS1 breakapart probes, according to a previously described method, revealed a ROS1 rearrangement (Figure 2B). We performed reverse-transcription polymerase chain reaction directed against ROS1 fusion transcripts on a formalin-fixed paraffinembedded specimen. A reaction with primers targeting TFG–ROS1 (50 -AGAACTTCGAAATAAAGTGAATC GT-30 and 50 -CACTGTCACCCCTTCCTTGG-30 ) followed by a sequencing analysis showed fusion of TFG exon 4 to ROS1 exon 35 (Figure 2C). Histopathology, 66, 603–612.
