Dural Marginal Zone Lymphoma With Extensive Crystal Storing Histiocytosis: Spotting the Zebra Among the Horses

To the Editor:

Crystal storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intralysosomal accumulation of crystallized immunoglobulin reported most commonly in patients with lymphoplasmacytic neoplasms. This entity rarely occurs in the central nervous system (CNS) where other histiocytic disorders are more commonly reported as dural-based lesions, including Langerhans cell histiocytosis, Rosai-Dorfman disease, and Erdheim-Chester disease. Here we describe a rare case of stage IE dural-based extranodal marginal zone lymphoma (MZL) with associated CSH and its potential diagnostic challenges, especially during intraoperative consultation.

A 55-year-old woman with hypertension, hyperlipidemia, and hypothyroidism presented to the emergency department following a fall down 5 stairs at home and subsequent generalized tonic-clonic seizure. A diagnostic head CT revealed a right parietal extra-axial hematoma as well as right tentorial and mid-falcine subdural hematoma (SDH) without significant midline shift. She was started on anticonvulsant medication and discharged home. She then presented back to the emergency department 7 months later following a generalized tonic-clonic seizure during sleep. Her neurological examination and EEG were unremarkable. A repeat head CT revealed an anterior parafalcine SDH and lobular hyperdensity along the right tentorium extending to the temporal parietal convexity in the same location as the prior SDH, now concerning for an underlying extra-axial lesion. A subsequent MRI of the brain revealed contrast-enhancing dural-based lobular lesions in the interhemispheric fissure (Fig. 1A) and along the right tentorium with adjacent bony involvement (Fig. 1B–D), suggestive of a dural-based metastasis versus lymphoma versus en plaque meningioma. Further staging was negative for other sites of disease involvement. Laboratory studies revealed a small IgG lambda clone (0.06 g/dL) in a polyclonal background on serum protein electrophoresis and immunofixation. Partial resection of the dural-based mass was performed with provisional diagnosis of meningioma. Her postoperative course was uneventful and she was subsequently discharged on anticonvulsant medication and a steroid taper.

FIGURE 1.

MRI of the brain. Representative T1-weighted fat saturated contrast-enhanced images showed contrast-enhancing dural-based lobular lesions in the interhemispheric fissure (A, C) and along the right tentorium with adjacent bony involvement (B, D) (A, B, axial; C, coronal; D, sagittal).

Gross examination of the dural-based mass revealed tan-pink soft tissue. Intraoperative consultation showed sheets of histiocytes with abundant pale pink cytoplasm containing fibrillary crystallized material (Fig. 2A), suggestive of a histiocytic lesion with foci of inflammatory cells. Hematoxylin and eosin (H&E)-stained sections of the formalin-fixed paraffin-embedded (FFPE) tissue showed diffuse infiltration by histiocytes with a multifocal lymphoplasmacytic infiltrate (Fig. 2C). The histiocytes demonstrated small, round, cytologically bland nuclei, and abundant eosinophilic cytoplasm containing crystalline inclusions (Fig. 2B). There was no evidence of emperipolesis, well-formed whorls, or atypical epithelial cells. In addition, the craniotomy bone showed atypical lymphoplasmacytic and histiocytic infiltrates.

FIGURE 2.

Pathology of the dural-based mass. A diffuse infiltration of histiocytes with crystalline inclusions was seen on frozen (A) and FFPE permanent sections (B) with multifocal lymphoplasmacytic aggregates (C). The histiocytes were positive for CD68 (D), while the inclusions stained for IgM (F) and lambda. The lymphoplasmacytic aggregates were positive for CD20 (E) and CD138 (G) with lambda light chain restriction by in situ hybridization (I) without kappa light chain expression (H) (A, B, 1000× under oil; C, 200×; D, E, G–I, 100×; F, 400×).

Further workup revealed clonal lymphoplasmacytic infiltrate consistent with a B-cell lymphoma with plasmacytic differentiation (Fig. 2E, G–I). The histiocytic population had strong and diffuse immunoreactivity for CD163 and CD68 (Fig. 2D), but was negative for CD1a, S100, EMA, PR, CD34, STAT6, ALK, desmin, Myf-4, GFAP, and MCK. Special stains for microorganisms were negative for fungi (Grocott methenamine silver, periodic acid-Schiff [PAS]) and acid-fast bacilli. The histiocyte cytoplasm was negative for PAS, PAS-D, IgG, IgG4, IgA, and IgD, while the crystalline inclusions appeared positive for IgM (Fig. 2F) and lambda light chain.

Overall, the final diagnosis of MZL expressing IgM lambda light chain with CSH was rendered. Subsequent B-cell gene rearrangement studies were positive for clonal immunoglobulin gene rearrangement, further supporting the diagnosis. Due to her residual localized intracranial disease, she received whole brain radiation treatment consisting of 30 Gy in 15 fractions. Two months status-post completion of radiotherapy, an MRI-brain showed overall disease response. She reported occasional episodes of localized right-sided headaches, but denied any other neurological symptoms.

CNS extranodal MZL (EMZL) is an indolent, low-grade, radiosensitive non-Hodgkin lymphoma with good prognosis and treatment outcomes such that most cases reported in the literature document complete remission with localized therapies (1, 2). This contrasts with the aggressive behavior of primary CNS lymphomas and those in which meningeal involvement occurs as a result of secondary dissemination, underlining the importance of recognizing these low-grade B-cell lymphomas as a distinct clinicopathological entity (2). Furthermore, as a lymphoproliferative disorder, EMZL is commonly associated with excess production of frequently monoclonal immunoglobulins. Accumulation and possible alteration of these immunoglobulin molecules can lead to crystallization and subsequent phagocytosis by histiocytes, resulting in CSH associated with the underlying hematologic disorder (3).

There have been prior case reports of CSH associated with EMZL in predominantly extracranial sites in the literature (4–10). Herein, we present a case of EMZL localized to the intracranial dura whose diagnosis was complicated by an extensive background of histiocytes with cytoplasmic inclusions. This background detracted from the neoplastic lymphoplasmacytic population and raised the concern for primary CNS histiocytic lesions before eventually being recognized as an associated immunoglobulin CSH.

Cases of CSH pose a diagnostic challenge to pathologists. In some instances, the histiocyte cytoplasm can be deeply eosinophilic and opaque on H&E sections such that inclusions, crystals, or striations may be obscured, which may result in a missed diagnosis (3, 11). Additionally, the histiocytic component may dominate the specimen and ultimately mask the neoplastic nature of any background lymphoplasmacytic cells (3–5, 7). In particular, a clinicopathological study of 13 cases of CSH by Kanagal et al (5) found that 77% of the time CSH represented more than 50% of the neoplastic infiltrate, which is what we observed in our case. Obscuring the underlying hematologic disorder may raise the differential diagnosis of a storage disorder, hemophagocytosis, or mesenchymal lesion, which can delay identification and subsequent treatment of the actual malignancy (12). Furthermore, additional diagnostic difficulties arise when there is discordance between the clonality of the crystals and a serum paraprotein as seen in this case, which has been noted in the literature (3, 13), yet the exact mechanism is unknown and may represent a separate monoclonal gammopathy of undetermined significance.

Once the diagnosis of CSH is established, attention should be directed toward investigating the cause, which, in the majority of individuals, will be either an underlying lymphoproliferative or plasma cell disorder (3). Thus, patients with CSH should undergo screening for an occult but treatable lymphoplasmacytic neoplasm. Given the rarity of primary dural-based CNS lymphoma, when CSH is found in the CNS the differential diagnosis usually includes other causes of histiocytic lesions, such as Langerhans cell histiocytosis, Rosai-Dorfman disease, and Erdheim-Chester disease (14). Thus, as previously stated, awareness of dural-based EMZL with CSH is important because the sheets of crystal-laden histiocytes may obscure the underlying neoplasm, posing a diagnostic challenge.

Our case highlights a key pathologic finding in which there was a discrepancy in the H&E morphologic appearance of the lesional tissue on intraoperative frozen sections compared to the permanent FFPE material. In particular, the cytoplasm of the crystal-laden histiocytes appeared pale and relatively clear on frozen sections, consistent with their typical vacuolated morphological appearance. However, these cells appeared deeply eosinophilic on FFPE sections, which cast doubt on their classification as histiocytes, thus requiring a panel of immunohistochemical stains to exclude other entities known to mimic CSH.

Unfortunately, not much can be found in the literature regarding the detailed morphologic assessment of histiocytic lesions, including CSH, at intraoperative consultation. One rare report describes the evaluation of an enlarged cervical lymph node, which was clinically diagnosed as metastatic carcinoma in a patient with a history of carcinoma of the tongue. Surprisingly, at intraoperative consultation, they discovered extensive histiocytosis containing crystalline materials, resulting in the final diagnosis of CSH (13).

When you hear hoofbeats think horses, but be prepared for zebras. In pathology practice, common diseases are to be considered first. However, our case of CNS EMZL with extensive CSH raises awareness that this rare entity may involve the dura, underscoring the importance of catching these zebras in order to reveal the true nature of the underlying pathologic process and aid timely diagnosis of potentially treatable entities.

COMPETING INTERESTS

The authors have no duality or conflicts of interest to declare.