2020 HPATH-B Case 9 FINAL Proof

2020 HPATH-B: Case 9 – Idiopathic Multicentric Castleman Disease, HHV8-Negative, Not Otherwise Specified

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Case InformationClinical Information

The patient is a 48-year-old man who presents with fever, night sweats, fatigue, violaceous skin papules, and a five-month history of multistation lymphadenopathy. He has no previous significant illnesses or past medical history. He undergoes an excisional biopsy of a 4-cm, tan, fleshy lymph node with a homogeneous cut surface. After his excisional biopsy, he experiences a progressive decline in clinical status with tachycardia, hypovolemia, and multi-organ failure, and is transferred to the intensive care unit for supportive therapy.

Specimen Source Axillary lymph node

Clinical Image

Computed tomography (CT) imaging reveals multiple lymph nodes which are hypermetabolic on positron emission tomography (PET)-CT scan (Image) with bulky adenopathy in the left axilla and mediastinum and enlarged lymph nodes in the retroperitoneal and iliac regions.

Test Results

CBC: CBC Test WBC RBC HGB HCT MCV MCH MCHC RDW PLT

Result 8.5 x 103/uL

4.9 x 106/uL

10.5 g/dL

31.5% 93 fL 32.4 pg 35.0 g/dL

13.0% 564 x 103/uL

Reference Range

4.0-10.0 x 103/uL

3.7-5.3 x 106/uL

11.7-16.0 g/dL

35%-47%

82.0-99.0 fL

26.5-34 pg

32-36 g/dL

11.5%-15%

140-450 x 103/uL

Manual Differential Neutrophils Lymphocytes Monocytes Eosinophils Basophils

Result 6.7 x 103/uL 1.2 x 103/uL 0.5 x 103/uL 0 x 103/uL 0.1 x 103/uL


© 2020 College of American Pathologists. All rights reserved.

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Reference Range

1.8-8.0 x 103/uL 1.2-3.3 x 103/uL 0.3-1.0 x 103/uL 0.0-0.4 x 103/uL 0.0-0.1 x 103/uL

Whole Slide Image

Representative H&E stain of the excisional lymph node biopsy. https://www.digitalscope.org/LinkHandler.axd?LinkId=00fe1f9e-a95d-4cdc-8555-d3c7a4e62061

Ancillary Studies

Ancillary Studies Choices

Which of the following ancillary studies are appropriate to order for this case? Select each ancillary study to see if it is appropriate and to review the study results.

A. Bone marrow biopsy B. FISH studies to detect rearrangements in MYC, BCL2, and BCL6 C. Flow cytometry D. CD3, CD20, CD138, kappa, lambda, IgG, and IgG4 IHC stains E. HHV8 IHC and EBER ISH F. HIV antibody and viral PCR G. Infectious disease workup, including microbiologic cultures for bacteria and fungi; PCR

testing for Mycobacteria tuberculosis complex and Epstein-Barr virus DNA H. Serum immunoglobulin levels (eg, IgG, IgM, IgA, IgE), serum and urine protein

electrophoresis/immunofixation (SPEP/UPEP/IFE) I. Serologic/immunologic workup (including antineutrophil antibodies, anti-Sm,

antiphospholipid antibodies, complement, C-reactive protein, direct antiglobulin test, erythrocyte sedimentation rate, etc) in consultation with rheumatology service

J. Treponema pallidum IHC stainAncillary Studies Feedback

Option A

Bone marrow biopsy – This is an appropriate choice. The pathology that may be uncovered on bone marrow biopsy could be invaluable to the diagnostic workup on the intended response in this case. It could reveal a number of findings, including the presence of monoclonal plasma cells driving the lymphoplasmacytic proliferation seen on the lymph node biopsy; or it could highlight bone marrow involvement by a malignancy/lymphoproliferative disorder that could be mimicking the intended response. In this case, the bone marrow biopsy showed maturing trilineage hematopoiesis with increased numbers of plasma cells (around 10% overall), which showed polytypic immunoglobulin light chain expression.

Option B

FISH studies to detect rearrangements in MYC, BCL2, and BCL6 – This choice is noncontributory. Rearrangements in these genes are currently used to provide genetic support for a so-called “double-hit” or “triple-hit” lymphoma in B-cell lymphoma cases with morphologic features of either diffuse large B-cell lymphoma or blastoid/Burkitt lymphoma-like morphology. However, in the present case, the histology is that of nodal architectural preservation with an exuberant interfollicular proliferation of plasma cells, not of diffuse nodal effacement by medium-to-large lymphoma cells. Thus, this choice would not contribute significantly to the diagnostic workup.

Option C Flow cytometry – This is an appropriate choice. Flow cytometry can be useful in uncovering monotypic populations of B-cells and plasma cells. It may also detect any overt pan-T cell aberrancies. In this case, no monotypic B-cell or plasma cell populations nor immunophenotypic abnormalities in T-cells were identified.

Option D

CD3, CD20, CD138, kappa, lambda, IgG, and IgG4 IHC stains – This is an appropriate choice.



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These follow-up IHC stains are an appropriate way to highlight the immunoarchitecture of the excisional biopsy. CD3 IHC decorates the sparse interfollicular T-cell component (Image 1), while CD20+ B-lymphoid follicles are generally widely spaced (Image 2). The exuberant interfollicular plasmacytosis is further underlined by CD138 (Image 3). Kappa and lambda are essential to evaluate immunoglobulin light chain expression. In this case, the plasmacytosis demonstrated around a 2:1 ratio of kappa-to-lambda light chain expression (kappa and lambda stains not shown here). In this case, IgG4 highlighted only a rare subset of plasma cells (less than 10 per high-power fields) (Image 4). IgG stain was not performed. Ancillary Studies Image 1: CD3 stain, 20x.

Ancillary Studies Image 2: CD20 stain, 20x.

Ancillary Studies Image 3: CD138 stain, 20x.



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Ancillary Studies Image 4: IgG4 stain, 100x.

Option E

HHV8 IHC and EBER ISH – This is an appropriate choice. The combination of clinical features with severe systemic symptoms, multicentric adenopathy, and the histopathology in this case should raise several diagnostic considerations, including the plasma cell-rich variant of multicentric Castleman disease (MCD) as well as angioimmunoblastic T-cell lymphoma. In the appropriate morphologic and clinical setting, an HHV8 stain highlighting immunoblasts/plasmablasts rimming the mantle zone is diagnostic of HHV8-related MCD. Clonal B-cell populations with significantly increased EBER expression would strongly favor certain Epstein-Barr virus-related lymphoproliferative disorders. In this case, both HHV8 IHC (Image 1) and EBER in-situ hybridization (not shown) stains are negative. Ancillary Studies Image 1: HHV8 stain, 100x.



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Option F

HIV antibody and viral PCR – This is an appropriate choice. In light of the plasma cell-rich nature of this lymphadenopathy, the list of differential diagnostic possibilities should include infections such as HIV and HHV8-related lymphoproliferative disorder. Advising the patient’s treating physician to obtain HIV antibody and viral PCR testing is prudent. In this case, HIV antibody results are nonreactive; HIV viral load is undetectable.

Option G

Infectious disease workup, including microbiologic cultures for bacteria and fungi; PCR testing for Mycobacteria tuberculosis complex and Epstein Barr virus DNA – This is an appropriate choice. Although the histologic features do not necessarily show the typical features associated with bacterial, fungal, tuberculous, or viral infections, the severe clinical presentation in this case of multistation lymphadenopathy and severe inflammatory response syndrome warrants an extensive workup. This would include assessment for the possibility of acute infectious etiologies, such as MTB complex, Epstein-Barr virus infection, etc. In this case, an extensive workup is negative, indicating that an infectious agent is not the culprit for the disease.

Option H Serum immunoglobulin levels (eg, IgG, IgM, IgA, IgE), serum and urine protein electrophoresis/immunofixation (SPEP/UPEP/IFE) – This is an appropriate choice. In light of the disseminated lymphadenopathy as well as exuberant plasmacytosis in this excisional biopsy, it is wise to pursue baseline serum immunoglobulin studies and SPEP/UPEP/IFE to evaluate levels and the presence and type of monoclonal gammopathy. In this case, serum immunoglobulin levels showed multiple elevations in IgG, IgM, and IgA; the hypergammaglobulinemia is also reflected in the SPEP, but no M-protein was uncovered. This additional workup further highlights the polyclonal lymphoproliferation revealed in this patient.

Option I Serologic/immunologic workup (including antineutrophil antibodies, anti-Sm, antiphospholipid antibodies, complement, C-reactive protein, direct antiglobulin test, erythrocyte sedimentation rate, etc) in consultation with rheumatology service – This is an appropriate choice. In an excisional specimen demonstrating general preservation of nodal architecture and exuberant plasmacytosis, the possibility of an autoimmune disorder with a severe clinical presentation (multicentric adenopathy, polyclonal hypergammaglobulinemia, systemic inflammatory response syndrome, etc) must be painstakingly evaluated. In this case, immunologic markers (eg, antineutrophil antibodies, direct antiglobulin test) are negative/within



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normal limits. However, elevations in C-reactive protein and erythrocyte sedimentation rate are evident.

Option J Treponema pallidum IHC stain – This is an appropriate choice. The combination of reactive follicular hyperplasia and interfollicular polytypic plasmacytosis raises the differential diagnosis of syphilitic lymphadenitis. The IHC stain for Treponema pallidum is negative in this case.

Diagnosis

Diagnostic List

A. Angioimmunoblastic T-cell lymphoma B. Classic Hodgkin lymphoma C. Idiopathic multicentric Castleman disease, HHV8-negative, not otherwise specified D. IgG4-related lymphadenopathy E. Lymphoplasmacytic lymphoma F. Systemic lupus erythematosus

Case Discussion

The correct diagnosis is idiopathic multicentric Castleman disease, HHV8-negative, not otherwise specified. Use this link to view all regions of the annotated slide. Castleman disease (CD) can be classified clinically as unicentric (UCD) versus multicentric (MCD) or histologically as hyaline vascular (HV) versus plasma cell (PC) variants. Nodal architectural preservation is a constant feature (Region 1 and Diagnostic Image 1). The HV-CD variant features typically observed are germinal center “twinning” (two or more germinal centers contained by the same group of mantle zone lymphocytes – Region 2), the “lollipop” sign (hyalinized vessels radially penetrating into a follicle) and “onion-skinning” (prominent concentric multilayering of mantle zone lymphocytes around follicles (slide Region 3 and Diagnostic Image 2). Though the majority of UCD displays HV morphology and multicentric CD shows PC morphology, there can be a morphologic spectrum, an admixture of histologic features in clinically UCD and MCD. Within clinically multicentric CD are the following distinct subsets:

1) Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS)-associated MCD (MCD coexisting with POEMS syndrome)

2) Idiopathic MCD (which include iMCD, not otherwise specified, and iMCD-TAFRO) 3) HHV8-associated MCD (which occurs most commonly in HIV-positive individuals but

may also be diagnosed in HIV-negative individuals) HHV8-associated MCD (ie, HHV8+ MCD) can be readily diagnosed when HHV8+ immunoblasts/plasmablasts are detected. Though the interfollicular plasmacytosis is polytypic, closer inspection will reveal monotypic lambda expression of the HHV8-positive immunoblasts/plasmablasts rimming mantle zones. Diagnostic challenges arise when a biopsy reveals “Castleman disease” or CD-like morphology in the absence of HHV8 expression; at this point, HHV8-negative MCD (also known as idiopathic MCD/iMCD) must be seriously considered. The current case is that of an iMCD-NOS, which has a variable clinical course and can sometimes present with thrombocytosis (as in this case) and hypergammaglobulinemia, in contrast to the clinically much more aggressive iMCD-TAFRO. Specific consideration of the iMCD-TAFRO entity will not be further explored here as iMCD-TAFRO deserves its own discussion and is beyond the scope of the current educational exercise. The acronym TAFRO stands for Thrombocytopenia, Ascites, reticulin Fibrosis, Renal dysfunction, and Organomegaly. Figure 1: The morphologic spectrum underpinning the current clinical classification of Castleman disease.2



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Clinically multicentric CD cases display varying degrees of CD-associated histologic features (Figure 1). An international multidisciplinary expert panel crafted a consensus guideline document for the diagnosis of iMCD, with histomorphology on an excisional biopsy playing a major role. The guideline outlines five morphologic features to evaluate severity/grade; each feature is scored from 0 (absent) to 3 (very significant). These are:

1) Number of regressed/atrophic/atretic germinal centers 2) Prominence of follicular dendritic cells (Region 4) 3) Increase in vascularity (Region 3, Region 5, and Diagnostic Image 2) 4) Number of hyperplastic germinal centers 5) Degree of plasmacytosis (Region 6 and Diagnostic Image 2)

A detailed pictorial guide for grading these pathologic features is provided in the consensus document,1 with the requirement of a grade 2 to 3 for either regressive germinal centers or plasmacytosis, at a minimum. Fulfillment of the diagnostic criteria for iMCD necessitates a three-pronged approach satisfying the following: a) both major criteria of defined histopathology and multicentric adenopathy; b) presence of at least two pertinent clinical/laboratory findings (ie, minor criteria); and c) exclusion of entities that can simulate the clinical or morphologic features of iMCD. The minor criteria include six possible laboratory criteria and/or five possible clinical criteria (at least one must be laboratory based). The laboratory-based criteria are:

1) Elevated C-reactive protein or erythrocyte sedimentation rate 2) Anemia 3) Thrombocytopenia or thrombocytosis 4) Hypoalbuminemia 5) Renal dysfunction or proteinuria 6) Polyclonal hypergammaglobulinemia

The clinical-based criteria are:

1) Constitutional symptoms (eg, night sweats, fevers, weight loss, fatigue) 2) Splenomegaly and/or hepatomegaly 3) Fluid accumulation (eg, edema, anasarca, ascities, pleural effusions) 4) Eruptive cherry hemangiomatosis or violaceous papules

Castleman‐like histologic LN features

Clinically UnicentricCD

CD Mimics (Malignancy, Autoimmune, Infection)

Clinically Multicentric CD

POEMS‐MCD iMCD

iMCD ‐TAFRO

iMCD, NOS

HHV8+ MCD

HIV‐ HIV+

HYALINE VASCULAR / HYPERVASCULAR PATHOLOGY

PLASMA CELL/PLASMACYTIC PATHOLOGY

(1) Regressed germinal centers(2) Follicular dendritic cell prominence

(4) Hyperplastic germinal centers(5) Plasmacytosis

(3) Vascularity

HYALINE VASCULAR / HYPERVASCULAR PATHOLOGY



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5) Lymphocytic interstitial pneumonitis A key point is that histologic “Castleman disease” or CD-like morphology does not make a diagnosis of CD: iMCD is a diagnosis of exclusion requiring true clinicopathologic correlation. Many entities can exhibit CD-like morphology. Similarly, multicentric adenopathy and moderate-to-severe systemic signs and symptoms in certain malignant, infectious, and autoimmune processes can also mimic iMCD. Rigorous exclusion of infection-related disorders (such as HHV8-associated MCD, Epstein-Barr virus-related lymphoproliferations, acute and/or uncontrolled infections of HIV, toxoplasmosis, tuberculosis, and syphilis) is necessary. Meticulous evaluation for autoimmune/autoinflammatory mimics is also vital; these include rheumatoid arthritis, adult-onset Still disease, IgG4-related disease, systemic lupus erythematosus, to name a few. Finally, iMCD would be excluded if malignancies and lymphoproliferative disorders were diagnosed before or during the clinical disease presentation (including, but not limited to, Hodgkin and non-Hodgkin lymphomas, follicular dendritic cell sarcomas, myeloma or plasmacytoma, POEMS syndrome). Figure 2: Clinical Spectrum of Castleman Disease.2

Approximately 1,650 cases of MCD are diagnosed in the United States each year, with iMCD accounting for 50% to 60% of published MCD cases. It has been described in individuals of varied ages, ranging from 2 to 80 years (median 50 years). MCD is a group of disorders with a morphologically benign lymphoproliferation which can lead to excessive proinflammatory hypercytokinemia, some having markedly elevated levels of interleukin-6 (IL-6) and VEGF. iMCD patients’ clinical presentations are also heterogeneous, from mild flu-like symptoms to moderate-to-intense, life-threatening episodes of systemic inflammatory response symptoms, cytopenia’s, polyclonal lymphoproliferation, autoimmune manifestations, and organ impairment. In contrast, patients of UCD are typically asymptomatic or display only mild inflammatory symptoms (Figure 2). Unlike HHV8-associated MCD and POEMS-associated MCD, the etiology of HHV8-negative/iMCD is currently not well established and is actively being investigated by the Castleman Disease Collaborative Network. Clinical outcomes with traditional therapies reported in iMCD have been historically poor, with five-year overall survival rates at 65%—even worse outcomes than in breast or colon cancers with regional metastases (ie, stage III). Though IL-6 does appear to be a vital driver of iMCD-NOS, only some patients will respond to anti-IL-6

Castleman like histologic LN features

Clinically Unicentric CD Clinically Multicentric CD

iMCD

iMCD, NOSiMCD ‐TAFRO

MCD‐POEMS

HHV8‐associated

MCD

Asymptomatic to mild inflammatory manifestations

Constitutional symptomsSystemic inflammation

Polyclonal lymphoproliferationCytokine storm (IL‐6, VEGF)



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therapy. Other cytokines and mechanisms appear to also contribute to disease activity, including activated T-cells and the mTOR pathway. The international collaborative expert panel on iMCD has also published evidence-based guidelines on therapeutic algorithms, stratifying patients based on disease severity. First-line therapies in iMCD-NOS include blockade of IL-6 (siltuximab) and IL-6 coreceptor gp80 (tocilizumab), and corticosteroids. Siltuximab, for example, has been shown to improve long-term outcomes, with 34% of patients attaining complete or partial response as compared to 0% of patients on placebo. When patients are refractory to first-line therapies, a number of other interventions are employed, including rituximab, cyclosporin, lenalidomide, R-CHOP, sirolimus, and even allogeneic stem cell transplantation. Though much progress has been achieved over the past decade, there is a need for continued collaboration to learn more about this relatively rare disease entity. Clinically, angioimmunoblastic T-cell lymphoma (AITL) presents with similar symptoms to the disease in question, such as disseminated adenopathy, polyclonal hypergammaglobulinemia, generalized skin rash, and constitutional symptoms. In addition, early-stage AITL can be diagnostically challenging as it can show retention of nodal architecture in early stage, as well as polymorphous infiltrate and exuberant proliferation of high endothelial venules and follicular dendritic cells. However, AITL also contains some cytologically atypical (albeit bland) “water clear” cells that could display an aberrant follicular T-helper cell immunophenotype. Histologic review here does not show atypical “water clear” cells nor does the workup show immunophenotypic abnormalities in T-cells. Although interfollicular involvement by classic Hodgkin lymphoma is a diagnostic possibility given the reactive inflammatory infiltrate, careful histologic evaluation fails to show abnormal Hodgkin/Reed-Sternberg cells, essentially excluding this diagnosis. IgG4-related disease can also present with systemic lymphadenopathy and may have histopathologic features that could mimic the correct diagnostic entity, particularly the exuberant interfollicular plasmacytosis. Important features in this clinical vignette that speak against IgG4-related disease are elevated inflammatory markers (such as CRP and IL-6) and the absence of significant numbers of IgG4+ plasma cells in the excisional biopsy specimen (ie, greater than 50 IgG4+ plasma cells per high-power field, and an IgG4-to-IgG ratio of >40%). Additionally, patients with IgG4-related disease tend to have far less severe systemic inflammatory symptoms than iMCD. Severe manifestations of autoimmune/autoinflammatory disorders, such as systemic lupus erythematosus (SLE) and adult-onset Still disease, are particularly challenging considerations that must first be excluded before a definitive diagnosis of the intended response can be rendered. These disorders can display florid reactive follicular hyperplasia and exuberant interfollicular plasmacytosis. Consultation with rheumatology service and careful review of the history provided here shows the absence of elevated immunologic parameters (eg, serum ANA, anti-dsDNA levels); this would preclude a diagnosis of SLE.



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Slide Annotations

Region 1: Nodal architectural preservation with widely spaced follicles and open sinuses. H&E stain, 1x objective/low magnification.

Region 2: Twinning of germinal centers. H&E stain, 5x objective/low-to-intermediate magnification.



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Region 3: Atretic follicle with penetrating hyalinized vessels, and multilayered appearance of the mantle zone lymphocytes. H&E stain, 10x objective/intermediate magnification.

Region 4: Follicular dendritic cell prominence. H&E stain, 15x objective/intermediate-to-high magnification.



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Region 5: Hypervascularization with prominent endothelium in interfollicular zones. Significant vascular proliferation. H&E stain, 2x objective/low magnification.

Region 6: Exuberant interfollicular plasmacytosis. H&E stain, 10x objective/intermediate magnification.



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Diagnostic Images Diagnostic Image 1

Nodal architectural preservation with significant interfollicular proliferation of amphophilic cells on low magnification. H&E stain, 20x.



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Diagnostic Image 2

“Lollipop” sign with hyalinized blood vessel radially penetrating germinal center. Prominent mantle zone lymphocyte layering, creating “onion-skinning” morphology. Exuberant vascular proliferation. Numerous interfollicular plasma cells. H&E stain, 100x.



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Brief Feedback for Incorrect Answer Options Option A

Angioimmunoblastic T-cell lymphoma is incorrect. Clinically, angioimmunoblastic T-cell lymphoma (AITL) presents with similar symptoms to the disease in question, such as disseminated adenopathy, polyclonal hypergammaglobulinemia, generalized skin rash, and constitutional symptoms. In addition, early-stage AITL can be diagnostically challenging as it can show retention of nodal architecture in early stage, as well as a polymorphous infiltrate and exuberant proliferation of high endothelial venules and follicular dendritic cells. However, AITL also contains some cytologically atypical (albeit bland) “water clear” cells that could display an aberrant follicular T-helper cell immunophenotype. Histologic review here does not show atypical “water clear” cells nor does the workup show immunophenotypic abnormalities in T-cells.

Option B

Classic Hodgkin lymphoma is incorrect. Although interfollicular involvement by classic Hodgkin lymphoma is a diagnostic possibility given the reactive inflammatory infiltrate, careful histologic evaluation fails to show abnormal Hodgkin/Reed-Sternberg cells, essentially excluding this diagnosis.

Option D

IgG4-related lymphadenopathy is incorrect. IgG4-related disease can also present with systemic lymphadenopathy and may have histopathologic features that could mimic the correct diagnostic entity, particularly the exuberant interfollicular plasmacytosis. Important features in this clinical vignette that speak against IgG4-related disease are elevated inflammatory markers (such as C-reactive protein and IL-6) and the absence of significant numbers of IgG4+ plasma cells in the excisional biopsy specimen (ie, greater than 50 IgG4+ plasma cells per high-power field, and an IgG4-to-IgG ratio of >40%). Additionally, patients with IgG4-related disease tend to have far less severe systemic inflammatory symptoms than does the intended response here.

Option E

Lymphoplasmacytic lymphoma is incorrect. Lymphoplasmacytic lymphoma (LPL) may present a histopathologic challenge in this differential diagnosis as it can display retention of nodal architecture with patent and dilated sinuses. On the other hand, LPL is a small B-cell lymphoid neoplasm with variable degrees of plasmacytic differentiation; by definition, the small B-lymphocytes, lymphoplasmacytic cells, and plasma cells in LPL would be clonal. In the current case, flow cytometry is instrumental in excluding monotypia, as B-cells and plasma cells proved to have polytypic light chain expression. Furthermore, serum and urine protein electrophoresis/immunofixation SPEP/UPEP/IFE failed to uncover a monoclonal gammopathy.

Option F

Systemic lupus erythematosus is incorrect. Severe manifestations of autoimmune/autoinflammatory disorders, such as systemic lupus erythematosus (SLE) and adult-onset Still disease, are particularly challenging diagnostic considerations that must first be excluded before a definitive diagnosis of the intended response can be rendered. These disorders can display florid reactive follicular hyperplasia and exuberant interfollicular plasmacytosis. Consultation with rheumatology service and careful review of the history provided here shows the absence of elevated immunologic parameters (eg, serum ANA, anti-dsDNA levels); this would preclude a diagnosis of SLE.



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ResourcesReferences 1. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus

diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-57.

2. Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-64.

3. Sato Y, Kojima M, Takata K, et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman’s disease. Mod Pathol. 2009;22(4):589-99.

4. van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018;132(20):2115-24.

5. Wang W, Medeiros LJ. Castleman disease. Surg Pathol Clin. 2019;12(3):849-63.

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2020 HPATH-B Case 9 FINAL Proof