Castleman Disease (CD) is a rare lymphoproliferative disorder that can be separated into two primary forms: Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). UCD is localized, while MCD is systemic. Though UCD generally has a favorable prognosis following surgical resection, more aggressive forms of this disease have been identified, including cases associated with dendritic and spindle cell proliferation. Genetic analysis has deepened our understanding of UCD. Despite advancements in better understanding the pathophysiology of UCD, challenges persist in the diagnosis, management, and treatment due to its rarity and heterogeneity. Here, we review current knowledge on UCD, highlighting the epidemiology, clinical presentation, diagnostic criteria, and treatment options while emphasizing the need for further research and innovation in therapeutic strategies.

Essa revisão tem como objetivo principal familiarizar os patologistas com a nomenclatura CD de diferenciação dos leucócitos humanos e os anticorpos monoclonais correspondentes de importância vital em hematopatologia. Tal conhecimento se faz necessário não só para facilitar a comunicação entre os profissionais da área no dia-a-dia diagnóstico, como também para servir de guia para publicações em revistas especializadas.

Castleman disease (CD) is a rare lymphoproliferative disorder with distinct clinical subtypes. However, our understanding of the underlying pathogenesis of particular subtypes of CD remains unclear. While the characteristic morphologic changes within UCD, including occasional cases of overgrowth of spindled stromal and follicular dendritic cells have been described, the nature and origin of these spindle cells remain elusive. Few reports have suggested that underlying stromal cells in UCD are clonally neoplastic and may be of fibroblastic reticular cell (FRC) or follicular dendritic cell (FDC) origins given their close clonal relationship. Although certain histomorphologic features may aid diagnosis, there are no specific biomarkers that can differentiate a reactive process mimicking UCD from true UCD. Hence, we describe an index case with morphology consistent with the hyaline vascular subtype of UCD with concomitant atypical smooth muscle actin (SMA)-positive stromal spindle cell proliferation containing a recurrent PDGFRB N666S mutation and upregulation of p53 expression. Further analysis of 21 additional cases of UCD identified increased p53 expression by digital image analysis and SMA positive stromal cells predominantly within the paracortical and intrafollicular areas further strengthening the hypothesis of the stromal cellular derivation and origins of UCD.

The diagnosis of angioimmunoblastic T-cell lymphoma (AITL) is complex and requires the demonstration of a T-follicular helper (TFH) phenotype. Immunophenotypic markers that detect the TFH phenotype are highly variable, thereby necessitating the use of 3 to 5 TFH markers to substantiate a TFH phenotype. We tested the utility of germinal center markers human germinal center–associated lymphoma (HGAL) and LIM-domain only 2 (LMO2) in detecting a TFH phenotype. We compared their staining to that of 6 TFH markers in current use, PD-1, ICOS, CXCL13, SAP, CD10, and BCL6, in a cohort of 23 AITL. Our results show that although both markers can detect a TFH phenotype, HGAL was superior to LMO2 in the percent of cells stained and the intensity of staining, 2 variables used to generate H -scores. Using H -scores as the metric, HGAL was most comparable to BCL6 among the currently used TFH markers and was more sensitive than CXCL13, SAP, CD10, and LMO2. PD-1 and ICOS emerged as the most robust of the 8 markers tested in this study in detecting a TFH phenotype. We conclude that HGAL is a reliable marker of TFH cells and can aid in the diagnosis of lymphomas of TFH derivation, particularly in the recognition of early patterns of AITL.

The story of Thomas Grogan, MD is one of the most compelling narratives in the modern history of pathology. Progressing from a quintessential academic pathologist to an entrepreneur and a renowned inventor, his remarkable journey is one of creativity, courage, and a keen focus on improving the care of cancer patients. By enabling precision health and empowering the pathologist in that mission, he transformed the landscape of diagnostic pathology. In this review, we describe some of his salient contributions and how his vision has shaped and continues to shape hematopathology today.

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Angioimmunoblastic T-cell lymphoma (AITL) is a uniquely aggressive mature T-cell neoplasm. In recent years, recurrent genetic mutations in ras homolog family member A (RHOA), tet methylcytosine dioxygenase 2 (TET2), dNA methyltransferase 3 alpha (DNMT3A) and isocitrate dehydrogenase [NAdP(+)] 2 (IDH2) have been identified as associated with AITL. However, a deep molecular study assessing both DNA mutations and RNA expression profile combined with digital image analysis is lacking. The present study aimed to evaluate the significance of molecular and morphologic features by high resolution digital image analysis in several cases of AITL. To do so, a total of 18 separate tissues from 10 patients with AITL were collected and analyzed. The results identified recurrent mutations in RHOA, TET2, DNMT3A, and IDH2, and demonstrated increased dNA mutations in coding, promoter and cccTc binding factor (cTcF) binding sites in RHOA mutated AITLs vs. RHOA non-mutated cases, as well as increased overall survival in RHOA mutated patients. In addition, single cell computational digital image analysis morphologically characterized RHOA mutated AITL cells as distinct from cells from RHOA mutation negative patients. computational analysis of single cell morphological parameters revealed that RHOA mutated cells have decreased eccentricity (more circular) compared with RHOA non-mutated AITL cells. In conclusion, the results from the present study expand our understanding of AITL and demonstrate that there are specific cell biological and morphological manifestations of RHOA mutations in cases of AITL.

AimsAn indolent T‐lymphoblastic proliferation (iT‐LBP) is a benign, reactive expansion of immature terminal deoxynucleotidyl transferase (TdT)‐positive T cells found in extrathymic tissues. iT‐LBP can be challenging to distinguish from malignant processes, specifically T‐lymphoblastic lymphoma (T‐LBL), given the overlapping clinical and histological features. Recently, it has been shown that LIM domain only 2 (LMO2) is overexpressed in T‐LBL but not in reactive immature TdT+ T cells in the thymus. On the basis of these findings, the aim of this study was to investigate the expression of LMO2 by using immunohistochemistry and its role in differentiating iT‐LBPs from T‐LBLs.Methods and resultsWe retrospectively identified cases of iT‐LBP and T‐LBL from the pathology archives of four institutions. Seven iT‐LBP cases (including five new cases that have not been reported in the literature) and 13 T‐LBL cases were analysed. Clinical, morphological, immunophenotypic and molecular data were analysed. Immunohistochemical staining with LMO2 was performed on all iT‐LBP and T‐LBL cases. A review of five new iT‐LBP cases showed similar morphological, immunophenotypic and molecular features to those of previously reported cases. All iT‐LBP cases were negative for LMO2 (0/7), whereas 92% of T‐LBL cases (12/13) expressed LMO2; the sensitivity was 92% (confidence interval 64–100%) and the specificity was 100% (confidence interval 59–100%).ConclusionWe confirm previously published findings that iT‐LBP cases show highly overlapping morphological and immunophenotypic features with T‐LBL. Importantly, LMO2 expression is a sensitive and specific marker with which to rule out iT‐LBP.

Angioimmunoblastic T-cell lymphoma is a uniquely aggressive mature T-cell neoplasm. In recent years, recurrent genetic mutations in RHOA, TET2, DNMT3A and IDH2 have been identified which characterize this disease. However, a deep molecular study assessing both DNA mutations and RNA expression profile, combined with digital image analysis is lacking. We designed a study to assess the significance of molecular and morphologic features by high resolution digital image analysis in cases of AITL. Eighteen separate tissues from ten patients with AITL were identified and analyzed in this study. Our results confirm recurrent mutations in RHOA, TET2, DNMT3A, and IDH2, and demonstrate increased DNA mutations in coding, promoter and CTCF binding sites in RHOA mutated AITLs versus RHOA non-mutated cases as well as increased overall survival in RHOA mutated patients. In addition, single cell computational digital image analysis morphologically characterized RHOA mutated AITL cells as distinct from cells from RHOA mutation negative patients. Computational analysis of single cell morphological parameters revealed RHOA mutated cells have reduced eccentricity (more circular) compared to RHOA non-mutated AITL cells. Overall, this study expands our understanding of AITL and demonstrates that there are specific cell biologic and morphologic manifestations of RHOA mutations in cases of AITL. KeyPoints: 1) RHOA mutated AITL show distinctly increased and more deleterious mutations than RHOA unmutated cases 2) RHOA mutated T-cells have distinct morphologic features from RHOA unmutated T-cells Disclosures Ohgami: Agilent technologies: Other: received support/funding.

Context.— Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma. Objective.— To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution. Design.— A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted. Results.— Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naïve, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease. Conclusions.— NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyte-rich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation.

Castleman disease is a rare lymphoproliferative disorder known to represent at least four distinct clinico-pathologic sub-types. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on degree of nodal involvement (unicentric versus multicentric) and according to viral infection (human herpes virus 8 - HHV8 and Human Immunodeficiency Virus - HIV). However, we continue to lack a foundational understanding of the biologic mechanisms driving at least a subset of patients with these diseases. In recent years, significant molecular and genetic abnormalities that may be associated with this disease have been described; yet we are still unclear as to a unified vision of what loci and genes are involved in at least a subset of cases of Castleman disease. In our study we performed a meta-analysis of all cases (unicentric and multicentric) of Castleman disease described in literature to date, and correlate cytogenetic, molecular and genetic abnormalities with disease subtypes, phenotypes and clinical outcomes. We further performed targeted DNA deep sequencing and RNA-sequencing on a cohort of Castleman Disease cases. Our results demonstrate that genetic abnormalities in the MAPK-pathways, PI3K-pathway and Interleukin signaling are frequent in unicentric Castleman disease, whereas abnormalities in DNA methylation are seen more commonly in idiopathic multicentric Castleman disease, along with abnormalities in MAPK-pathways. We conclude that UCD and iMCD may share similar pathways of MAPK pathogenesis but can also be distinguished by cytokine and other DNA modification pathways that differ. Disclosures Ohgami: Agilent technologies: Other: received support/funding.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD), is a self-limited histiocytic disorder of unclear etiology which most commonly presents with cervical lymphadenopathy. Purely extranodal presentation of RDD is uncommon, and isolated intralymphatic/intravascular confinement of this entity has not previously been described. We report a 16-yr-old female who presented with vaginal swelling and mass-like enlargement of the right labia. The mass had been present for nearly a year without pain or tenderness. Clinically, the lesion was thought to be a Bartholin gland cyst. Following surgical resection, histologic examination demonstrated a hypocellular myxedematous stroma with a mixture of ectatic thin and thick-walled vessels within which there were numerous collections of histiocytes, lymphocytes, and plasma cells. The histopathologic differential diagnosis included localized vulvar lymphedema, a specialized genital tract neoplasm, and childhood asymmetric labium majus enlargement. The histiocytes showed occasional plasma cells and lymphocytes within their cytoplasm, consistent with emperipolesis. Immunohistochemical studies showed that the histiocytes expressed CD163 and S100, while ERG and D2-40 highlighted their intralymphatic confinement, ultimately leading to the diagnosis of intralymphatic RDD. Intralymphatic RDD may present as vulvar lymphedema and can potentially mimic other myxedematous neoplasms of the vulvovaginal region.

Systemic high-grade B-cell lymphomas (HGBCLs) with MYC gene rearrangements are clinically aggressive. In situ lesions with indolent behavior have not been described to date. We have identified 2 cases of in situ B-cell neoplasms with MYC rearrangements (IS-BCN, MYC +) occurring, and focally confined to ≤4 lymphoid follicles in otherwise healthy individuals and without clinical progression despite minimal intervention (surgical only). Morphologically similar to systemic HGBCLs, the low power view of these lesions showed a starry sky pattern with numerous mitotic figures. High power imaging demonstrated these cells to be medium-large in size with irregular nuclear contours, immature chromatin, and prominent nucleoli. Immunophenotypically these cells were light chain restricted, positive for CD20, CD10, c-Myc, and dim or negative for BCL2 with a Ki67 proliferative index of >95%. By fluorescence in situ hybridization studies, we detected MYC translocations in these cells but no rearrangements in BCL2 or BCL6. Microdissection of neoplastic cells in these patients followed by targeted next-generation sequencing identified a mutation in MYC, D2N, and an indel in TNFRSF14. Mutations in ID3 or TCF3 were not identified. Although rare, these lesions should be separated from HGBCLs involving follicles but with systemic spread which has been previously described. Unlike systemic lymphomas with MYC gene rearrangements, these in situ B-cell neoplasms with MYC rearrangements did not require systemic therapy and no progression has been seen in either patient beyond 1 year (29 and 16 mo). Our work offers pathologic and biologic insight into the early process of B-cell neoplasia.

Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8-/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1, PTPN6, and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins.

The diagnosis of nodal marginal zone lymphoma (NMZL) can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking NMZL. We and others have noted an atypical distribution of T-follicular helper (T FH ) cells in some cases of NMZL. This study was prompted by the diagnosis of NMZL in several cases in which a marked increase of T FH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of NMZL to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other T FH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. We describe in detail 5 of these cases in which PTCL was an initial consideration. This study illuminates the diverse immunohistochemical patterns encountered in NMZL and highlights a diagnostic pitfall important for diagnostic accuracy.

Castleman disease (CD) is a rare lymphoproliferative disorder, that can transform into malignant lymphomas during clinical progress. Histologically CD can be subdivided into a hyaline-vascular variant (CD-HVV), a plasma cell variant (CD-PCV) and an intermediate variant (CD-IV) and further sub-classified into localized unicentric CD (U-CD), and multicentric CD (M-CD). An association with human herpes virus 8 (HHV8) and human immunodeficiency associated virus (HIV) in some CD cases is well documented, though the pathogenesis of CD still remains to be understood (Casper et al. Br J Haematol 2005). In recent years, cytogenetic and molecular studies have demonstrated clonal abnormalities in CD (Fajgenbaum et al. Blood 2017) as well as somatic mutations in follicular dendritic cell sarcoma (FDCS) - a rare clinically aggressive mesenchymal tumor associated with CD-HVV (Griffin et al. Mod Pathol 2015). However, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. To the best of our knowledge, our study is the first to analyze the genetic and epigenetic features of CD and FDCS associated with CD.

We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.