5TH EDITION OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF TUMORS OF THE HEMATOPOIETIC AND LYMPHOID TISSUES.

This review focuses on mature T-cell, NK cell, and stroma-derived neoplasms in the 5th edition of the World Health Organization (WHO) classification of hematolymphoid tumors (WHO-HEM5), including changes from the revised 4th edition (WHO-HEM4R). Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, EBV-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the WHO-HEM5 can be applied in routine clinical practice.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Identification of amyloidosis of the urinary tract and prostate: Opportunities for early diagnosis & intervention in systemic disease.

OBJECTIVES: To determine the prevalence of different amyloid types and frequency of associated systemic amyloidosis in the urinary tract/prostate. METHODS: We studied Congo red-positive prostate (n = 150) and urinary tract (n = 767) specimens typed by a proteomics-based method between 2008 and 2020. Clinical follow up was available for a subset (urinary tract, n = 111; prostate, n = 17). Amyloid types were correlated with various clinicopathologic features. For patients with clinical follow up, chart review was performed to establish localized versus systemic disease, frequency of initial diagnosis of amyloidosis on urinary tract/prostate specimens, presence of cardiac disease, and death from disease-related complications. RESULTS: The most common amyloid types were AL/AH in urinary tract (479/767, 62 %) and localized ASem1 in prostate (64/150, 43 %). Urinary tract AL/AH amyloid was usually localized, but systemic AL amyloidosis occurred in both sites (urinary tract: 5/71, 7 %; prostate: 2/2, 100 %). ATTR amyloidosis was seen in over a third of cases (urinary tract: 286/767, 37 %; prostate: 55/150, 37 %). Urinary tract/prostate was the site of the initial ATTR amyloidosis diagnosis in 44/48 patients (92 %), and 38/48 (79 %) were subsequently found to have cardiac involvement. Seminal vesicle/ejaculatory duct involvement was pathognomonic for ASem1-type amyloidosis (39/39, 100 %). CONCLUSIONS: Over 40 % of patients had systemic amyloidosis, with urinary tract/prostate often the first site in which amyloid was identified. Since early recognition of systemic amyloidosis is critical for optimal patient outcomes, there should be a low threshold to perform Congo red stain. Proteomics-based amyloid typing is recommended since treatment depends on correctly identifying the amyloid type.

Long-term outcomes among adults with Langerhans cell histiocytosis.

Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells.

Malignant histiocytoses (MHs), or the 'M group' of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

BRAF testing modalities in histiocytic disorders: Comparative analysis and proposed testing algorithm.

OBJECTIVES: Understanding of histiocytic disorders has been revolutionized by demonstration of mitogen-activated protein kinase (MAPK) pathway mutations, most commonly BRAFV600E. The optimal testing strategy to assess BRAFV600E is unknown. We aimed to compare performance of testing modalities, to propose a framework for evaluation of BRAFV600E mutation status in histiocytic disorders. METHODS: We retrospectively reviewed patients with histiocytic disorders and BRAF mutation testing on a lesional tissue specimen. RESULTS: In 120 patients, BRAF assessment included immunohistochemistry (IHC) in 97 (80.2%), polymerase chain reaction (PCR) in 35 (28.9%), and next-generation sequencing (NGS) in 62 (51.2%). Forty-five underwent both NGS and IHC. With NGS as the gold standard, the sensitivity and specificity of IHC were 82.4% and 96.4%. Three false negatives were observed in biopsy specimens with low BRAFV600E variant allele frequency or decalcified tissue. One false-positive IHC was observed in a lung biopsy specimen, likely due to antibody cross-reactivity with respiratory cilia. Among 14 with successful NGS and PCR, a single discordance was observed. Two PCR-to-IHC discrepancies were observed, including one other false-positive IHC. CONCLUSIONS: Immunohistochemistry was highly specific for detection of BRAFV600E. Main caveats were false negatives and lack of detection of non-BRAFV600E mutations. We propose the use of IHC as initial screening in general practice with reflex molecular testing if negative.

Gastrointestinal amyloidosis: an often unexpected finding with systemic implications.

The gastrointestinal (GI) tract is a common site of amyloidosis, but the incidence, clinicopathologic features, and systemic implications of different types of GI amyloidosis are not well understood. GI amyloid specimens (N = 2511) typed using a proteomics-based method between 2008 and 2021 were identified. Clinical and morphologic features were reviewed in a subset of cases. Twelve amyloid types were identified, including AL (77.9%), ATTR (11.3%), AA (6.6%), AH (1.1%), AApoAIV (1.1%), AEFEMP1 (0.7%), ALys (0.4%), AApoAI (0.4%), ALECT2 (0.2%), Aß2M (0.1%), AGel (0.1%), and AFib (<0.1%). Amino acid abnormalities indicative of known amyloidogenic mutations were detected in 24.4% ATTR cases. AL, ATTR, and AA types all commonly involved submucosal vessels. They also showed some characteristic patterns of involvement of more superficial anatomic compartments, although there was significant overlap. Common indications for biopsy were diarrhea, GI bleed, abdominal pain, or weight loss. Amyloidosis was usually an unexpected finding, but most AL and ATTR patients were ultimately found to have cardiac involvement (83.5% of AL; 100% of ATTR). Although most GI amyloid is of AL type, over 10% are ATTR, over 5% are AA, and twelve different types were identified in total. GI amyloid is often unexpected but usually signals systemic amyloidosis, thus there should be a low threshold to perform biopsy with Congo red stain in patients with unexplained GI symptoms. Clinical and histologic features are nonspecific, and typing should be performed via a robust method such as proteomics as treatment hinges on correctly identifying the amyloid type.

A Rare Cause of Abdominal Pain: Erdheim-Chester Disease.

A 65-year-old man presented with hematuria, night sweats, nausea, intermittent nonbloody diarrhea, and abdominal pain. Computed tomography angiogram with enterography showed retroperitoneal fibrosis surrounding both kidneys and ureters without any evidence of vascular obstruction or hydronephrosis. Laparoscopic biopsy demonstrated fibroadipose tissue involved by a subtle histiocytic infiltrate in a background of marked fibrosis, scattered lymphocytes, and plasma cells. The histiocytes strongly expressed CD163, Factor XIIIa, and BRAF V600E. He was diagnosed with Erdheim-Chester disease, a rare histiocytic neoplasm uncommonly presenting with gastroenterological manifestations.

How I Diagnose Rosai-Dorfman Disease.

OBJECTIVES: Rosai-Dorfman disease (RDD) is one of 3 major types of histiocytosis, along with Erdheim-Chester disease and Langerhans cell histiocytosis. While historically, RDD was considered a benign self-limited condition, current data show MAPK/ERK pathway mutations in 30% to 50% of cases, indicative of a clonal process. Rosai-Dorfman disease was incorporated as a histiocytic neoplasm in the fifth edition of the World Health Organization classification of hematopoietic tumors and the International Consensus Classification. METHODS: We discuss the diagnosis of RDD using 2 illustrative cases, interpretative challenges, and a diagnostic algorithm. RESULTS: Rosai-Dorfman disease involves nodal and extranodal sites, including skin, sinuses, salivary gland, orbit, central nervous system, kidney, and bone. In a subset, RDD can coexist with other neoplasms (lymphomas, other histiocytosis) or autoimmune disease. Morphologically, RDD histiocytes are characterized by enlarged round to oval nuclei, distinct nucleoli, and voluminous cytoplasm with engulfment of inflammatory cells (emperipolesis). By immunohistochemistry, they express CD68, CD163 (majority), S100, OCT2, and cyclin D1. Appropriate use of ancillary studies is important to support the diagnosis of RDD while excluding other histiocytic neoplasms and reactive histiocytic proliferations. CONCLUSIONS: Management of RDD is dependent on the extent of organ involvement and clinical symptoms. In patients who require therapy, next-generation sequencing is recommended to identify MAPK/ERK pathway mutations for targeted therapy.

Proteomic and Clinicopathologic Assessment of Penile Amyloidosis: A Single Institutional Review of 12 Cases.

OBJECTIVES: There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of different amyloid types in surgical specimens from the penis involved by amyloidosis and correlate relevant clinicopathologic parameters with proteomic findings. METHODS: Since 2008, our reference laboratory has performed liquid chromatography/tandem mass spectrometry (LC-MS/MS) for amyloid typing. The institutional pathology archive and reference laboratory database were queried to retrospectively identify all penile surgical pathology specimens with LC-MS/MS results between January 1, 2008, and November 23, 2022. Archived H&E-stained and Congo red-stained sections were re-reviewed. RESULTS: Twelve cases of penile amyloidosis were identified, which represented 0.35% (n = 3,456) of penile surgical specimens. AL-type amyloid was most frequent (n = 7), followed by keratin-type amyloid (n = 3) and ATTR (transthyretin)-type amyloid (n = 2). AL-type amyloid cases often showed diffuse dermal/lamina propria deposition, whereas all keratin-type amyloid cases were localized to the superficial dermis. Two cases with keratin-type amyloid had concomitant cutaneous findings (penile intraepithelial neoplasia and condyloma). CONCLUSIONS: This series, the largest to date, demonstrates that penile amyloidosis has a heterogeneous proteomic landscape. To the best of our knowledge, this is the first study describing ATTR (transthyretin)-type penile amyloid.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Transformation of FL into DLBCL with a PMBL gene expression signature.

We investigated the clinicopathologic features of 5 follicular lymphomas (FLs) that transformed (tFL) morphologically to diffuse large B-cell lymphomas (DLBCLs) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile (tFL-PMBLsig-pos). None of the tFL-PMBLsig-pos cases arose in the mediastinum, all cases tested had a germinal center B-cell phenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole-exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58). Copy number (CN) analysis detected gains/amplification of REL and STAT6 in 60%, gains of SOCS1 in 40%, and gains of chromosome 16, including IL4R, in 40% of the cases. CN gains/amplification of BCL6 and MYC and loss of TNFRSF14 and TNFAIP3 were identified in 20% of the cases. Three of 5 cases lacked a BCL2 rearrangement. Despite having some features that are less common in DLBCL (MAL and CD23 expression and JAK-STAT activation), these tFL-PMBLsig-pos cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with gene expression and some genetic features reminiscent of PMBL, with potential treatment implications that include the use of novel targeted therapies.

Ophthalmologic Involvement in Adults with Histiocytic Disorders: Clinical Presentation and Treatment Outcomes.

PURPOSE: To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. DESIGN: Observational, retrospective chart review. PARTICIPANTS: Adult patients (age ≥ 18 years) at Mayo Clinic from January 1, 1996, to July 1, 2021, with histiocytic disorders. Inclusion criteria were (1) histiocytic disorder by biopsy and appropriate clinical phenotype; (2) available medical records; and (3) ocular, orbital, optic nerve, or cavernous sinus involvement. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Response to therapy, measured in clinical and radiographic impact. RESULTS: Thirty-two patients were identified: 7 with Langerhans cell histiocytosis (LCH); 15 with Erdheim-Chester disease (ECD); 1 with mixed LCH/ECD phenotype; 8 with Rosai-Dorfman disease (RDD); and 1 with mixed RDD/ECD phenotype. Ophthalmologic involvement was part of the initial presentation in 69% of patients (22/32). Eyelid edema (13/32, 41%) and proptosis (12/32, 38%) were the most frequent presentations. Isolated orbital or cavernous sinus involvement was present in 3 of 7 patients with LCH and 1 of 8 patients with RDD. Optic nerve sheath involvement was present in 2 of 7 LCH patients, 14 of 15 ECD patients, and 1 RDD/ECD patient. Diffuse (> 75%) orbital involvement was seen in 12 of 15 ECD patients and 1 of 7 LCH patients. Ocular involvement was seen in 1 of 15 ECD patients, 6 of 8 RDD patients, and 1 of 1 mixed RDD/ECD patient. The cavernous sinuses were involved in 1 of 7 LCH patients, 5 of 15 ECD patients, and both mixed phenotype patients. Visual acuity was affected in 14 patients (14/24, 58%) with a median logarithm of the minimum angle of resolution visual acuity of 0.1 (range, -0.12 to 3). BRAF V600E mutations were found in 75% (3/4) of LCH patients and 91% (10/11) of ECD patients. Patients received a variety of treatment, and response was variable across disease types. CONCLUSIONS: Orbital involvement was more commonly seen in LCH and ECD, whereas ocular involvement was more common in RDD. Visual acuity may be impacted from ocular involvement or compression of the optic nerve with diffuse orbital involvement.

Proteomic Identification and Clinicopathologic Characterization of Splenic Amyloidosis.

The spleen is a commonly encountered specimen in surgical pathology. However, little is known about the incidence, morphologic pattern, and clinical features of spleens involved by amyloidosis. We retrospectively identified 69 spleen amyloid cases typed using a proteomics-based method between 2008 and 2020. The frequency of amyloid types, clinicopathologic features, and distribution of amyloid deposits were assessed. Four amyloid types were detected: immunoglobulin light chain (AL) (N=30; 43.5%); leukocyte chemotactic factor 2 amyloidosis (ALECT2) (N=30; 43.5%); amyloid A (AA) (N=8; 11.6%); and fibrinogen alpha (AFib) (N=1; 1.4%). The splenic amyloid showed 5 distinct distribution patterns: (1) diffuse pattern, exhibited by most AL cases; (2) red pulp pattern, exhibited by most ALECT2 cases; (3) multinodular pattern, seen in subsets of AA and AL-kappa cases; (4) mass-forming pattern, seen in the AFib case; and (5) vascular only, seen in a subset of AA cases. Atraumatic splenic rupture was the most common reason for splenectomy in AL cases, while most ALECT2 spleens were removed incidentally during an unrelated abdominal surgery. Splenomegaly was significantly more common in AA spleens than in AL or ALECT2 spleens and was often the reason for splenectomy in this group. In conclusion, splenic amyloid may be underrecognized as it is often an incidental finding. Although, as expected, many of the spleens were involved by AL amyloidosis, ALECT2 emerged as another common spleen amyloid type. Although the spleen amyloid types exhibited characteristic distribution patterns, proteomics-based typing is warranted as some morphologic overlap still exists. Awareness of ALECT2 as a major spleen amyloid type is important for appropriate diagnostic workup and patient management.

Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status.

Importance: Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments. Objective: To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD. Design, Setting, and Participants: This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis. Main Outcomes and Measures: Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD. Results: A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs. Conclusions and Relevance: In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.