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CASE REPORT
Increased double-negative αβ+ T cells reveal adult- onset autoimmune lymphoproliferative syndrome in a patient with IgG4-related disease
Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of defective lymphocyte apoptosis characterized by non-malignant expansion of CD4 and CD8 double negative T-cell receptor (TCR) αβ+ T cells (αβ+DNT) leading to chronic lymphadenopathy, splenomegaly, autoimmune cytopenias and increased susceptibility to malignancy, particularly Hodgkin and non-Hodgkin lymphoma.1 ALPS is driven by mutations in the FS-7 fibroblast cell line-associated surface antigen (FAS)/CD95 signaling pathway, with deleterious hem- izygous mutations in the FAS gene representing approx- imately 70% of cases. Other less commonly involved genes are FASL, FADD and CASP10.1 Affected patients are typically diagnosed in early childhood, however due to incomplete penetrance and variable expressivity, some patients are asymptomatic or may present in adult- hood.2 Genotype-phenotype correlations have also been described, with a more severe disease course associated with dominant negative FAS mutations involving the intracellular death domain, while FAS mutations in the extracellular domain may lead to haploinsufficiency and a milder phenotype.1
IgG4-related disease (IgG4-RD) is a systemic immune- mediated fibroinflammatory disease characterized by infiltration of lymphocytes, eosinophils and IgG4-posi- tive plasma cells in various organs with associated fibro- sis.3 Onset of IgG4-RD typically occurs between 50 and 70 years of age and the symptoms vary depending on the affected organ.3 The most commonly involved organs include the salivary and lacrimal glands, pancreas and biliary tract, kidneys and lymph nodes. Laboratory find- ings may include elevated serum IgG4, eosinophilia, increased serum IgE and increased serum plasmablasts. Tissue biopsy is the diagnostic gold standard for IgG4- RD, which classically demonstrates a dense lymphoplas- macytic infiltrate, storiform fibrosis, obliterative phlebitis, and an elevation in IgG4+ plasma cells. Various cutoffs for the IgG4/IgG ratio and absolute number of IgG4+ cells per high-power field (hpf) have been pro- posed, and this metric has been incorporated into the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria.4 The co-occurrence of ALPS and IgG4-RD is extremely rare with only two cases currently reported in the English literature.5-6 In both prior reports, the patients were initially diagnosed with ALPS with subsequent development of IgG4-RD several years later. Herein we report the first case of an adult patient with IgG4-RD, in which expansion of αβ+DNT by flow cytometry and subsequent genetic testing ultimately uncovered an underlying diagnosis of ALPS with a path- ogenic FAS mutation.
A 63-year-old female with a history of peripheral T- cell lymphoma, not otherwise specified (PTCL, NOS) and invasive ductal carcinoma (IDC) of the breast pre- sented with left axillary lymphadenopathy. At 54 years of age, she was diagnosed with stage IIIA PTCL and treated on a clinical trial with six cycles of cyclophos- phamide, etoposide, vincristine, and prednisone alter- nating with pralatrexate with a complete remission fol- lowed by consolidative autologous stem cell transplant. At 59 years of age, she was diagnosed with stage IA (pT1bN0) triple negative IDC of the left breast and treat- ed with lumpectomy, adjuvant carboplatin/paclitaxel
and radiotherapy. One-year following treatment for breast cancer, she developed bilateral cervical lym- phadenopathy with a waxing and waning course. She was observed for approximately 1 year until an excision- al biopsy of a right cervical lymph node was performed. The biopsy showed no evidence of carcinoma or lym- phoma, but rather increased IgG4+ cells (>50/HPF, and >40% IgG4:IgG4 ratio) and multicentric Castleman dis- ease-like features, including interfollicular plasmacyto- sis, follicles showing multiple germinal centers (“twin- ning”), concentric layering of mantle zone lymphocytes around follicles (“onion skinning”) and germinal center lymphocyte depletion (“regression”) (Figure 1). Serologic examination for human immunodeficiency viruse (HIV) and human gamma herpesvirus 8 (HHV8) were negative, with the differential diagnosis including IgG4-RD and HHV8-negative idiopathic multicentric Castleman dis- ease (iMCD). The patient continued to experience wax- ing and waning cervical and axillary adenopathy, ulti- mately leading to a positron emission tomography (PET) scan, which showed extensive hypermetabolic adenopa- thy above and below the diaphragm, along with PET- avid lesions in the pancreas and spleen, concerning for recurrent lymphoma (Figure 2A). A fine needle aspira- tion and core biopsy performed on the pancreatic lesion showed an increase of IgG4+ cells (>25/HPF [high power field of microscope] and an IgG4:IgG ratio >50%) and storiform fibrosis (Figure 2B to D). Serum IgG4 and IgE were markedly elevated at 18.33 g/L (normal 0.11-1.57 g/L) and 24,98 kU/L (normal <100 kU/L), respectively. Peripheral blood B-cell phenotyping showed an increase in serum CD19+CD38+CD27+ plasmablasts, enumerat- ed at 63.9% of B cells (normal 0.7-6%). Overall, the clin- ical, pathologic, and serologic findings were diagnostic of IgG4-RD per the 2019 ACR/EULAR classification cri- teria. Prior to starting treatment for IgG4-RD, excisional biopsy of a PET-avid right level V cervical lymph node was performed to rule out recurrent lymphoma. This biopsy showed similar findings of increased IgG4+ cells (>50/HPF, and >80% IgG4:IgG4 ratio) and multicentric Castleman disease-like features (Figure 3A to D). Flow cytometry demonstrated an increase in αβ+DNT (7.1% of lymphocytes and 14.2% of CD3+ T cells), and immunohistochemistry showed paracortical localization of these T-cells around reactive germinal centers raising suspicion for ALPS (Figure 3E to H). Peripheral blood flow cytometry confirmed an increase in circulating αβ+DNT (4.3% of lymphocytes, 6.1% of CD3+ T cells, 27 cells/uL). Additional laboratory testing revealed ele- vated soluble FAS ligand (824 pg/mL) and markedly ele- vated serum vitamin B12 level above the measured range for our laboratory instrument (>1,000 pg/mL). T-cell receptor β and γ chain rearrangements by next-genera- tion sequencing (NGS) were negative, while targeted NGS mutational analysis (Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Malignancies) detected a pathogenic FAS c.841T>A (p.W281R) muta- tion, that resulted in an amino acid substitution likely to be damaging in a region essential for formation of the death-inducing signaling complex involved in apoptosis induction.1 This variant had an allele frequency of 56% suggesting a germline mutation and confirming the diag- nosis of ALPS-FAS.1
ALPS caused by FAS mutation (ALPS-FAS) usually manifests in early childhood at a median age of 2-3 years.1 However, due to incomplete penetrance, variable expressivity, and variation in phenotype according to genotype, a subset of patients may be asymptomatic or present in adulthood.1,2 In these cases acquisition of fam-
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