Bisegna

Heavy chain diseases (HCDs) are rare B-cell neoplasms characterized by the production of a monoclonal immunoglobulin composed of the only heavy chain without corresponding light chains.
These alterations are caused by the loss of a large portion of the constant region C1 domain of the heavy chain, which prevents the normal link to the light chain.[1] Monoclonal heavy chains do not result in a monoclonal peak at routine serum protein electrophoresis and are detectable only by immunofixation. The 2017 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues includes three variants of HCD: gamma-HCD (with IgG production), mu-HCD (with IgM production), and alfa-HCD (with IgA production). Gamma-HCD (γHCD), also known as Franklin's disease, is a mature B-cell neoplasm, usually with plasmacytic differentiation, first described by Franklin in 1964. It is a rare adult disease that may involve the most common lymph nodes, bone marrow, and spleen. Histologically γHCD has a broad morphologic spectrum and may resemble various lymphoproliferative disorders. Some cases are difficult to classify and do not fall into a distinct WHO-defined entity. Most patients show systemic symptoms such as anorexia, weakness, fever, weight loss, recurrent bacterial infections, organomegaly, and increasing circulating lymphocytes and plasma cells. Autoimmune manifestations are also common (25-70% of cases), frequently preceding the diagnosis of gamma-HCD, and they are maybe due to an autoimmune response stimulating the capability of the abnormal gamma heavy chain. The clinical course is highly variable, from indolent to rapidly progressive, depending on the extension of the disease (localized or disseminated). For this reason, treatment was reserved for symptomatic patients in the largest series of HCD.[2] We present the case of a patient with γHCD and concomitant T- cell large granular lymphocyte (T-LGL) disorder. Other six similar cases were described in the literature before.[3-5] A 65-year-old woman came to our observation because of pancytopenia at routine blood tests, with hemoglobin 9.6 g/dL, white blood cells 4.78 x10⁹/L, neutrophils 1.6 x10⁹/L, lymphocytes 2.47x10⁹/L and platelets 47 x10⁹/L. She complained of mild widespread joint pain, especially in the upper limbs and pelvis. LDH levels and liver and kidney function were normal and physical examination was negative for superficial adenopathy or splenomegaly. A blood smear showed an increase in LGL, equal to 42% of total lymphocytes, while PB flow cytometry revealed 9% B-lymphocytes CD19+, CD20+, CD22+, CD200+, CD38+, and CD5- with a small aberrant population lacking expression of light chains (5% of total lymphocytes). Natural killer (NK) and T-NK cells were 1% and 3%, respectively. T4/T8 ratio was about 1.64%. Bone marrow (BM) aspirate showed an increase in lymphocytes (34%) and plasma cells (8%), along with preserved hemopoietic maturation and absence of blasts. The cytogenetic study displayed a normal female karyotype. BM biopsy identified 20% interstitial infiltrate of small B-lymphocytes CD20+/CD5-/CD23-/CyclinD1-/DBA.44-/IgM-/IgD along with mature plasma cells CD138 and IgG positive and negative for IgM, IgD and both kappa and lambda light chains, similarly as observed with flow cytometry (Figure 1a). Moreover, an additional 10% interstitial and intrasinusoidal T-cell infiltrate CD3+, CD8+, CD57+/-, and CD4- consistent with T-LGL expansion was found (Figure 1b). Molecular analysis on PB and BM showed a monoclonal rearrangement of the T-cell receptor gamma chain gene (TCR), confirming the clonal nature of the T-LGL component and, accordingly to PB morphologic and immunophenotypic data, the diagnosis of T-LGL lymphoproliferative disorder. Serum electrophoresis showed hypo-gammaglobulinemia at 0.35 g/dL with increased alfa-2-region at 1.6 g/dL but no clear monoclonal component (Figure 3a). IgA and IgM levels were reduced, while about IgG, the subclasses IgG1, IgG2, and IgG3 were increased, with a normal level of IgG4. Nevertheless, serum immunofixation identified a monoclonal IgG heavy chain without corresponding light chains (Figure 3b), also present in the urine, according to flow cytometric analysis. A total body CT scan resulted negative for lymphadenopathy and hepatosplenomegaly. Due to the clinical history of arthralgia, the patient was tested for autoantibodies: only a low titer of IgM cryoglobulin was found, while ANA, ENA, C3, C4, anti-ccp, and anti-DNA native resulted negative. The final diagnosis was gamma-HCD with concomitant T-LGL disorder. For the lack of symptoms, the patient was kept under watchful control without any specific treatment. In February 2022, our patient developed a COVID-19 infection but remained asymptomatic despite the immunosuppression linked to his disease. At 36 months after diagnosis, she only suffers mild widespread joint pain. We observed spontaneous improvement of PB cells count (hemoglobin 10.3 g/dL, white blood cells 5.46 x10⁹/L, neutrophils 2 x10⁹/L, lymphocytes 2.91 x10⁹/L, platelets 198 x10⁹/L), normal renal function, increased 24-hour proteinuria and quite stable IgG values at 3 g/dL. The occurrence of γHCD and, even more, the association with T-LGL is rare. Our literature review identified only six patients with γHCD and concomitant T-LGL disorder, one of which was without clinical and biological description.[3-5] T-LGL is a persistent (more than six months) clonal expansion of cytotoxic T-cells that can arise as a primitive disease or associate with autoimmune disorders and/or B cell lymphoproliferative diseases.[6-9] As shown in Table 1, they were middle-aged adults investigated to study cytopenia, splenomegaly, or lymphadenopathy. Clinically, patients have either claimed few or several systemic symptoms, and histologically, there was a broad morphologic spectrum. The therapeutic approach used in the cases reported depends on clinical and histological findings with a favorable outcome. Cytopenia, more precisely neutropenia, is the most common clinical finding, but up to 60% of cases are asymptomatic. Moderate splenomegaly is frequent, while lymphadenopathy is very rare. The clinical course is usually indolent and non-progressive; since the association of γHCD and T-LGL disorder is exceptional, currently, there are no defined therapeutic strategies; “watch and wait” could be a valid attitude with accurate clinical observation, especially for asymptomatic patients. Currently, the prognosis of these patients remains unclear. However, the somatic mutations on genes involved in the pathogenesis of these entities (i.e., STAT3) may play a role in the course of the disease.[10] In conclusion, we report a rare association of two lymphoproliferative diseases, one with B phenotype and the other with T phenotype. As postulated in previous reports, it may be a non-casual coexistence since it could result from strong common antigen stimulation mediated by an infectious agent or autoantigen. However, the exact etiopathogenetic substratum is still to be clarified. Further investigations of the pathogenesis of γHCD with or without T-LGL disorders in a larger study cohort could be of value.

Figure 1. Histologic features of the B-cell and plasma cell component, consistent with gamma-heavy chain disease. CD138 (A) and CD20 (A, inset) show a mild, interstitial infiltrate made up of mature plasma cells and small B-lymphocytes. The plasma cell component is positive for IgG (B) but does not express light chains (C: kappa; D: lambda).

Figure 2. Histologic features of the T-cell component, consistent with T-cell large granular lymphocyte lymphoproliferative disorder. CD3 (A) highlights a discrete interstitial and intrasinusoidal T-cell component, made up by small cells with prevailing cytotoxic CD8+ phenotype (B: CD4; C: CD8) and partial expression of CD57 (D).

Figure 3. Serum electrophoresis (A) and serum immunofixation (B).

Table 1. Clinicopathological features of gamma-HCD associated with T-LGL LPD reported in the literature.

Gamma Heavy Chain Disease Associated with T-Cell Large Granular Lymphocyte Lymphoproliferative Disorder: Case Report and Literature Review