The International Union of Immunological Societies (IUIS) divides the inborn errors of immunity (IEI) to ten categories1.

Six of these categories include entities that may be associated with increased risk of lymphoproliferations. These are: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, auto inflammatory disorders and phenocopies of inborn errors of immunity. See table 1 for a list of IEI associated lymphoproliferations.

The evaluation of lymphoproliferative processes in tissue biopsies from patients with inborn errors of immunity is challenging. These patients often have either abnormal or distorted lymphoid tissue architecture, or benign lymphoproliferations in various tissues, some of which may even be monoclonal. Differentiating these processes from true malignant lymphoma may be very difficult even for experienced pathologists given the rarity of particular entities in clinical practice and the paucity of literature on discrete entities. Therefore, acquaintance with the broad range of normal in the context of various forms of immunodeficiency is required to avoid overcalling benign processes as malignant in these patients. On the other hand, many inborn errors of immunity are also associated with increased risk of lymphomas, especially B cell lymphomas (viral or non-viral associated), and therefore an accurate distinction between a non-malignant and malignant lymphoproliferation is critical. In this review we will discuss the difficulties in the diagnosis of these processes and provide illustrative examples with discussion about how to avoid over and underdiagnosis.

In this article we will use the WHO 5th edition of the classification of Hematolymphoid tumors nomenclature46 of lymphoproliferative disorders and lymphomas arising in immune deficiency and immune dysregulation settings which is based on a three-part unifying nomenclature including: 1) the name of the histological lesion 2) presence or absence of one or more oncogenic virus (es) like EBV, HHV8 and 3) the specific immunodeficiency setting47. See table 2.

The optimal management of lymphoma in the setting of IEI is controversial, but frequently a diagnosis of lymphoma would result in combination chemotherapy and irradiation therapy, with significant morbidity from treatment. A distinction between a benign or malignant pathological diagnosis can radically change the management of a patient. Because of this it is crucial to maintain communication between clinicians and pathologists, so that the clinician can accurately convey the context of the acute disease and underlying problems, such as IEI, and so that the pathologist can accurately represent the nuances of a diagnosis or a differential diagnosis in the case that there is no definitive diagnosis. The following examples of collected cases reflect instances in which astute pathologic distinctions resulted in a diagnosis of a benign process which, out of context, could have been interpreted as malignant. These distinctions guided a gentler, less morbid approach to treatment which, in these instances, proved justified.