The diagnostic process is very complex and requires an understanding of the decision-making strategies commonly used in health care. Central to this is formulating a differential diagnosis and defining the pretest probability of disease. An understanding of common modes of cognition can aid good decision making. Central to this is the problem of premature closure of the differential diagnosis. We present some tactics to avoid that in the clinical encounter.

This explores the phenomenon of auditory verbal hallucinations (AVHs) as an example of entanglements of spirituality and psychopathology, and looks at ‘spiritually significant voices’ (identified by those who hear them as having spiritual/religious significance). Some have proposed making a differential diagnosis between ‘genuine’ spiritual experiences and mental illness, but the criteria for making such distinctions can be controversial and misleading, based on a false presupposition that the two are mutually exclusive. Research shows that patients identify some experiences as both part of an illness and spiritually significant. Patients with a psychiatric diagnosis are often subjected to epistemic injustice, wherein their claim to know things (e.g. spiritually) is discredited owing to prejudice associated with their diagnosis. A case study explores entanglement of spirituality with AVHs and considers implications for assessment/treatment. Voices of this kind may be meaningful for those who hear them, whether or not associated with a diagnosis, and affirmation of this and patients’ positive spiritual coping, where possible, can be a positive factor in promoting recovery.

Possession states are a complex phenomenon that takes a variety of different cultural and religious forms, which may or may not be associated with a psychiatric diagnosis. A case study demonstrates how demonic attributions may be employed as a form of negative religious coping and may lead to spiritual struggles. It illustrates the importance of understanding theological/religious context of belief in spirit possession and the difficulties of reaching a psychiatric diagnosis when the patient belongs to a faith community that understands such experiences as spiritually determined and not symptomatic of illness. Possession states are considered unusual in the UK and yet they are very common worldwide. Exorcism (or disobsession or spirit release) has in some contexts been proposed as an appropriate (if controversial) psychiatric treatment. While, in appropriate religious/cultural contexts, it can be helpful, there is also evidence that it can be harmful when applied in the wrong way to patients with certain diagnoses. This raises important questions about collaboration with faith leaders, safeguarding those who are vulnerable and not pathologising culturally normative practices.

This chapter describes the normal maturation pattern of plasmacytoid dendritic cells (pDCs), as well as the dynamic antigenic changes during pDC differentiation. Common markers used to define the pDC lineage are included, with their advantages and limitations discussed. Key immunophenotypic features associated with neoplastic pDC proliferations (blastic plasmacytoid dendritic cell neoplasm, myeloid neoplasms with plasmacytoid dendritic cell differentiation, and mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm) are covered. Minimal residual disease evaluation of pDC neoplasms is also discussed. Finally, the differential diagnosis associated with pDC proliferations is addressed.

Hepatosplenic T-cell lymphoma (HSTCL) is an aggressive T-cell lymphoma with characteristic clinicopathologic features. This chapter highlights the key immunophenotype of HSTCL and underscores the distinct differences between HSTCL and its mimickers, such as γδ T-LGLL and aggressive NK-cell neoplasm.

This chapter briefly describes the clinicopathologic features of mycosis fungoides and Sezary syndrome. We focus on their immunophenotype as well as the differential diagnosis, which includes T-prolymphocytic leukemia, adult T-cell leukemia/lymphoma, T follicular helper cell lymphoma, and reactive T cells.

This chapter provides the key immunophenotypic features of various subtypes of T-large granular lymphocytic leukemia (T-LGLL). The differential diagnosis of T-LGLL, including reactive T-LGL proliferation, T-cell clone of uncertain significance, and other T-cell leukemias/lymphomas, especially hepatosplenic T-cell lymphoma, is also discussed. Diagnostic pitfalls associated with T-LGLL are highlighted.

ALK-negative anaplastic large cell lymphoma (ALCL) is a mature T-cell neoplasm characterized by large pleomorphic cells with uniformly strong CD30 expression but without ALK rearrangement or expression. This chapter focuses on the immunophenotypic features of ALK-negative ALCL, including cases without and with DUSP22 rearrangement. The differential diagnosis of ALK-negative ALCL is also discussed, with a focus on flow cytometric immunophenotypic findings, including peripheral T-cell lymphoma, adult T-cell lymphoma/leukemia, NK/T-cell lymphoma/leukemia, T-lymphoblastic leukemia/lymphoma, and acute myeloid leukemia/myeloid sarcoma. Flow cytometric immunophenotypic features that can be helpful for the differential diagnosis are discussed.

Anaplastic large cell lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) is a mature T-cell neoplasm characterized by large pleomorphic cells with uniformly strong CD30 expression and ALK rearrangement with protein expression. This chapter focuses on the immunophenotypic features of ALK+ ALCL, including the common and uncommon morphologic patterns such as the small cell/lymphohistiocytic patterns. The differential diagnosis of ALK+ ALCL is also discussed, with a focus on the findings of flow cytometric immunophenotypic analysis, including peripheral T-cell lymphoma, reactive lymphohistiocytic proliferations, T-lymphoblastic leukemia/lymphoma, acute myeloid leukemia/myeloid sarcoma, and ALK+ large B-cell lymphoma. Flow cytometric immunophenotypic features that can be helpful for the differential diagnosis are discussed.

This chapter describes the immunophenotype of adult T-cell leukemia/lymphoma (ATLL). The differential diagnosis, including mycosis fungoides/Sezary syndrome (MF/SS), T-prolymphocytic leukemia (T-PLL), anaplastic large cell lymphoma (ALCL), and normal T-regulatory cells, is discussed in detail.

This chapter covers the immunophenotype of acute myeloid leukemia (AML) with RUNX1::RUNX1T1. In addition to RUNX1T1, rare cases have RUNX1T3 as the fusion partner with RUNX1, and their immunophenotype is also described. The major differential diagnosis is mixed-phenotype acute leukemia and the distinction is highlighted.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL) are the two prototypical CD5-positive B-cell neoplasms. Both are characterized by CD5 expression, and distinguishing one from the other is essential when rendering a diagnosis. Therefore, these two entities are discussed together. The immunophenotype of typical and atypical CLL/SLL is described, along with minimal residual disease evaluation of CLL/SLL by flow cytometry. For MCL, the immunophenotype of the classic, leukemic non-nodal, and cyclin D1-negative subtypes is discussed. The differential diagnosis between CLL/SLL and MCL, as well as their distinction from reactive CD5+ B cells and other CD5+ B-cell lymphomas/leukemias, is also addressed.

This chapter described the immunophenotypic characteristics of different subtypes (hypergranular and microgranular) and different patterns (A to D) of acute promyelocytic leukemia (APL). APL with variant RARA translocations (involving partners other than PML) and cases with translocations involving RARB or RARG are also discussed. The differential diagnosis includes normal versus neoplastic promyelocytes, microgranular APL versus acute monocytic leukemia, and APL versus other subtypes of AML with an APL-like immunophenotype.

This chapter describes normal erythroid maturation and the dynamic antigenic changes during erythroid differentiation. Common markers used to define the erythroid lineage are discussed, with their advantages and limitations included. Key immunophenotypic features associated with erythroid aberrancies are highlighted. For acute erythroid leukemia, three subtypes and their immunophenotypic profiles are described. Finally, the differential diagnosis of AEL is addressed.

There are three subtypes of T-prolymphocytic leukemia (T-PLL) based on their cytogenetic presentations, all of which share a similar immunophenotype. This chapter discuss their immunophenotype in detail. Occasional cases with atypical immunophenotypes, such as negative CD3 or CD45 expression, are also described. Tumor heterogeneity, with populations displaying different immunophenotypes, is discussed, along with immunophenotypic shift. Differential diagnosis is addressed, with a focus on the challenges in distinguishing TCL1-family negative T-PLL from other leukemic T-cell lymphomas/leukemias.

This chapter describes the diverse immunophenotypic features of AML with NUP98 rearrangement. The fusion partners for NUP98 are diverse, and accordingly, the immunophenotype differs depending on the specific partner involved. Immunophenotypic shift is relatively common in AML with NUP98 rearrangement. Rare cases with a mixed immunophenotype are present.