The diagnosis of cutaneous T-cell lymphomas (CTCLs) requires a careful evaluation of the clinical features, as well as a comprehensive histologic and immunophenotypic analysis. The skin is the most common site of extranodal T-cell lymphomas, and mycosis fungoides (MF) is the most frequent T-cell lymphoma overall.^1,2,3 Extranodal NK-cell lymphomas are overall rare in the Western hemisphere but more common in Asia and some areas of central and South America, where Epstein–Barr virus (EBV) infection occurs at a young age.^4,5 The most frequent forms of cutaneous and systemic T- and NK-cell lymphomas with secondary skin involvement are listed in Table 11-1.

There is a substantial disagreement among pathologists in CTCL diagnosis. A study of Herrera et al.⁶ has shown a concordance of 64% in the lymphoma diagnosis of systemic T-cell lymphomas when comparing referring centers and National Comprehensive Cancer Network (NCCN)-designated review (n = 131). This study has shown that in nearly 50% of cases where a discrepancy was found, reevaluation of the existing data (H&E and IP stains) led to a revised diagnosis. Expert reclassification might have resulted in a treatment change in 44% of cases. Weisenburger et al. also showed discordance in lymphoma diagnosis in 15% of cases (n = 1010 cases), leading to a treatment change in 12.9% of all cases.⁷ The International T-cell lymphoma project (n = 1153) has shown major diagnostic disagreement in several diagnostic categories of T-cell lymphomas, including cutaneous variants (cutaneous anaplastic large cell lymphoma—66% rate of interobserver agreement; subcutaneous panniculitis-like T-cell lymphoma—75% rate of interobserver agreement).⁸ A study by Guitart et al.⁹ has shown an extraordinary poor consensus agreement in the diagnosis of early MF, the most common type of CTCL (the rate of consensus agreement was 48%).

Diagnosing CTCLs at an early stage is difficult as both the clinical and histologic presentations include a broad spectrum of common inflammatory skin conditions. Molecular testing can be also misleading as clonal inflammatory processes are not uncommon. Therefore, adequate chronologic reporting of the location and clinicopathologic characteristics of the lesions are capital to achieve a diagnosis.

Many CTCLs share identical histologic findings, and a diagnosis relies on clinical presentation.^10,11 For example, MF and types B and D lymphomatoid papulosis (LyP) may share the same histology but differ in the chronology and clinical appearance of the lesions: while MF follows a progressive course with progression from patches to plaques and sometimes tumors, LyP is characterized by papulonecrotic lesions that will regress spontaneously in a relatively short period of time (weeks to few months).

Similarly, tumor-stage MF with large cell transformation, type C LyP, and primary cutaneous anaplastic large cell lymphoma (PC-ALCL) can present with overlapping histologic patterns, but differ in the clinical appearance of the lesions: from tumors (on a preexistent history of MF) to self-remitting papulonecrotic lesions (LyP), to large single ulcerated tumors (PC-ALCL).

Pagetoid reticulosis (a localized variant of MF with a more frequent CD8⁺ phenotype) and aggressive CD8⁺ T-cell lymphomas (AETCLs) can both share identical histopathology, but differ in the clinical appearance. (Pagetoid reticulosis presents as a solitary lesion in the acral location and AETCL presents as multiple ulcero-nodular lesions in similar locations)

Another caveat in the differential diagnosis of CTCL is that histopathology is often not correlative with clinical course. For example, aggressive-appearing histopathology is seen in clinically indolent entities such as LyP, PC-ALCL. Inversely, biopsies from Sézary syndrome (SS) patients often show nonspecific findings, such as lack of epidermotropism and preserved CD7 expression, even though the prognosis of SS is dismal, with less than 50% survival rates at 5 years. Cases of adult T-cell leukemia lymphoma (ATLL) are frequently associated with a skin involvement and histologically resemble patch and plaque stage of MF, with sparse infiltrates lacking large cell component. Cutaneous involvement by systemic peripheral T-cell lymphomas is often associated with an aggressive clinical course. Skin rashes occur in nearly 75% of patients with angioimmunoblastic T-cell lymphoma (AITL).¹² While direct cutaneous extension of AITL can occur, the majority of patients show features of nonspecific perivascular dermatitis.¹³ T-cell prolymphocytic leukemia might clinically resemble rosacea, as involvement of the head and neck area is very common.^14,15,16 Nonetheless, the disease has an aggressive clinical course.

The location, appearance, and chronology of the lesions are important clues for diagnosis. Conventional MF typically presents on the trunk and buttocks (sun-protected areas).^17,18 The most common sites of involvement of folliculotropic MF are the head, neck, and upper back.¹⁹ Syringotropic MF as well as solitary PR has predilections for the distal extremities.²⁰ Most lesions have the appearance of a patch or a plaque, with hyper- or hypopigmentation. Some cases can also show a poikilodermatous appearance. Hypopigmented MF is more common in children and has a CD8⁺ phenotype.²¹ Notoriously, while adult follicular MF has a worse prognosis, its occurrence in children does not have a more aggressive correlate. LyP usually presents as grouped papular or papulonecrotic areas in the trunk and extremities. The lesions tend to develop as relapsing and remitting crops in different stages of evolution.²² PC-ALCL has the clinical appearance of ulcerated tumors or nodules in the head and neck, trunk, and extremities. Spontaneous resolution has been reported in up to 20% of cases.²³ In SS, there is generalized erythroderma with intense and severe pruritus with diffuse scaling and very frequent nail changes. Generalized erythroderma is not exclusive to lymphomas, as psoriasis, drug eruptions, and eczema can also present similarly.^24,25 The small- to medium-sized CD4⁺ T-cell lymphoma (SMPTCL) usually presents in the head and neck region, as an isolated papule, plaque, or nodule.²⁶ Nodules in the trunk and extremities with a panniculitic picture are the frequent clinical characteristics of the lesions of subcutaneous panniculitis-like T-cell lymphoma (SPTCL), but such findings can also be present in inflammatory panniculitides.²⁷ Among the aggressive CTCLs are AETCL and primary cutaneous γδ T-cell lymphoma (PCGDTCL); ulcerated nodules, plaques and tumors, in the trunk, acral sites (AETCL), and extremities^28,29,30 are the typical clinical presentations. The systemic T-cell lymphomas do not show a characteristic clinical appearance other than tumors and nodules, but patients with T-PLL have frequent facial involvement.