Continuing Education Activity

Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell neoplastic entities impacting millions of individuals worldwide annually. In 2018, the World Health Organization updated the diagnostic criteria for the various subtypes of this group of tumors to assist dermatologists and pathologists in classifying them. Cutaneous B-cell lymphomas (CBCLs) are often distinguished clinically by their indolent behavior. Prominent dermal B cell infiltrates are often present, which is remarkable because B cell collections are not typically found in normal skin and are rarely observed in reactive conditions or other types of CL. The following activity outlines the evaluation of these tumors and highlights many pathologic underpinnings when managing patients with primary cutaneous lymphomas.

Objectives:

• Identify all subtypes of cutaneous T- and B-cell lymphomas according to updated World Health Organization guidelines.
• Summarize general histopathologic features of cutaneous T- and B-cell lymphomas.
• Outline immunophenotypic and molecular findings of cutaneous lymphomas.
• Review pertinent clinicopathologic findings associated with different cutaneous T- and B-cell lymphomas.

Introduction

Primary cutaneous lymphomas (CLs) are a heterogeneous group of skin-based non-Hodgkin lymphomas lacking extracutaneous manifestations at the time of diagnosis and are the second most common form of extranodal lymphomas.[1] 

In 2018, the World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) published an updated classification of CLs in the fourth edition of the WHO Classification of Skin Tumors Blue Book, which serves as the gold standard in the diagnosis.[2] CLs more frequently originate from a T-cell than a B-cell lineage.[3] In the Western world, cutaneous T-cell lymphomas (CTCLs) make up approximately 75% of all CL, with the majority classified as Mycosis fungoides (MF).[4] Around 6.4 per million persons worldwide are affected by CTCL, and the likelihood of the disease increases significantly with age.[5] The median age of diagnosis is approximately 54 years old, although rarely, it may occur in children and adolescents.[6][7] 

Patients with CTCL have increased risks of secondary cancers such as other non-Hodgkin lymphomas, melanoma, lung cancer, and bladder cancer.[8] When neoplastic MF cells are found in the blood, the condition is known as Sézary syndrome.[9] CLs are often complex and require clinical evaluation, light microscopic examination, immunohistochemistry analysis, and molecular work-up of skin biopsies.[10]

Cutaneous B-cell lymphomas (CBCLs) are often distinguished clinically by their indolent behavior. Prominent dermal B cell infiltrates are often present, which is remarkable in that B cell collections are not typically found in normal skin and are rarely observed in reactive conditions or other types of CL.[11]

A complete list of both CTCL and CBCL diagnoses according to the 2018 WHO-EORTC is listed below with respective abbreviations, which will be used throughout the rest of this chapter. Provisional diagnoses are included:[2]

Cutaneous T-cell Lymphoma  

• Mycosis fungoides (MF)
• MF variants
  • Folliculotropic MF (FMF)
  • Pagetoid reticulosis (PR)
  • Granulomatous slack skin (GSS)/Granulomatous mycosis fungoides
• Sézary syndrome (SS)
• Adult T-cell leukemia/lymphoma (ATL)
• Primary cutaneous CD30+ lymphoproliferative disorders
  • Primary cutaneous anaplastic large cell lymphoma (C-ALCL)
  • Lymphomatoid papulosis (LyP)
  • Large cell transformation of mycosis fungoides
• Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
• Extranodal natural killer (NK)-cell/T-cell lymphoma, nasal type
• Primary cutaneous peripheral T-cell lymphoma, rare subtypes
  • Primary cutaneous gamma/delta T-cell lymphoma (PCGDTL)
  • Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (CD8+ AECTCL, provisional)
  • Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (CD4+SMT-LPD, provisional)
  • Primary cutaneous acral CD8+ T-cell lymphoma (provisional)
  • Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (NOS)

Cutaneous B-cell Lymphoma

• Primary cutaneous marginal zone lymphoma (PCMZL)
• Primary cutaneous follicle center cell lymphoma (PCFCL)
• Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBLC, LT)
• EBV+ mucocutaneous ulcer (EBVMCU, provisional)
• Intravascular large B-cell lymphoma (IVBCL)

Issues of Concern

According to the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study published in 2020, patient characteristics associated with a significant decrease in quality of life (QoL) in MF/SS include newly diagnosed women and those with alopecia and confluent erythema.[12] 

In 2021, a published study of one-on-one patient interviews suggests that those with CTCL, such as MF, often report sleep interference, lack of understanding of their disease, feelings of uncertainty, depression, hopelessness, treatment/tumor burden, and sometimes suicidal thoughts.[13] Overall diminished health-related QoL occurs in both patients with CTCL and CBCL, especially those with advanced-stage disease, and this is well-reviewed in current literature.[14]

Causes

UV radiation is a risk factor for CTCL, given multiple studies supporting genetic evidence.[15][16][17] Except for adult T-cell leukemia/lymphoma (ATL), which is an aggressive peripheral T-cell lymphoma caused by the human T-lymphotropic virus type-1 (HTLV-1) and presents with skin findings in about half of cases, epidemiologic studies have failed to identify or associate environmental or viral causes of most CTCL subtypes.[18][19] However, certain medications, such as hydrochlorothiazide, may induce significant antigen-driven CTCL after chronic exposure (i.e., greater than one year).[20][21][20] 

As with most cases of CL/CTCL, the cause of CBCL is yet to be fully understood. However, chronic antigen stimulation is a potential etiology,[22] perhaps due to specific infectious agents like Borrelia burgdorferi, Helicobacter pylori, and Epstein-Barr virus.[23][24][25][26]

Anatomical Pathology

Histology is vital in the diagnostic evaluation and work-up of cutaneous lymphoma, and unique growth patterns exist between CTCL and CBCL. The former often demonstrate atypical T-cell lymphocyte infiltration of the epidermis (epidermotropism), whereas the latter typically presents with dense dermal B-cell lymphocyte infiltrates (as described above) without significant epidermal involvement.[11][27] 

Six major anatomic/histologic patterns occur in CL: epidermotropic, nodular, diffuse, subcutaneous, angiocentric/angioinvasive, and intravascular. Epidermotropic infiltrates are commonly found in the initial stages of most CTCL (e.g., MF, patch, and plaque stage). In contrast, nodular and diffuse infiltrates are more common in later CTCL stages (e.g., MF, tumor stage) and CBCL. Subcutaneous growth suggests sub-dermal CL (e.g., SPTCL). Angiocentric/angioinvasive infiltrates are seen mainly in primary cutaneous gamma/delta and aggressive NK-cell/T-cell CLs but may also be present in less-aggressive CD30+ T-cell lymphoproliferative disorders (e.g., LyP, Type E). Intravascular growth, finally, can be seen in intravascular anaplastic large cell, large B-cell, NK-cell, or pseudolymphomas.[27]

Because of overlapping histologic features and growth patterns, immunohistochemistry (IHC, or immunophenotyping) is necessary for further CL subtyping. Anatomic features with respective IHC for each 2018 WHO-EORTC subtype are summarized below:

Cutaneous T-cell Lymphoma

MF/SS: Band-like papillary dermal infiltrate with epidermotropism (patch stage) and formation of Pautrier's microabscesses (collection of atypical lymphocytes in the epidermis), atypical lymphocytes with 'cerebriform' nuclei in the upper dermis and epidermis (plaque stage), or diffuse dermal lymphocyte infiltrate (tumor stage). Lymphocytes may tag along the dermo-epidermal junction. Reactive, inflammatory skin changes (e.g., spongiosis) are typically absent.[28] The papillary dermis exhibits wiry collagen. IHC: CD3+, CD4+, CD5+/-, CD7-, CD25+/-, CD30+/-, CD56-, CCR4+.[29]

MF Variants

• FMF: Atypical lymphocyte infiltrate surrounding hair follicles (folliculotropism) with follicular mucinosis. Hair follicles may be intact, destructed, or have cysts with or without basaloid folliculolymphoid hyperplasia. It may be accompanied by eosinophils, granulomatous dermatitis, or perieccrine infiltrates (syringotropism).[30][31] IHC: CD3+, CD4+, CD8-, with an elevated CD4:CD8 ratio (6-10:1); CD30 may be positive in large cell transformation.[31][32] 
• PR: Epidermal atypical mononuclear (pagetoid) cell hyperplasia with eosinophilic cytoplasm. A dermal mixed inflammatory infiltrate with or without CD8+ epidermotropism may also be present. IHC: variable CD4, CD8, and CD30 expression; Ki-67/MIB1 may show active proliferation but is not specific.[33][34][35] 
• GSS: Diffuse loss of elastic fibers, non-caseating granulomatous T-cell infiltrates in the upper dermis, and multinucleated giant cells may all be present.[36][37] IHC: CD4+/45RO+/30+; multinucleated giant cells, often CD68+, and may have surrounding CD1a+ cells.[38][39][40]

ATL: Dermal tumor cell lymphocyte infiltrate with occasional epidermotropism. Patterns may vary from resembling MF to C-ALCL, or peripheral T-cell lymphoma, NOS.[29][41] IHC: CD3+, CD5+, CD45RO+, CD8+/-, CD25+/-, CD30+/-, CD7-, CD20-, CD79a-; elevated Ki-67 may be present in more aggressive forms of ATL.[42]

Primary cutaneous CD30+ lymphoproliferative disorders

• C-ALCL: Large, irregular polygonal lymphocytes in sheets throughout the dermis. Epidermotropism with or without subcutaneous or adnexal involvement may be present. Cutaneous lymphatic infiltration may be present. The "hallmark" feature of eosinophilic cells with horseshoe nuclei is not always present. IHC: CD30+ membranous and Golgi pattern expression in over 75% of tumor cells. Cytotoxic phenotype (i.e., CD8, TIA-1, granzyme, perforin) positivity may occur in angioinvasive cases.[2][43][44]
• LyP: (Type A) Wedge-shaped CD30+ tumor cells in scattered or clustered patterns with a mixed inflammatory infiltrate. (Type B) Epidermotropic CD30+/- tumor cells with cerebriform nuclei (resembling MF). (Type C) Sheets of large CD30+ atypical lymphoid cells with minimal reactive inflammatory cells. (Type D) Epidermotropic small- to medium-sized CD8+ and CD30+ tumor cells (resembling CD8+ AECTCL). (Type E) Large necrotic "eschar"-like lesions with angioinvasion secondary to CD8+ and CD30+ co-expressed atypical lymphocytes. IHC: CD3+, CD4+, CD25+, CD30+, CD45RO+, CD56+/-, CD2-, CD3-, CD5-, CD7-. CD8 positivity, as opposed to CD4, is more frequently seen in Type D and Type E.[2][45]

SPTCL: Lobular panniculitis with atypical lymphocyte infiltrate. IHC: CD3+, CD4-, CD8+, CD56-, Ki-67+, cytotoxic granules+, EBER-ISH-.[29]

Extranodal NK-cell/T-cell lymphoma, nasal type: Pleomorphic atypical lymphoid cells primarily limited to subcutis with angioinvasion and extensive connective tissue/blood vessel necrosis. IHC: CD3+, cytotoxic granules+, CD56+, CD43+/-, CD45RO+/-, CD4-, CD8-, CD16-, CD57-.[46] 

CAEBV infection: Cutaneous and subcutaneous adipocyte necrosis with septal atypical lymphocyte infiltrate; Reed Sternberg-like cells may be present in an NK-cell variant.[47] IHC: EBV+ lymphocytes with EBER positive signaling (>100/HPF); atypical T-cells may express CD3, CD4, CD5, CD7, CD8, TIA-1, or GRB (negative for CD2, CD56); Ki-67 positivity may show active proliferation.[48] 

Primary cutaneous peripheral T-cell lymphoma, rare subtypes

• PCGDTL (provisional): Atypical lymphocyte infiltrate in the dermis and subcutis with occasional epidermotropism. IHC: CD3+, CD4-, CD5-, CD8+/-, cytotoxic granules+; T cell receptor (TCR)-γδ+ (TCR-αβ-).[29][49][29]
• CD8+ AECTCL (provisional): Marked CD8+ epidermotropism with diffuse dermal atypical lymphocyte infiltrate. IHC: CD3+, CD4-, CD5-, CD8+, CD30-, cytotoxic granules+, EBER-ISH-.[29][49][29] 
• CD4+ SMT-LPD (provisional): Nodular to diffuse atypical dermal lymphocytes without epidermotropism and surrounded by a mixed inflammatory infiltrate. IHC: CD3+, CD4+, PD-1+, BCL6+, CXCL3+, CD8-, cytotoxic granules-.[29][49][29]
• Primary cutaneous acral CD8+ T-cell lymphoma (provisional): Diffuse dermal atypical lymphocyte infiltrate without epidermotropism. IHC: CD3+, CD8+, CD4-, CD30-, CD56-, TIA-1+, EBER-ISH-.[29][49][29]
• Primary cutaneous peripheral T-cell lymphoma, NOS: Remaining aggressive T-cell lymphoproliferative histologic entities which do not fit other established CTCL categories (namely CD4+ SMT-LPD, CD8+ AECTCL, and PCGDTL).[49][50] 

Cutaneous B-cell Lymphoma

PCMZL: Nodular or diffuse dermal lymphoplasmacytoid or monocytoid marginal zone B-cells with or without T-cells. Lymphoid follicles may be present. IHC: CD20+, CD79a+, BCL2+, BCL6-, CD5-, CD10-, CD16-.[29][49]  

PCFCL: Dense proliferation of neoplastic follicular central B-cells ("centrocytes") separated from the epidermis by Grenz zone and exhibit background dendritic meshwork. The Ki-67 proliferation index is low. It may have surrounding reactive T-cells. IHC: CD19+, CD20+, CD22+, CD79a+, PAX5+, BCL6+, CD10+/-, BCL2-.[51]

PCDLBLC, LT: Diffuse dermal sheets of monomorphic large B-cells with open chromatin and prominent nucleoli. The proliferation lacks background dendritic meshwork and shows a high proliferation index. IHC: CD19+, CD20+, CD22+, CD79a+, PAX-5+, BCL2+, IRF4/MUM-1+, FOXP1+.[52] 

EBVMCU (provisional): EBV+ atypical large B-cells resemble the appearance of DLBCL and classic Hodgkin lymphoma. A mixed inflammatory infiltrate may be present. Reactive T-cells may surround B-cell clusters. IHC: CD15+, CD30+, CD19+, CD22+, CD79a+, PAX-5+, EBV+, IRF4/MUM-1+, CD20+/-, CD10-, BCL6-.[2] 

IVBCL: Large atypical B-cells with large nuclei and varying nucleoli demonstrating intravascular proliferation/destruction. IHC: CD79a+, CD20+, IRF4/MUM-1+, CD5+/-, CD10+/- , CD29-, CD54-.[53]

Clinical Pathology

T- and B-cell clonality studies are necessary ancillary tests to support the diagnosis of CTCL and CBCL, respectively, especially when distinguishing hyperplasia from monoclonality. The use of primers against gene targets such as IGH, IGK, IGL, TRG, and TRB is up to 90% sensitive in detecting most types of CL. However, these tests must be used alongside clinical, histologic, morphologic, and immunophenotypic data.

Clinical following may be indicated in certain patients whose clinical and anatomic pathologic findings do not correlate initially with cutaneous lymphoma. Dermatopathologists may ask for new samples from skin biopsies of different lesion sites when uncertain. Linking results of gene rearrangements in skin biopsies with results of peripheral blood samples may increase the reliability of these tests as well.[54]

Although circulating atypical Sézary cells may be found in cases of MF, peripheral blood smear evaluation is necessary for patients with suspected SS (e.g., older-aged, erythrodermic, lymphadenopathy, generalized pruritus).[55] Furthermore, biomarker positivity for PD1 (CD279) and KIRLD2 (CD158k) can provide additional data that me help in differentiating SS from other erythrodermic inflammatory dermatoses in the skin and peripheral blood.[2][56][57] 

Alongside establishing definitive atypical, neoplastic T-cell monoclonal populations in the skin and blood, an absolute Sézary cell count of >1000/microliter in the peripheral blood with expanded CD4+ T cell population resulting in a CD4/CD8 ratio ≥ 10, CD4+/CD7- cells ≥ 30%, or CD4+/CD26− cells ≥ 40% is necessary to establish a diagnosis of SS, according to the 2018 WHO-EORTC.[2]

In patients with suspected ATL, peripheral blood smear showing “flower” or “cloverleaf” cells (polylobated T-cells with condensed chromatin) is pathognomonic. HTLV-1 infection should be confirmed by ELISA (highest sensitivity), western blot, or PCR. Recommended cytologic panel evaluation includes CD3, CD4, CD5, CD7, CD8, CD25, and CD30.[58][59][58] Patients with EBV-associated CL (e.g., CAEBV infection, EBVMCU, extranodal NK-cell/T-cell lymphoma, nasal type) require confirmation of viral infection for definitive diagnoses as well.[60]

In patients with CBCL and lymphocytosis, peripheral blood flow cytometry is recommended, as well as bone marrow biopsy for those with disseminated skin disease or lymphadenopathy. In any patient with PCDLBCL-LT, both peripheral blood flow cytometry and bone marrow biopsy are recommended, given this condition’s poor prognosis compared to other CBCL sub-types (5-year survival of about 50%).[49]

Biochemical and Genetic Pathology

Although monoclonality by molecular analysis may help diagnose cutaneous lymphoma, its presence does not necessarily mean a malignancy, nor does its absence rule it out.[27] Analysis of antigen receptor genes (ARG) via rearrangement studies, such as IGH, are functional assays to help determine and distinguish CL from other lymphoproliferative entities.[61] 

Targeting mutations in genes involved in the MYC, BCL6, NF-κB, and JAK-STAT signaling pathways, among others, may assist and serve as critical ancillary tests when working-up CTCL and CBCL.[2][62] Several notable markers are mentioned in this chapter's "Clinical Pathology" section. This aspect of CL evaluation is continually evolving as more research is carried out to understand the underlying etiologies.

Clinicopathologic Correlations

Clinicopathology correlation is essential when establishing a cutaneous lymphoma subtype diagnosis since most CLs demonstrate similar histology and immunophenotypes.[27]

Cutaneous T-cell Lymphoma

MF: Presents as erythematous patches, plaques, tumors, or erythrodermic “stages,” most frequently involving non-sun-exposed “bathing suit” areas in older individuals. Lesions may accompany epidermal atrophy, scaling, or pruritis. Hypo- or hyper-pigmented patches/plaques may both be seen, especially in patients with skin of color. It rarely presents in children or adolescents (MF variants are more common in this population).[63][64]

MF Variants

• FMF: Presents as grouped erythematous patches, plaques, and tumors accentuated around follicles on the neck and face (especially eyebrows). Patients often have alopecia (up to 81%), comedones, or rosacea-like skin changes. Although the mean age of onset is from 46 to 59 years old (in men more than women), FMF is a common variant of juvenile MF.[65]
• PR: Localized PR, also known as Woringer-Klopp disease (WKD), presents as solitary, hyperkeratotic verrucous, or psoriasiform plaques on the extremities of patients between their third and sixth decades of life. Like FMF, PR may show in pediatric individuals.[34][66] Widespread PR is referred to as Ketron-Goodman disease and is more aggressive. Ketron-Goodman disease and metastatic PR are more challenging to treat and have higher mortality rates.[67][68]
• GSS: Presents as erythematous, pruritic lax skin and wrinkles, mainly in flexure/axillary regions in men during their third to fourth decades of life. Plaques may be violaceous with atrophy and have mild desquamation.[36][37] 

SS: Presents more frequently in older persons as generalized erythroderma (i.e., greater than 80% body surface area) with exfoliation, edema, pruritus, or lichenification. Lymphadenopathy is common.[9] Skin classification, stage of disease, elevated LDH, advanced age, comorbidities, race, male sex, peripheral eosinophilia, and large cell transformation are all associated with a worse prognosis.[69]

ATL: Presents as large, rapidly growing cutaneous papules, nodules, or tumors.[70] ATL is caused by HTLV-1, which affects around 10 million people worldwide annually. It is endemic in the north and south of Japan, the Caribbeans, Africa, the Middle East, South America, and Central America. Rapidly progressive disease is associated with chemotherapeutic resistance, immunosuppression, and an overall poor prognosis.[71][72][73]

Primary cutaneous CD30+ lymphoproliferative disorders

• C-ALCL: Presents as solitary, grouped, or multifocal (approximately 20% of the time) nodules or tumors that often persist for at least 3 to 4 weeks. Superficial ulceration may be present and frequently involves the extremities and face (less commonly the trunk). Cutaneous relapse may occur, and partial or complete regression happens in about 25% of patients. Most commonly, C-ALCL arises in patients between 50 to 70 years old but may occur in some pediatric populations.[43][74] Leg, extensive skin, muscle, and deep fascia involvement all correlate with a poorer prognosis.[75][76][77]
• LyP: Presents as a benign, chronic, and often relapsing papulonodular eruption over the face, trunk, or limbs. Post-inflammatory hypopigmented macules and atrophic scars in sites of spontaneous resolution may occur.[45] Older age and T-cell monoclonality are significant risk factors for secondary disease/cutaneous lymphoid malignancies (such as MF, C-ALCL, and Hodgkin lymphoma).[78][79][78]

SPTCL: Often presents as multiple, relapsing, self-healing subcutaneous nodules on the trunk or extremities. Nodules are painless and may appear in the same or different skin locations. About 75% of patients have multifocal skin involvement. Associations of SPTCL include serosal effusions, hemophagocytosis, and pancytopenia.[80]

Extranodal NK-cell/T-cell lymphoma, nasal type: Often presents as ulcerating, necrotizing, or destructive lesions on the midface, nose, or upper airways. Surrounding edema and erythema may frequently occur. It is most common in Asia and Latin American geographic regions and among similar heritage groups. Positive EBV detection via in situ hybridization (ISH) is necessary to confirm the diagnosis.[46]

CAEBV infection: According to the 2018 WHO-EORTC, this diagnosis includes EBV+ lymphoproliferative disorders (LPD) in childhood, which has two sub-classifications: hydroa vacciniform-like LPD (HV-like LPD) and severe mosquito bite allergy (sMBA).[81][82]

• HV-like LPD: Presents as a papulovesicular eruption on sun-exposed skin areas (e.g., face, ear lobes, back of hands) with or without systemic symptoms (e.g., fever, lymphadenopathy). Extensive non-sun-exposed skin involvement, facial swelling, and extensive ulcers may suggest the severity of the disease.
• sMBA: Presents as ulceronecrotic lesions at the site of mosquito bites with similar systemic symptoms as seen in patients with HV-like LPD. This condition is most common in children and young adults, and patients of Asian or Hispanic descent.

Primary cutaneous peripheral T-cell lymphoma, rare subtypes

• PCGDTL (provisional): May present as diffuse superficial patches and plaques on the extremities with or without facial tumor ulceration. Lesions may appear similar to Pyoderma gangrenosum on the legs, deep nodules on the trunk, or in conjunction with MF-like plaques on non-sun-exposed skin areas. It is more likely to present in adults aged 40 to 70 and has a poor prognosis.[83]
• CD8+ AECTCL (provisional): May present as Pyoderma gangrenosum-like lesions or PR-like patches and plaques with hyperkeratosis. Lesions may appear as annular or erythematous widespread papules, plaques, and ulcerated tumors without precursor lesions. They tend to appear suddenly and rapidly within weeks to months and may be locally aggressive. They occur most commonly on acral skin surfaces; oral involvement indicates a poor prognosis. The age of presentation is broad, from young adults to the elderly.[84]
• CD4+SMT-LPD (provisional): Commonly presents as asymptomatic, solitary, slow-growing violaceous or erythematous papules, plaques, nodules, or tumors. Most cases involve the head and neck, followed by the trunk and upper extremities. Pain or pruritus may occur, but ulceration is rare. Although these occur predominately in elderly persons in the sixth and seventh decades of life, pediatric patients may also be affected.[85]
• Primary cutaneous acral CD8+ T-cell lymphoma (provisional): Presents most commonly in adult males older than 50 as solitary, slow-growing nodules on the ear, although they may occur on the nose, hands, and feet. Symmetric skin involvement is not uncommon, and this disease exhibits an indolent course.[86]
• Primary cutaneous peripheral T-cell lymphoma, NOS: May present as solitary erythematous to violaceous tumors or nodules throughout the body. Ulceration and subsequent infection may occur, and rapid dissemination with systemic symptoms is not uncommon. The prognosis is abysmal, with a five-year disease survival rate of less than 20%, and is more likely to appear in older adults/elderly persons.[50]

Cutaneous B-cell Lymphoma

PCMZL: Typically presents as pink, red, or violaceous papules, plaques, or nodules. They commonly occur on the arms or trunk instead of the head and neck and predominately appear in adult males 50 to 60. However, they frequently appear as rare cases of CL among children and adolescents.[87]

PCFCL: Presents as one or more localized, erythematous papules, plaques, or tumors on the scalp, forehead, or trunk of adult males 50 to 60 years old.[51] 

PCDLBLC, LT: Often presents as rapidly developing red to plum nodules or tumors on one or both legs of older women (median age of diagnosis is 70 years old). This condition frequently spreads to extracutaneous sites, namely lymph nodes and bone marrow, and warrants further hematopathology evaluation due to its poor prognosis.[52] 

EBVMCU (provisional): Appears as shallow, well-circumscribed mucosal or cutaneous ulcers with indolent disease progression. Most patients experience spontaneous regression. The median patient age upon presentation is around 66 years old, with a slight female predominance.[88]

IVBCL: A rare subtype of DLBCL with intravascular involvement leading to blood vessel destruction and necrosis. Lesions may present anywhere in the body, but skin involvement is more common in persons of Western populations. Constitutional B symptoms may also occur. Disseminated disease most commonly affects elderly persons around 70 years old without gender predilection.[53]

Clinical Significance

In light of discussions from the 2021 Clinical Advisory Committee (CAC) and recognition of updated WHO guidelines, the 2022 International Consensus Classification (ICC) of lymphomas continues to acknowledge the frequent evolution of CL subtype classification.

Clinically, accurate diagnosis of which cutaneous lymphoma subtype is present is essential as different entities have varying expected behavioral patterns and prognostic implications. Practitioners should understand that many CL subtypes have overlapping histopathologic features, which is significant as dermatopathologists rely heavily on the presentation and features of clinical lesions (i.e., clinicopathologic correlation) to determine the most accurate CL subtype diagnosis for each patient.

Although a complete understanding of CL is yet to be determined, continued collaborative extensive cohort studies and advances in biomolecular detective technology (i.e., genetic, epigenetic) may help dermatopathologists, dermatologists, and other practitioners in characterizing and further subclassifying these various entities to provide outstanding patient care.[89]