Comprehensive Notes: Spectrum and Classification of Cutaneous Pseudolymphomas

Spectrum of Cutaneous Pseudolymphomas — Comprehensive Study Notes

  • Source context

    • Based on a collection of slides from the 17th Summer Academy of Dermatopathology (Graz, 2025) focusing on the spectrum of cutaneous pseudolymphomas (PSL).
    • PSLs are lymphocytic infiltrates that histopathologically and/or clinically simulate lymphomas, with multiple etiologies and clinical presentations.
    • Etiologies span infections, drugs, and foreign agents; in many cases no trigger is identified (idiopathic PSL).
    • Four main histopathologic/clinical groupings used in the literature:
    • (a) nodular PSL,
    • (b) pseudo mycosis fungoides (pseudo‑MF) and simulators of other CTCLs,
    • (c) other PSL (distinct clinical entities),
    • (d) intravascular PSL.

  • Definitions and key concepts

    • PSL: reactive lymphoproliferative process that mimics lymphoma in skin, requiring clinical-pathologic correlation for accurate diagnosis.
    • Benign vs malignant: PSLs are non-neoplastic but can closely resemble malignant CTCLs or B-cell lymphomas; clonality testing aids interpretation.
    • Important histopathologic clue is the pattern of infiltrate (band-like vs nodular) and the phenotype of the dominant lymphocyte population (T-cell vs B-cell).
    • Clonality testing is essential in many cases to distinguish reactive PSL from true lymphoma; TCR gene rearrangement by PCR is commonly used.

  • Etiology and epidemiology (major categories)

    • Infections (most prominent categories): Borrelia burgdorferi-related and other infectious triggers.
    • Drugs: diverse medications can trigger PSL; includes anticonvulsants, antihypertensives, antidepressants, monoclonal antibodies, etc.
    • Foreign agents: tattoos, vaccines/SIT (specific immunotherapy), arthropod bites (e.g., Borrelia bite reactions as a trigger), and other external stimuli.
    • Post-viral/HIV infections: a smaller but notable category.
    • Other/idiopathic PSL: no identifiable trigger.
    • Approximate distribution of etiologies (from the summarized figure in the slides):
    • Borrelia: ~29%
    • Tattoo: ~26%
    • Drugs: ~16%
    • Post-viral/HIV: ~4%
    • Bites/arthropod-related (e.g., scabies, hirudo): ~9%
    • Vaccines/SIT: ~9%
    • Other: ~7%

  • Histopathologic remarks (general patterns and clues)

    • PSL can show a band-like T-cell infiltrate with intraepidermal lymphocytes in many contexts; this is not specific for MF or CTCLs and can be seen in lichenoid dermatoses and other inflammatory diseases.
    • B-cell PSLs typically show a prominent reactive lymphocyte population with possible nodular aggregates; neoplastic populations must be identified to avoid misclassification.
    • Key diagnostic element: identification and characterization of the neoplastic population (phenotype, proliferation pattern).
    • Kappa/lambda light-chain ratio and clonality assessment:
    • κ/λ ratio=10:1\kappa/\lambda\text{ ratio} = 10:1 for detection of monoclonality; λ/κ=4:1\lambda/\kappa = 4:1 is another referenced ratio; these assist in identifying monoclonal B-cell populations.

  • Mimickers of mycosis fungoides (MF) and other CTCLs

    • A diverse list of mimickers can resemble MF histologically or clinically, including:
    • Lichen aureus, Actinic reticuloid, Lichen planus, Non-MF-associated follicular mucinosis, Eczematous dermatoses (including LE, superficial variants), Lymphomatoid keratosis, Psoriasis, Bullous pemphigoid, Superficial idiopathic PSL, Lichen sclerosus (genital), Annular lichenoid dermatitis of youth, Vitiligo (inflammatory stage), Drug eruptions (CD8+ T-cell dermatitis in HIV+), Tattoos (lichenoid type CD8+ dermatitis in mogamulizumab-treated patients), Lichen striatus, Pityriasis lichenoides, Syphilis, HTLV‑I infectious dermatitis, and others.
    • Genital lichen sclerosus (LSA) can display MF-like features and epidermotropism, especially in pseudo‑MF genital cases; the epidermotropic cells are often CD8+ predominant; TCR rearrangements can be monoclonal in about half of genital cases.
    • Palmoplantar psoriasis with band-like infiltrates can mimic MF; true MF restricted to palms/soles is rare in the literature, and many such cases may represent psoriasis with a band-like lymphocytic infiltrate rather than MF confined to palms/soles.
    • Lichen sclerosus should be added to the list of cutaneous T-cell PSLs; careful clinicopathologic correlation is essential.

  • Genital LSA and pseudo-MF (key findings)

    • Genital LSA often presents with dense band-like lymphocytic infiltrates; epidermotropic lymphocytes predominate in many genital lesions (~93.6%), but not in extragenital lesions.
    • Immunohistochemistry in genital pseudo‑MF shows CD8+ epidermotropic lymphocytes predominance; TCR gene rearrangement can be monoclonal in about half of cases, suggesting clonal expansions can occur in otherwise non-MF conditions.
    • Conventional LS features (collagen homogenization and sclerosis) are often missing or focal in genital pseudo-MF cases; clinical-pathologic correlation is crucial.
    • 121 reported genital LS cases with dense infiltrates: 94 genital; male-to-female ratio ~93:1; age range 2–87; 93.6% had epidermotropic lymphocytes; monoclonality observed in roughly half of cases.

  • Annular Lichenoid Dermatitis of Youth (ALDY)

    • Clinicopathologic entity described in children/young patients; resembles morphea, annular erythema, vitiligo, or MF clinically, but histology mimics MF.
    • Classical ALDY features: dense lichenoid infiltrate with squaring (necrosis of keratinocytes at rete ridges) and basal vacuolization; polyclonal TCR rearrangement.
    • Benign behavior with spontaneous resolution in many cases; long-term follow-up advisable due to diagnostic confusion with MF.
    • Series reported: 6 cases (ages 10–45); most lesions on trunk (flanks/abdomen); lesions may resolve with or without topical therapy; predominance of CD4+/CD8+ T cells with polyclonal TCR.
    • Suggested renaming: consider “annular lichenoid dermatitis” as a broader entity; differential diagnosis with MF is critical for management.

  • Lichen aureus and related pigmented purpuric dermatoses (PPPD)

    • Lichen aureus is a persistent localized form of PPPD with band-like inflammatory patterns.
    • About 50% show T-cell clonality in the infiltrate; prognosis generally favorable with spontaneous resolution in many cases, though lesions may persist or recur.
    • Some genital cases show epidermotropic lymphocytes and clonality; follow-up advised due to potential clonal dermatoses.
    • A notable study compared SPTCL vs LEP; Ki-67 and CD123 patterns help distinguish nontumorous hypocellular infiltrates from lymphoma-like processes.

  • Seborrheic keratosis (SK) with pseudolymphomatous infiltrate

    • Rare variant where SK lesions harbor a dense lymphoid infiltrate with MF-like features.
    • Immunophenotype can show CD3+ T cells with CD4/CD8 subsets; small CD30-positive cells may be present in the dermis.
    • Case demonstrated response to pegylated interferon alfa-2a plus narrowband UVB; lesion regression observed at 4 months.
    • Important reminder that SK can mimic MF and require clonality testing and clinical correlation to avoid overtreatment.

  • Lymphomatoid drug eruption and lymphomatoid E‑ dermatitis (eczematous variant)

    • Drug eruptions can mimic MF or LyP; band-like lymphoid infiltrates with activated T cells and often high proliferation indices (>90% Ki-67 in some cases).
    • Epidermotropism is usually minimal; cytologic atypia can be striking depending on the agent.
    • CD30+ activated lymphocytes may predominate in perivascular infiltrates; differential includes LyP and cALCL.
    • Lymphomatoid dermatitis features can be CD8+ predominant in eczematous contexts.

  • Lymphomatoid keratosis and other mimickers

    • Lymphomatoid keratosis is listed among mimickers of MF, with overlapping features that can complicate diagnosis.
    • The spectrum includes angiocentric patterns, folliculotropic variants, and LyP-type presentations; morphology alone is insufficient without clinical correlation.

  • HSV/VZV infections and other viral mimickers

    • Herpes infections (HSV-1/2, VZV) can present with dense lymphoid infiltrates and atypical lymphocytes that mimic cutaneous lymphoma.
    • A study of 65 cases demonstrated a spectrum of immunohistochemical outcomes, often T-cell–predominant with variable CD30/CD56 expression; some cases harbored clonal TCR rearrangements by PCR, underscoring diagnostic challenges.
    • In some cases, short-term follow-up and antiviral therapy clarified diagnosis when lesions regressed after treatment.
    • A notable case highlighted a lymphomatoid pattern that persisted on biopsy but resolved with antiviral therapy and/or clinical improvement.

  • Borrelia burgdorferi-associated lymphocytoma cutis (LC) and related LPDs

    • LC is a common cutaneous B-cell PSL in endemic areas; most lesions occur on the nipple, earlobe, or genital regions, with trunk/exremities also described.
    • PCR for Borrelia DNA was positive in about 67% of tested cases (54/80); serology positive for Borrelia in most cases tested.
    • Histology shows dense lymphoid infiltrates with prominent germinal centers; GC atypia can mimic diffuse large B-cell lymphoma when confluent.
    • IgH gene rearrangement: polyclonal in ~31/33 tested; monoclonal in 2 cases; thus clonality does not always imply malignancy in LC.
    • Key diagnostic point: integrate Borrelia serology/PCR, clinical appearance, localization, and clonality data to avoid misdiagnosis.
    • Sites with higher predilection and staged descriptions emphasized nipple predominance and special sites like earlobe and genital areas.

  • Actinic reticuloid (a prototypic T-cell PSL)

    • Clinically can resemble erythroderma; histology may show hyperplastic epidermis with spongiotic changes.
    • Immunophenotype often skewed toward CD8+ T cells in the skin; UV/phototesting helps confirm diagnosis.
    • Considered a prototypic PSL, but many cases do not resemble MF histologically; clinical correlation remains essential.

  • Lupus erythematosus panniculitis (LEP) vs Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL)

    • Distinction is challenging; some cases (SPTCL with LE features) show overlapping lineages and serology.
    • Ki-67 proximal adipocyte rimming: a key distinguishing feature, with high Ki-67 proliferation in SPTCL and lower in LEP.
    • CD123 positive plasmacytoid dendritic cells within subcutaneous lobules are more characteristic of LEP and help differentiate LEP from SPTCL.
    • A notable study examined 19 SPTCL and 17 LE panniculitis specimens; kinetics of periadipocytic proliferation (Ki-67), CD123 patterns, and TCR clonality helped delineate two conditions that may lie on a spectrum.
    • Coexistence of LEP and SPTCL can occur; some authors propose a spectrum model rather than strict separation.

  • Intralymphatic histiocytosis and related intravascular/intralymphatic proliferations

    • Intralymphatic histiocytosis: clusters of histiocytes within lymphatic vessels (CD68+, CD163+); vessels often express podoplanin and endothelial markers.
    • Clinical association with rheumatoid arthritis is common; lesions can be confined to the dermis or subcutaneous tissue with reticulated erythema.
    • Reported cases include various locations and presentations; the condition is generally benign.
    • Intravascular CD30+ T-cell proliferations and related benign/inflammatory variants can mimic intravascular lymphoma; these cases emphasize careful clinicopathologic correlation and consideration of trauma as a trigger.
    • Diagnostic approach emphasizes distinguishing intravascular proliferations from intravascular large B-cell lymphoma (IVL) and other malignant intravascular processes; podoplanin (D2-40) helps exclude intravascular large cell lymphoma when vessels are involved but cells lack overt malignant features.

  • Pseudolymphomas associated with molluscum contagiosum and other infections

    • Molluscum contagiosum can be associated with a pseudolymphomatous infiltrate in a cyst-like lesion, mimicking leukemia cutis; deeper sections revealed molluscum bodies within cornified cells with infiltrates of T-lymphocytes.
    • Other reports describe cutaneous pseudolymphomas in association with molluscum contagiosum and with tattoo- or vaccine-related reactions; these examples highlight the need for thorough histologic evaluation and clinical history to avoid misdiagnosis.

  • Pseudolymphoma triggered by vaccination and aluminum-containing adjuvants

    • EBER (EBV-encoded RNA) in situ hybridization can help differentiate aluminum granulomas/lymphoid hyperplasia from other pseudolymphomas and lymphomas when nodules are subcutaneous and vaccination-related.
    • Aluminum granulomas show characteristic histiocytic aggregates with EBER positivity in the histiocytes, aiding in avoiding misdiagnosis as lymphoma.

  • Pseudolymphoma features in cutaneous malignancies with abundant CD30+ cells (benign CD30+ LPD spectrum)

    • A spectrum exists from reactive inflammatory infiltrates with CD30+ cells to lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma (cALCL).
    • In reactive infiltrates, CD30+ cells can be abundant but are oligoclonal or polyclonal; context and clonality testing are essential to avoid over-diagnosing LPDs.
    • Large CD30+ cells can appear in Milker’s nodules, HSV/VZV infections, leishmaniasis, molluscum contagiosum, leprosy, pernio, and post-vaccination scars; these must be interpreted in light of clinical context.

  • Practical diagnostic pointers and tests

    • Immunophenotyping: assess CD3, CD4, CD8, CD20, CD30, CD56, CD123, TIA-1, etc., to define T- vs B-cell predominance and cytotoxic features.
    • TCR gene rearrangement testing: PCR for TCRγ (and other TCR loci) to assess clonality; monoclonality supports lymphoma but is not exclusive to malignant processes (e.g., genital LS pseudo‑MF may show monoclonality).
    • Ki-67 (MIB-1) proliferation index: useful for distinguishing SPCTL from LEP; SPCTL tends to show higher proliferation within periadipocytic rimming.
    • CD123-positive plasmacytoid dendritic cells within subcutaneous tissue support LEP vs SPTCL distinction.
    • EBER in situ hybridization: helpful in differentiating aluminum-related pseudolymphomas from true lymphomas in post-vaccination nodules and aluminum granulomas.
    • Borrelia serology and PCR: combined approach improves diagnostic accuracy in borrelia-associated PSL; germinal centers may be polyclonal even in LC, with occasional monoclonal clones reported.

  • Notable case types and take-home messages

    • Palmoplantar MF vs psoriasis: palmoplantar MF is not a distinct entity; psoriasis may show MF-like band-like infiltrates, and true palmo-plantar MF is rare.
    • Genital LS with MF-like features requires careful correlation: epidermotropic CD8+ lymphocytes with band-like infiltrates are common; many cases show monoclonality by TCR rearrangement, which does not necessarily indicate MF.
    • ALDY can occur in adults and children; although histology may mimic MF, immunohistochemistry and molecular analysis typically reveal a polyclonal pattern; management should reflect benign prognosis with careful follow-up.
    • Genital LS pseudo-MF often presents with phimosis in young males and may lack typical LS features in biopsy; concordant clinical-pathologic data improve accuracy.
    • LSA and LP variability: the genital setting often carries higher likelihood of MF-like epidermotropism; this underscores site-specific histopathologic variation in PSL.
    • Lymphomatoid drug eruption and HSV infections emphasize that non-neoplastic processes can mimic MF both clinically and histologically; follow-up after drug withdrawal or antiviral therapy is informative.
    • Intralymphatic histiocytosis and related intravascular processes: not malignant but may mimic intravascular lymphoma; vessel-focused immunohistochemistry and context are critical.
    • The role of clonality testing in PSLs is nuanced: monoclonality does not always imply malignancy; many PSLs can be clonal due to limited reactive populations or site-specific factors. Correlate with clinical course and other data.

  • Case-cited insights (highlights from the slides)

    • “Lymphomatoid drug eruption”: Proudly shows MF-like patterns with high Ki-67; CD30+ cells may be prominent; often resolves after stopping the drug.
    • “Lymphomatoid dermatitis (eczematous)” and “Lymphomatoid keratosis” illustrate a spectrum of CTCL-like reactions within inflammatory dermatoses.
    • “Lupus panniculitis with pseudolymphomatous infiltrates” and overlap with SPTCL illustrate spectrum/endpoints between LEP and SPTCL; Ki-67 and CD123 help in differential.
    • “Borrelia burgdorferi-associated lymphocytoma cutis”: 106 cases studied; nipple and earlobe are common sites; polyclonal IgH patterns predominate; a minority show monoclonality; Borrelia testing is integral to diagnosis.
    • “Nevoid hyperkeratosis of the nipple and areola” can mimic MF on histology; multiple cases show MF-like changes; immunophenotype and TCR arrangement help to clarify association with MF vs NHNA.
    • “Pseudolymphomatous reaction to arthropod bite” confirms that arthropod bites can create PSL-like patterns with CD30+ cells, requiring careful evaluation to avoid misdiagnosis as LyP or cALCL.
    • “ALDY” and “ALDY beyond”: six cases demonstrate that ALDY can persist or resolve and may affect adults; immunohistochemistry favors a T-cell infiltrate with a polyclonal TCR.
    • “Seborrheic keratosis with pseudolymphomatous infiltrate” demonstrates MF-like features within SK lesions that improved with systemic therapy.
    • “Intravascular CD30+ T-cell proliferation after trauma” documents a benign reactive intravascular proliferation; important diagnostic pitfall for IVL (intravascular lymphoma).

  • Key concepts to remember for exams and clinical practice

    • PSLs are a diagnostic umbrella for reactive lymphoid skin infiltrates that mimic lymphoma; management hinges on accurate distinction between reactive and malignant processes.
    • Pattern recognition matters: band-like infiltrates trend toward PSLs, while nodular patterns may be B-cell–dominant PSLs.
    • Site-specific mimickers exist (genital LS, palmoplantar psoriasis, genital ALDY, etc.); genital pseudolymphomas require particularly careful clinico-pathologic correlation.
    • Clonality testing is important but not definitive on its own; interpret clonality alongside clinical features, imaging, and follow-up data.
    • The differential diagnosis of PSLs includes infections (HSV/VZV, Borrelia), drugs, and vaccination-related responses; a broad differential reduces misdiagnosis.
    • Distinctions between LEP and SPTCL rely on adipocyte involvement patterns, Ki-67 index, CD123+ plasmacytoid dendritic cells, and TCR clonality; treat as a spectrum when appropriate.
    • Always consider aluminum granulomas and vaccination-related nodules; EBER ISH is a helpful adjunct in distinguishing reactive aluminum-induced lesions from lymphomas.

  • Summary takeaways for exam preparation

    • PSLs are a spectrum of reactive lymphoid infiltrates that may clinically and histologically mimic lymphomas but are primarily non-neoplastic.
    • Four main PSL categories help organize disease: nodular PSL, pseudo-MF/CTCL simulators, non-MF PSLs, and intravascular PSLs.
    • Etiologies are diverse: Borrelia, tattoo, drugs, vaccines/SIT, arthropod bites, post-viral/HIV, and idiopathic cases.
    • Genital LS can masquerade as MF (pseudo-MF), with CD8+ epidermotropism and variable clonality; careful clinicopathologic correlation is essential.
    • ALDY is a pediatric/young-patient entity that mimics MF but is typically polyclonal and benign; long-term follow-up is recommended.
    • Lichen aureus is a PPPD variant with potential clonality; prognosis is usually favorable but follow-up is advised due to clonal possibilities.
    • Drug-induced PSLs are common; drug classes include antihypertensives, anticonvulsants, antidepressants, and monoclonal antibodies; onset median around 120 days; histology often T-cell–predominant with occasional CD30+ cells.
    • HSV/VZV-related PSLs can imitate CTCLs; clonality can be detected by TCR testing in some cases; antiviral treatment and follow-up help clarify diagnosis.
    • Borrelia LC highlights the need for integrating serology, PCR, histology, and IgH clonality data; monoclonality can occur in a predominantly polyclonal background.
    • LEP and SPTCL overlap is possible; Ki-67 and CD123 are helpful adjuncts; recognize the potential for spectrum-like presentations.

  • Key numerical and technical references (LaTeX-ready expressions)

    • Infiltrate patterns and clonality indicators:
    • Band-like T-cell infiltrate with intraepidermal lymphocytes can be seen in PSLs beyond MF: not MF-specific.
    • κ/λ ratio=10:1  (for detection of monoclonality)\kappa/\lambda\text{ ratio} = 10:1\;\text{(for detection of monoclonality)}
    • λ/κ=4:1  (alternative clonality ratio)\lambda/\kappa = 4:1\;\text{(alternative clonality ratio)}
    • Proliferation indices and markers:
    • Ki-67 (MIB-1) proliferation index helps distinguish SPCTL vs LEP; higher index supports SPCTL involvement of adipocytes.
    • CD123+ plasmacytoid dendritic cells within subcutaneous lobules support LEP vs SPTCL distinction.
    • Sites and frequencies (representative data from the lecture content):
    • Genital LS pseudo-MF: monoclonality observed in roughly half the genital cases; 93.6% epidermotropic lymphocytes in genital LS, but not all genital cases show classic LS features on biopsy.
    • Borrelia LC: PCR positive in ~67% of tested cases; serology positive in most; IgH clonality: polyclonal in ~31/33 cases; monoclonal in 2.

  • Suggested exam-oriented study questions

    • Define cutaneous pseudolymphomas and list the four main histopathologic/clinical groups.
    • What are the typical etiologies of PSLs, and which ones are most common according to the lecture data?
    • How can genital lichen sclerosus mimic MF, and what immunohistochemical/molecular tests help differentiate them?
    • Describe the ALDY clinical and histopathologic features and its significance in differential diagnosis with MF.
    • What role does Ki-67 play in distinguishing SPTCL from LEP, and what are the limitations of using clonality alone?
    • How can HSV/VZV infections masquerade as lymphoma, and what tests help prevent misdiagnosis?
    • Explain how Borrelia burgdorferi–associated lymphocytoma cutis can present with clonal or polyclonal patterns on IgH rearrangement and why clinical correlation matters.
    • What is intravascular histiocytosis, and how is it differentiated from intravascular lymphoma?
    • Why is EBER in situ hybridization useful in aluminum-related pseudolymphomas?

  • Final takeaway

    • The spectrum of PSLs is broad and clinically important because management hinges on distinguishing reactive processes from true lymphomas. A careful combination of histopathology, immunophenotyping, TCR clonality testing, site/clinical correlation, and follow-up is essential for accurate diagnosis and appropriate treatment.