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Make notes for md dermatology exam, keeping only the relevant important information on these topics each- mast cells, epidermolytic hyperkeratosis, role on in vitro and patch test in drug reaction, histiocytes and its immunological markers

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Dermatology Exam Notes

1. Mast Cells

Origin & Distribution
  • Derived from pluripotent bone marrow (CD34+) precursors; progenitors circulate in blood, then enter tissues and mature locally.
  • Most abundant at epithelial interfaces (skin, mucosa) - positioned as first-line defense against pathogens/environmental insults.
  • Long-lived (months-years), retain proliferative capacity in tissue.
  • Maturation driven by stem cell factor (SCF/KIT ligand) binding c-kit (CD117), plus IL-3.
  • Two subtypes: mucosal (tryptase-only, MC_T) and connective tissue/skin (tryptase + chymase, MC_TC) mast cells - heterogeneous but both participate in allergic reactions.
Activation
  • Constitutively express high-affinity FcεRI (IgE receptor); antigen cross-linking of surface-bound IgE is the classic trigger for degranulation (even low allergen doses suffice).
  • Also bind IgG via FcγRII.
  • Pattern recognition receptors (TLRs) allow direct pathogen sensing:
    • TLR4 (LPS) -> cytokine production without degranulation
    • TLR2 (peptidoglycan) -> degranulation and cytokine production
  • Other activators: complement (C3a, C5a - anaphylatoxins), neuropeptides (substance P), venom/bacterial toxins.
Granule Contents (preformed mediators)
  • Histamine (main), serotonin
  • Proteases (tryptase, chymase - used as clinical markers of mast cell activation/mastocytosis)
  • TNF-alpha, VEGF
  • Antimicrobial peptides (cathelicidins), chemokines
Mediators generated on activation (de novo)
  • Cytokines: TNF-alpha, IL-3, IL-4, IL-5, IL-6
  • Lipid mediators: leukotrienes, prostaglandins, platelet-activating factor (PAF)
Clinical relevance: central effector cell in urticaria, anaphylaxis, atopic/allergic disease, and mastocytosis (KIT/CD117 mutation, D816V being classic).
  • Fitzpatrick's Dermatology, Vol 1-2

2. Epidermolytic Hyperkeratosis (EHK)

A histologic reaction pattern (not a single disease) - key for exams because it appears across multiple conditions.
Histology - 4 classic components
  1. Clear/vacuolated spaces of varying size surrounding nuclei in stratum spinosum and stratum granulosum
  2. Indistinct cell borders with reticulated, lightly-staining cytoplasmic material
  3. Markedly thickened granular layer with increased, irregularly-shaped basophilic keratohyalin-like granules (coarse)
  4. Compact hyperkeratosis (thick stratum corneum)
  • Basal layer is normal/spared.
  • Ultrastructurally: clumped tonofilament aggregates (perinuclear).
Molecular basis: mutations in keratin 1 (KRT1) or keratin 10 (KRT10) disrupting the keratin intermediate filament network of suprabasal keratinocytes.
Conditions showing EHK on biopsy (high-yield list)
  • Epidermolytic ichthyosis (formerly bullous congenital ichthyosiform erythroderma/Brocq) - generalized, KRT1/KRT10 mutation
  • Epidermolytic palmoplantar keratoderma (EPPK, "Vörner type") - vs non-epidermolytic (Unna-Thost type)
  • Epidermolytic acanthoma (solitary or disseminated) - incidental/localized finding
  • Ichthyosis with confetti, some epidermal nevi (inflammatory linear verrucous type)
  • Can be an incidental finding in follicular cysts, seborrheic keratoses, atypical nevi, actinic keratoses, cutaneous horns
Clinical pearl: When EHK is present histologically (e.g., in porokeratosis-like or keratoderma lesions), oral retinoids can worsen skin fragility/blistering - avoid or use cautiously.
  • Dermatology (Bolognia), 2-Vol Set 5e

3. Role of In Vitro Tests and Patch Testing in Drug Reactions

General principle: Except for specific IgE assays, no in vitro test for drug causality is fully validated - all have limited sensitivity/specificity and are adjuncts, not confirmatory.
In vitro tests
TestWhat it measuresComment
Lymphocyte Transformation Test (LTT)In vitro T-cell proliferation when patient lymphocytes are exposed to graded drug concentrations - detects delayed (T-cell mediated) hypersensitivityMost studied; useful in SJS/TEN and DRESS causality work-up; timing after reaction affects sensitivity (best 1 week-several months post-reaction)
Histamine release testMast cell/basophil histamine release on drug exposureLimited validation
Basophil degranulation/activation testFlow-based basophil activation (CD63/CD203c)Used more in immediate (IgE-mediated) reactions
Migration inhibition factor (MIF) test / leucocyte migration inhibition test (LMIT)Cell-mediated immunity markerHistoric interest, not standard clinical use now
Lymphocyte toxicity assayDirect cytotoxicity of drug/metabolite on lymphocytesResearch use
Specific IgE assaysOnly validated in vitro test category (e.g., for penicillin, some biologics)Only reliable exception among in vitro tests
Patch testing
  • Drug (in petrolatum or alcohol vehicle) applied to upper back, read at 48-96 hours (delayed-type/Type IV reaction).
  • Utility is reaction-pattern dependent - positivity rates vary widely by eruption type:
    • Higher yield: AGEP, DRESS, fixed drug eruption (best tested at the fixed lesion site itself), maculopapular/exanthematous eruptions, SDRIFE (~50% positivity)
    • Low/unreliable yield: SJS/TEN (also concern about triggering relapse - use cautiously)
  • Confounders: concurrent systemic immunosuppressants can cause false negatives - if drug cannot be stopped, minimize dose before testing.
  • Newer FDA-approved patch systems exist for standardized allergen/drug testing.
Complementary in vivo tests
  • Prick and intradermal tests: useful for immediate reactions (urticaria/angioedema) - contraindicated in SJS/TEN (relapse risk).
  • Delayed-reading intradermal test: increasingly used in DRESS when causality is uncertain and pretest probability high; delayed reading also important for amoxicillin-induced morbilliform eruptions.
  • Rechallenge: gold standard for causality but contraindicated after severe cutaneous adverse reactions (SCARs) due to risk of a more severe recurrence; may be considered only in select high-need clinical situations (e.g., essential antituberculous therapy) under specialist supervision. Negative rechallenge does not exclude causality (recurrence is not 100%).
Bottom line for exams: Patch testing has variable, eruption-specific value (best for AGEP/exanthem/FDE, useless/risky in SJS-TEN); in vitro tests (LTT especially) support causality assessment but are not standardized/validated enough for definitive diagnosis; specific IgE is the only well-validated in vitro assay category.
  • Dermatology (Bolognia) 2-Vol Set 5e, Ch. 21 Drug Reactions

4. Histiocytes and Immunological Markers

Histiocytes = tissue macrophages and dendritic cells derived from myeloid precursors; classified into Langerhans cell (L) group, cutaneous/mucocutaneous non-Langerhans (R) group ("xanthogranuloma family"), malignant (M) group, and Rosai-Dorfman disease per revised histiocytosis classification.
Key immunological marker panel (high-yield table)
Cell typePositive markersNegative markers
Langerhans cells / LCHCD1a, S100, Langerin (CD207), Birbeck granules (EM)CD68 often negative/weak
Indeterminate dendritic cell tumorCD1a, S100 (no Birbeck granules)Langerin, CD30, CD163, CD21, CD23, CD35
Plasmacytoid dendritic cellsCD68, CD123-
Follicular dendritic cellsCD21, CD23, CD35-
Juvenile xanthogranuloma (JXG) / non-Langerhans histiocytesCD68, CD163, Factor XIIIa (mature histiocyte/dermal dendrocyte markers); S100 sometimes positive in large cellsCD1a and CD207/Langerin typically negative
Malignant histiocytosis (histiocytic sarcoma)At least 2 of: CD68, CD163, CD4, lysozyme-
Rosai-Dorfman diseaseS100, CD68, CD163CD1a negative (key differentiator from LCH)
Dermatofibroma / fibrous histiocytoma (dermal dendrocyte-derived)Factor XIIIa, CD68 (variable)CD34 usually negative (helps distinguish from DFSP)
Practical exam pearls
  • CD1a + Langerin (CD207) + Birbeck granules = confirms Langerhans cell lineage (LCH).
  • S100 positive but CD1a negative with CD68/CD163 positive -> think Rosai-Dorfman disease or non-Langerhans histiocytosis, not LCH.
  • Factor XIIIa and CD163 are the classic "mature/dermal" histiocyte markers used for JXG and dermatofibroma-type lesions.
  • CD68 is a pan-macrophage/histiocyte marker (least specific, positive in many histiocytic and even some non-histiocytic lesions like giant cell tumors).
  • Diagnosis of malignant histiocytic neoplasms requires panel-based exclusion of lymphoma/melanoma/carcinoma, not a single marker.
  • Dermatology (Bolognia) 2-Vol Set 5e; Harrison's Principles of Internal Medicine, 22nd Ed; Henry's Clinical Diagnosis and Management by Laboratory Methods
Quick recall aid for histiocyte markers: "CD1a + Langerin = Langerhans"; "Factor XIIIa + CD163 = dermal/non-Langerhans (JXG, dermatofibroma)"; "CD68 = everything (non-specific pan-histiocyte marker)."
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