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Palisading macrophages
Giant cell
Horizontal "necrobiosis"
Layer of macrophages
3.6 Granulomatous/Histiocytic Disorders
A
Giant cell
B
Fig. 3.61 Necrobiosis lipoidica. (A) Low magnication. (B) The layered cake appearance of granulomas is often subtle. (From Rapini RP: Noninfectious granulomas. In:
Rapini RP, ed. Practical Dermatopathology. 3rd ed. Philadelphia: Elsevier; 2021:101–118.)
Pathogenesis
• Genetic predisposition (e.g., NOD2) 1 defective microbial
clearance, mucosal compromise or altered gut ora
balance (dysbiosis) → exaggerated Th1 and Th17 response
to gut ora → granulomatous lesions in gut and skin
Clinical features
• Genital Crohn’s: labial or scrotal edema 1 erythema/
ulceration/ssures (Fig. 3.63)
• Perianal Crohn’s: ulcers, sinus tracts, ssures, or eroded
vegetating plaques; lesions frequently extend to perineum,
buttocks, abdomen, and abdominal surgical or ostomy sites
■
Peristomal Crohn’s: ssures and stulae around ostomy
• Oral Crohn’s: “cobblestoning” of buccal mucosa,
pyostomatitis vegetans, cheilitis granulomatosa, gingival
hyperplasia, diffuse oral swelling, ssures, aphthous-like
ulcers, linear ulcers, and small gingival nodules
• Extragenital (“metastatic”) Crohn’s: dusky red papules/
plaques → ulcerations with undermined edges, stulas,
Fig. 3.62 Necrobiotic xanthogranuloma in a patient with a paraproteinemia.
(From Piette WW. Dysproteinemias, plasma cell disorders, and amyloidosis. In:
Callen JP, Jorizzo JL, Zone JJ, etal. Dermatological Signs of Systemic Disease.
5th ed. Philadelphia: Elsevier; 2017:171–182.)
draining sinuses and scarring; most common sites 5
lower extremities/soles (38%) . abdomen/trunk (24%)
. upper extremities (15%), face/lips (11%), exures
(8%), generalized (4%)
155
CHAPTER 3 • General Dermatology
Fig. 3.63 Cutaneous Crohn’s disease. Note the swelling and violaceous discoloration of the labia majora. (From Hagen JW, Swoger JM, Grandinetti LM. Cutaneous manifestations of Crohn disease. Dermatol Clin. 2015;33[3]:417–431.)
Histopathology
• Non-caseating tuberculoid granulomas w/ inammatory
rim of lymphocytes in supercial and deep dermis;
frequent Langhans GCs
Treatment/prognosis
• First line: oral metronidazole, topical/intralesional
steroids, and TCIs
• Severe cases: oral steroids, sulfasalazine, MTX, MMF,
cyclosporine, thalidomide, AZA, 6-MP, and TNF-a inhibitors
• Disease tends to be chronic; severity of cutaneous and GI
disease often not correlated
Sarcoidosis
• Drug-induced sarcoid:
■
Hepatitis C patients on treatment (IFN-a, ribavirin)
■
HIV patients on HAART
■
Other meds: TNF-a inhibitors, vemurafenib,
ipilimumab, and alemtuzumab
Clinical features
• Cutaneous ndings:
■
35% of patients with sarcoidosis develop skin lesions
■
Skin may be the only site of involvement
All patients w/ cutaneous sarcoid require CXR, PFTs,
and regular eye exams
■
Lesions present as red-brown or erythematous papules
and plaques w/ characteristic “apple jelly” color with
diascopy (better appreciated on light-skinned patients)
Lesions typically lack secondary changes
Predilection for face (Fig. 3.64) (especially lips and
nose), neck, and upper half of the body
Lesions often arise within preexisting scars,
piercings, or tattoos
Less common presentations: hypopigmented,
ichthyosiform, angiolupoid (prominent
telangiectasias), psoriasiform, annular, verrucous,
cicatricial alopecia, and erythrodermic
• EN: most important non-specic manifestation of
sarcoidosis since it predicts a benign, self-limited course
• Other areas of involvement:
■
Lung disease (90%): alveolitis, bronchiolitis, and
pleuritis; may culminate in “honeycombing” of lung,
w/ brosis and bronchiectasis
■
Lymphadenopathy (90%): hilar and/or paratracheal;
typically asymptomatic
■
Ocular involvement (20%–50%): anterior uveitis
(most common), retinitis, lacrimal inammation, and
conjunctivitis → may result in blindness
■
Hypercalcemia (10%): due to calcitriol synthesis by
sarcoidal granulomas (convert 25-hyroxyvitamin D
into more active 1,25-dihyroxyvitamin D) →
hypercalcemia, hypercalciuria, and nephrocalcinosis
→ renal failure
■
Other: nail changes (clubbing, onycholysis, and
subungual hyperkeratosis), oral involvement (salivary
Epidemiology
• Bimodal incidence peaks: 25–35 yo and 45–65 yo
• F . M
• African Americans have highest incidence and disease
tends to be more severe/progressive
• ↑ Incidence of cases in spring/winter → environmental/
infectious trigger hypothesis
Pathogenesis
• Multisystem granulomatous disease caused by
upregulation of CD41 Th1 cells
• Genetic predisposition 1 unknown antigen presented by
monocytes with MHC class II molecules → activation of
CD41 Th1 cells → ↑ IL-2, IFN-g, TNF-a, and monocyte
chemotactic factor → monocytes leave circulation and
enter peripheral tissues, including skin, where they form
granulomas → granulomas have potential to result in
end-organ dysfunction
156
Fig. 3.64 Sarcoidosis characteristic papules on the nares. (From James WD,
Berger TG, Elston DM, Neuhaus IM. Macrophage/Monocyte disorders. In: An-
drews’ Diseases of the Skin. 12th ed. Philadelphia: Elsevier; 2016:699–725.)
3.6 Granulomatous/Histiocytic Disorders
Table 3.18 Sarcoid Variants
Lupus pernio
Darier-Roussy Subcutaneous sarcoid; painless, firm, deep-seated mobile nodules; 90% have hilar adenopathy and multiple lesions; a/w good
Löfgren syndrome
Heerfordt syndrome
(“uveoparotid fever”)
Mikulicz syndrome Outdated, non-specific term (may be seen in TB, sarcoid, Sjögren’s syndrome, lymphoma), referring to enlargement of salivary,
Blau syndrome
Drug-induced
cutaneous sarcoid
Violaceous (rather than red-brown) papules coalescing into infiltrative plaques; nose/earlobes/cheeks 5 most common sites;
“beaded” appearance along the nasal rim (Fig. 3.65); resolves with scarring (unlike most cutaneous sarcoid); strongly a/w
chronic sarcoid lung (75%) and upper respiratory tract (50%) disease , cystic degeneration of bones of distal phalanges, ocular
involvement, and reticuloendothelial involvement; rarely involutes and has poor prognosis
prognosis
Acute form of sarcoidosis; p/w erythema nodosum 1 hilar adenopathy 1 fever 1 migrating polyarthritis 1 acute iritis; most
common in Scandinavians, rare in Blacks; a/w good prognosis
Uveitis 1 parotid gland enlargement 1 fever 1 cranial nerve palsy (facial nerve most commonly)
lacrimal, and parotid glands
Early-onset (age , 5 yo) sarcoid-like disease; caused by NOD2 mutation; triad of skin, eye, and joint disease
IFN-a (hepatitis C patients), HIV patients on HAART, TNF- a inhibitors
gland, gingiva, hard/soft palate, and tongue), liver, and
heart involvement
• Sarcoid variants (Table 3.18)
Histopathology
• Supercial and deep dermis packed w/ nodules of well-
formed, non-caseating, “naked epithelioid granulomas”
(epithelioid granulomas lacking a signicant
inammatory rim of lymphocytes or plasma cells)
■
Asteroid bodies (star-shaped eosinophilic inclusions of
collagen) and Schaumann bodies (basophilic calcium
and protein inclusions) are commonly seen within
histiocytic GCs
Laboratory testing
• Kveim-Siltzbach test (not routinely performed):
injecting suspension of sarcoidal spleen into the skin of
a patient w/ sarcoidosis → sarcoidal granuloma at
injection site
• CXR or CT scan (most sensitive): hilar/paratracheal
lymphadenopathy 1/– pulmonary inltrates
• PFTs: restrictive lung disease pattern → ↓ total lung
capacity, ↓ diffusing capacity, and ↓ vital capacity
• ↑ ACE level (60%; more useful in monitoring response to
treatment than for diagnosis)
• ↑ ESR; hypercalcemia, lymphopenia
Treatment
• First line: oral prednisone for systemic involvement 1/–
topical or IL-steroids for skin involvement; the degree of
lung, eye, and other internal involvement determines how
quickly you can taper prednisone
• Other treatments for chronic skin-predominant disease:
hydroxychloroquine, chloroquine, TNF-a inhibitors (treat
systemic symptoms), MMF, AZA, minocycline, leunomide
Additional boards factoids
• Granulomatous dermatitis summary (Fig. 3.66,
Tables 3.19 and 3.20)
Foreign body reactions
(Tables 3.21 and 3.22)
• Non-organic and high molecular weight organic materials
that are deposited into the dermis/subcutis and are
resistant to biologic degradation by inammatory cells
may → foreign body reaction
• p/w indurated red or red-brown papules coalescing into
plaques 1/– ulceration
• Histopathology: foreign body granulomas 1/–
recognizable foreign material
• Less common reaction patterns: pseudolymphomatous,
lichenoid, and eczematous
Fig. 3.65 Sarcoidosis, lupus pernio type, with coalescing violaceous papules on
the nose. (From Marchell RM, Judson MA. Chronic cutaneous lesions of sarcoidosis. Clin Dermatol. 2007;25[3]:295–302.)
Histiocytoses
• Group of proliferative disorders that share a common
CD341 progenitor cell in bone marrow
• This common ancestor later differentiates into a variety of
so-called “histiocytes”:
■
Langerhans cell: potent APC that migrates to and from
epidermis, stains positively with CD1a, S100, and
157
CHAPTER 3 • General Dermatology
NON-INFECTIOUS GRANULOMAS: ALGORITHM FOR HISTOLOGIC DIAGNOSIS
Non-infectious granulomas
With plasma
“Naked”
Sarcoidosis
Epithelioid
tubercle
Caseation
Crohn’s
disease
Appreciable
lymphocytes
Consider
infection
Syphilis
cells
With
lymphocytes
Granulomatous
slack skin
Diffuse infiltrate,
no palisade
With
neutrophils
Ruptured cyst
or follicle
Palisaded
granuloma
Horizontal
“tiers”
Prominent
Necrobiosis
lipoidica
Necrobiotic
xanthogranuloma
Granuloma
annulare*
Elastophagocytosis
Superficial
dermal
Nodular
infiltrate
Diffuse infiltrate,
marked collagen
alteration
Subcutis
cholesterol
clefts
Annular elastolytic
giant cell granuloma
Fig. 3.66 Non-infectious granulomas: algorithm for histologic diagnosis. Interstitial granulomatous dermatitis and palisaded neutrophilic and granulomatous dermatitis
may represent an additional diagnostic consideration. *May also have a patchy dermal interstitial pattern without palisades, or subcutaneous palisades with more
mucin than rheumatoid nodules. (From Rosenbach MA, Wanat KA, Reisenauer A, White KP, Korcheva V, White CR Jr. Non-infectious granulomas. In: Bolognia JL,
Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia: Elsevier; 2018:1644–1663.)
Rheumatoid
nodule
Table 3.19 Clinical Features of the Major Granulomatous Dermatitides
Sarcoidosis
Average age
(years)
Sex predilection Female Female Female None Female Male
Racial/ethnic
predilection
in the United
States
Sites Symmetric on face,
Appearance Red to red-brown
Size of lesions
No. of lesions Variable 1–10 1–10 1–10 1–5 1–10
Associations Systemic manifestations
25–35, 45–65
African American None None Caucasian Ashkenazi Jews None
neck, upper trunk,
extremities
papules and
plaques; occasionally
violaceous or annular
0.2 to .5 cm
of sarcoidosis; INF-a
therapy for hepatitis
C viral infection »
melanoma
a
Classic Granuloma
b
Annulare
,30
Hands, feet,
extensor aspects of
extremities
Papules coalescing
into annular
plaques
1–3 mm papules,
annular plaques
usually , 6 cm
Rare diabetes
mellitus, HIV
infection,
malignancy
Necrobiosis
Lipoidica AEGCG
30 50–70 35 40–50
Anterior and lateral
aspects of distal
lower extremities
Plaques with
elevated borders,
telangiectasias
centrally
3 to .10 cm
Diabetes mellitus Actinic damage Intestinal Crohn’s
Face, neck,
forearms (sites
of chronic sun
exposure)
Annular plaques Dusky erythema
1–6 cm Variable 1–3 cm
Cutaneous
Crohn’s Disease
Genital areas,
lower . upper
extremities
and swelling,
ulceration
disease
Rheumatoid
Nodule
Juxta-articular
areas,
especially
elbows, hands,
ankles, feet
Skin-colored,
firm, mobile
subcutaneous
nodules
Rheumatoid
arthritis
c
158
3.6 Granulomatous/Histiocytic Disorders
Table 3.19 Clinical Features of the Major Granulomatous Dermatitides—cont'd
Classic Granuloma
b
Annulare
Central
hyperpigmentation
Special clinical
characteristics
Sarcoidosis
a
Occasional central
atrophy and
hypopigmentation;
development within
scars
a
Clinical variants include lupus pernio and subcutaneous (Darier–Roussy), psoriasiform, ichthyosiform, angiolupoid, and ulcerative sarcoidosis.
b
Clinical variants include generalized, micropapular, nodular, perforating, subcutaneous, and patch granuloma annulare.
c
Although rheumatoid arthritis has a female:male ratio of 2–3:1.
AEGCG, Annular elastolytic giant cell granuloma; HIV, human immunodeciency virus; IFN, interferon.
Modied from Rosenbach MA, Wanat KA, Reisenauer A, White KP, Korcheva V, White CR Jr. Non-infectious granulomas. In: Bolognia JL, Schaffer JV, Cerroni L.
Dermatology. 4th ed. Philadelphia: Elsevier; 2018:1644–1663.
Table 3.20 Histologic Features of the Major Granulomatous Dermatitides
Sarcoidosis
Typical location Superficial and
deep dermis
Granuloma
Annulare
Superficial
and mid
Necrobiosis
Lipoidica AEGCG
Entire dermis,
subcutis
dermis
Granuloma pattern Tubercle
with few
peripheral
lymphocytes
(“naked”)
Necrobiosis (altered
No Yes (“blue”) Yes (“red”) No No Yes (“red”) Yes (“blue”) Yes (“blue”)
Palisading
or
interstitial
Diffuse
palisading
and interstitial;
horizontal
“tiers”
collagen)
Giant cells Yes Variable Yes Yes Yes Yes Variable Variable
Elastolysis No Variable Variable Yes No No Variable Variable
Elastophagocytosis No No No Yes No No No No
Asteroid bodies Yes Variable Variable Yes No No Variable Variable
Mucin No Yes Minimal No No Variable Minimal Variable
Extracellular lipid No Variable Yes No No Variable No No
Vascular changes No Variable
a
Interstitial granulomatous dermatitis and palisading neutrophilic and granulomatous dermatitis are often considered two ends of a spectrum.
Yes No No Yes No Yes
AEGCG, Annular elastolytic giant cell granuloma.
Modied from Rosenbach MA, Wanat KA, Reisenauer A, White KP, Korcheva V, White CR Jr. Non-infectious granulomas. In: Bolognia JL, Schaffer JV, Cerroni L.
Dermatology. 4th ed. Philadelphia: Elsevier; 2018:1644–1663.
Necrobiosis
Lipoidica AEGCG
Yellow-brown
atrophic centers,
Central atrophy and
hypopigmentation
ulceration
Cutaneous
Crohn’s
Disease
Superficial
and mid
dermis
Palisading,
irregular
Superficial
and deep
dermis
Tubercle with
surrounding
lymphocytes
Cutaneous
Crohn’s Disease
Draining sinuses
and fistulas
Interstitial
Rheumatoid
Nodule
Deep dermis,
subcutis
Granulomatous
Dermatitis
Mid and deep
dermis
Palisading Palisading
in small
“rosettes”
a
Rheumatoid
Nodule
Occasional
ulceration,
especially at
sites of trauma
Palisading
Neutrophilic and
Granulomatous
Dermatitis
a
Entire dermis
Palisading;
prominent
neutrophils and
leukocytoclasia
Table 3.21 Foreign Body Reactions
Foreign Body Clinical Presentation Histopathology Other Key Points
Tattoo inks Red tattoos ( mercuric sulde, aka cinnabar) are
most common cause of delayed reactions, usually
lichenoid or pseudolymphomatous papules and
nodules
Eczematous dermatitis
Photoallergic reactions, usually to yellow ink (cad-
mium sulde), red ink (cadmium selenide) or yel-
low-red (azo dyes)
Lichenoid dermatitis or
pseduolymphoma (red
tattoo)
Spongiotic dermatitis (many
others)
Granulomatous (aluminum, and
others)
Tattoo pigment granules in dermis are
smaller and darker than endogenous pigments (hemosiderin and melanin)
Various Q-switched lasers are ToC for tat-
toos: QS-ruby (694 nm), QS-alexandrite
(755 nm), QS-Nd:YAG (1064 or 532 nm)
Ruby, alexandrite, and Nd:YAG (1064 nm) all
treat black, blue, dark brown
Ruby or alexandrite is ToC for green
Only frequency-doubled Nd:YAG (532 nm) is
effective for red, yellow, light brown,
violet, and white
If tattoo is inamed, excise (instead of laser)
to ↓ risk of systemic allergic rxn
Silica (silicon
dioxide)
Penetrating injuries involving sand, soil, rocks,
glass; prolonged incubation period (up to 25
years); p/w nodules, indurated plaques within scar
Sarcoidal granulomas containing
colorless, birefringent
crystals
Rx: excision
Disseminated papules (blast injuries)
Continued
159
CHAPTER 3 • General Dermatology
Table 3.21 Foreign Body Reactions—cont'd
Foreign Body Clinical Presentation Histopathology Other Key Points
Talc (hydrous
magnesium
silicate)
Zirconium
Beryllium Used in manufacturing of uorescent lights in the
Aluminum Persistent subcutaneous nodules at vaccine
Zinc Rare injection-reaction due to zinc-containing insulin
Starch Due to contamination of wounds from surgical
Cactus (Opuntia
is most common
genus)
Jellyfish, corals,
sea urchin
spines
Keratin Ruptured epidermoid cysts
Intralesional
corticosteroids
Suture Inflamed papule in wound that opens to form a fistula Foreign body granulomas with
Modied from Abdallah MAR, Abdallah MMA, Abdallah M. Foreign body reactions. In: Bolognia JL, Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia:
Elsevier; 2018:1664–1674.
Common component of dusting powders (umbilical
stump, intertriginous areas of obese pts), surgical
glove lubricants, and as ller for med tablets (IV
drug abusers who mash up meds and inject)
p/w sarcoid-like papules; may appear pyogenic gran-
uloma-like
Zirconium in antiperspirants → persistent, soft
brown papules in axilla
past; could result in systemic or local reactions:
Systemic berylliosis: industrial exposure via inhalation
→ granulomatous lung disease with rare skin involvement (,1%) by scattered sarcoidal papules
Localized cutaneous Berylliosis: puncture wound by
uorescent bulb → slowly healing nodules/ulcers
injection sites; arise several months after
vaccination
shots; p/w furuncles at injection sites → heals with
atrophic scars
gloves with starch lubricant; p/w papules, nodules
Clusters of dome-shaped, skin-colored papules with
a central black dot; occurs in those who peel/sell
prickly pear fruit
Pruritic lichenoid papules and plaques (onset
2–3 weeks after exposure)
Linear, zig-zag, and whip-like (agellate) patterns
of erythema/edema (early), hyperpigmentation or
lichenoid papules (late)
Pseudofolliculitis/acne keloidalis
Pyogenic granuloma-like lesions, ingrown nails
Pilonidal sinus
Due to failure of dispersion of injected material →
weeks to months later develop FB rxn
Skin-colored to yellow-white papules at site of prior
IL-steroid injection
Sarcoidal or foreign body
granulomas with needleshaped or round crystals that
are white and birefringent on
polarized light
Sarcoidal granulomas; no
polarizable particles seen
Caseating granulomas
(localized cutaneous form); no
polarizable particles seen
Granulomas with central
granular debris and palisade
of surrounding histiocytes; no
polarizable particles seen
Dense neutrophilic infiltrate with
birefringent rhomboidal
crystals → granulomas and
fibrosis (end-stage)
Foreign body granulomas with
ovoid basophilic starch
granules that stain PAS1
Sarcoidal or foreign body
granulomas w/ PAS1 spines
(extra- and intracellular)
Lichenoid dermatitis May see birefringent calcite crystals (sea ur-
Foreign body granulomas w/
birefringent keratin debris
Foreign body granulomas with
central pale bluish material
(resembles mucin) on H&E
birefringent suture material
On H&E, the color of the needle-shaped or
round talc crystals is highly variable (clear,
blue-green or yellow-brown)
Rx: excision
Zirconium particles are too small to be seen
by polarized light microscopy → need advanced X-ray/electron imaging techniques
Rx: excision
Bronchioalveolar lavage recommended
for Dx of systemic berylliosis
Beryllium particles are too small to be seen
by polarized light microscopy → need advanced X-ray/electron imaging techniques
Rx: excision
Topical aluminum chloride for hemostasis
can give similar stippled appearance to
histiocytes in healing wound
Aluminum particles are too small to be seen
by polarized light microscopy → need advanced X-ray/electron imaging techniques
Rx: excision
Rx: excision
chin spines)
Rx: IL steroids for delayed-type reactions
Table 3.22 Distinguishing Staining Characteristics of Foreign Body
Granulomas
Birefringent Non-Birefringent
PAS (1) PAS (–)
Starch, cactus spines,
wood splinters
PAS, Periodic acid–Schiff.
Silica, talc, zinc,
keratin, sea urchin
spines, sutures,
arthropod parts
Aluminum, beryllium,
zirconium
160
Langerin (CD207 is most specic, stains Birbeck
granules); has pathognomonic intracytoplasmic
Birbeck granules on electron microscopy
■
Mononuclear cell/macrophage: migrates to and from
dermis, has phagocytic and APC abilities, and stains
positively w/ CD68 and HAM56
■
Dermal dendrocyte/dendritic cell (two types exist):
Type 1 dermal dendrocyte: versatile factor XIIIa
cell; resides in papillary dermis; involved in antigen
presentation, phagocytosis, collagen production,
and wound healing
1
3.7 Monoclonal Gammopathies of Dermatologic Interest
Type 2 dermal dendrocyte: less known about this
CD341 cell; resides in reticular dermis
• Abnormal proliferation of any of these histiocyte cell
types leads to the various forms of histiocytosis
• There is a high degree of clinical and histopathologic
overlap between entities within a group (i.e., the various
non-Langerhans cell histiocytoses are very similar to each
other, but all are different than LCH)
Langerhans cell histiocytosis (LCH)
Epidemiology and pathogenesis
• Malignancy of immature hematopoietic myeloid
precursors (not true Langerhans cells) affecting primarily
young (1–3 yo) children (White . Black)
■
BRAF V600E activating mutation (50%–60%) →
↑ brosarcoma kinase activity → activation of
RAS-RAF-MEK-ERK-MAP kinase pathway
Histology
• Dense proliferation of Langerhans cells (with reniform
nuclei), regulatory T cells (FoxP31, CD41), and
eosinophils in papillary dermis, with single and nested
LCH cells in the epidermis
■
S1001, CD1a1, Langerin (CD207)1, CD681
Negative for Factor XIIIA and HAM56
Clinical features and prognosis
• Prognosis is primarily determined by extent of systemic
involvement
■
New classication systems classify LCH according to
degree of systemic involvement (single vs. multisystem,
risk organ involvement [liver, spleen, bone marrow])
Bone marrow biopsy in all patients suspected of
having multisystem disease
Testing: CBC, LFTs, electrolyte assessment, skeletal
survey, CXR, U/S liver/spleen
■
Most commonly affected organs: bone (80%; skull #1)
. skin (usually if skin is involved, other organs [liver
#1] are too) . pituitary . liver/spleen/hematopoietic
system/lungs (usually in adults, major cause of
mortality) . lymph nodes . CNS (non-pituitary)
Skin presentation varies widely:
♦ Infants w/ petechial seborrheic dermatitis-like
eruption (crusted papules) on scalp 1 groin
involvement (Fig. 3.67)
♦ Tiny red esh-colored papules/pustules w/
dermatitis/seborrheic dermatitis-like eruption,
petechial/purpuric eruption, vitiligo-like lesions,
xanthoma-like lesions
♦ Trunk, head, and face most common sites
♦ Ulcers in the genital and oral mucosa can occur
• Progression of skin-limited disease to systemic
involvement is uncommon, but skin-limited disease only
occurs in 2% of patients
• Most frequent sequelae: diabetes insipidus . orthopedic
problems (facial asymmetry, vertebral collapse) . hearing
loss . other neurologic issues (neurodegeneration)
• 5-year survival in patients with risk organ involvement
70%–80%; single system LCH and multisystem disease w/
NO risk organ involvement 100% survival rate
Fig. 3.67 Langerhans cell histiocytosis, seborrheic dermatitis–like eruption with
hemorrhage. (From James WD, Elston DM, Treat JR, Rosenbach MA, Neuhaus
IM. Macrophage/Monocyte disorders. In: Andrews’ Diseases of the Skin. 13th
ed. Philadelphia: Elsevier; 2020:704–730.)
• Features predictive of poor prognosis: BRAF V600E mutation
(i.e., ↑ chance neurologic and pituitary issues), multisystem
disease w/ risk organ involvement, craniofacial abnormalities,
and failure to respond to treatment by 6 weeks
Treatment
• Mild cutaneous disease: potent topical steroids, spontaneous
resolution; diffuse disease: steroids 1 vinblastine
■
Other treatment options: nitrogen mustard,
imiquimod, PUVA/NB-UVB, MTX, AZA, 6-MP, retinoids
• Multisystem LCH: vinblastine/prednisone 3 1 year; other
options: cladribine, cytarabine, clofarabine; emerging
options: BRAF inhibitors, MEK inhibitors, sorafenib
Non-langerhans cell histiocytoses (discussed in Table 3.23)
• All are CD681, 1/ Factor XIIIa1
• All are negative for Langerin
• S100 is negative in all (except ICH and Rosai-Dorfman)
• CD1a is negative in all (except ICH)
Malignant histiocytic disorders
• Langerhans cell sarcoma (high mortality, skin, Langerin/
S100/CD1a (1)), follicular dendritic cell sarcoma (,20%
mortality, cervical lymph node, CD21/CD35 (1)),
histiocytic sarcoma (high mortality, skin, CD68/CD163
(1)), indeterminate cell sarcoma, interdigitating dendritic cell
sarcoma (high mortality, single lymph node)
3.7 MONOCLONAL GAMMOPATHIES
OF DERMATOLOGIC INTEREST
• Monoclonal gammopathies often arise in setting of
plasma cell dyscrasia or multiple myeloma
• Their associations w/ various dermatoses is important
to know (Table 3.24)
• IgG4-related disease: not a monoclonal gammopathy;
seen in middle-aged men primarily
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CHAPTER 3 • General Dermatology
Table 3.23 Non-Langerhans Cell Histiocytoses
Histiocytosis Age (Years) Clinical Presentation Other High-Yield Facts
Primarily cutaneous, self-resolving
JXG 0–2 (15% at
Benign cephalic
histiocytosis (likely a
JXG variant)
Generalized eruptive
histiocytosis (likely a
JXG variant)
Indeterminate cell
histiocytosis (ICH)
Primarily cutaneous, progressive
Progressive nodular
histiocytosis
Cutaneous 1 frequent systemic involvement
NXG 50s Destructive multisystem disease; yellow xanthomatous
Reticulohistiocytosis
(multicentric
reticulohistiocytosis
and solitary
reticulohistiocytoma)
Rosai-Dorfman 10–30 Multisystem disease of children or young adults;
Xanthoma
disseminatum
Systemic, usually without skin involvement
Erdheim-Chester Any Fever, bone lesions, diabetes insipidus, exophthalmos,
ICH, indeterminate cell histiocytosis; JXG, juvenile xanthogranuloma; NF-1, type 1 neurobromatosis; JMML,
cephalic histiocytosis; NXG, necrobiotic xanthogranuloma; LCH, Langerhans cell histiocytosis; GEH, generalized eruptive histiocytosis; ESR, estimated sedimentation rate
birth, 75%
in first year
of life)
Infants (,1
yo usually)
Adults
(20–50 yo)
. kids
Any Solitary and generalized variants exist; trunk, extremities;
Any Generalized yellow papules/nodules, with predilection for
30–40s (very
rare in kids)
,25 (60%),
but any age
One to few lesions » numerous/widespread; pink to red/
yellow; head/neck . upper trunk, extremities
(Fig. 3.68); mucosal JXG is rare; unilateral eye involvement in 0.5% (iris most common) → hyphema, glaucoma → blindness
Can occur in adults (20–30s) and usually solitary papule/
nodule
Numerous (more lesions than typical JXG) red-brown
macules & papules of face/neck (Fig. 3.69) that may
progress to upper torso
Recurrent eruption of hundreds of small (,1 cm) red-
brown papules in axial distribution (trunk, proximal
extremities . face); heal with hyperpigmentation
eruption clinically and histologically indistinguishable
from BCH and GEH → need immunostains to
distinguish
face
plaques 1/– ulceration; periorbital » other face, trunk,
extremities; 50% have ophthalmic complications;
hepatosplenomegaly, leukopenia and ↑ ESR
Multicentric form: F . M; red-brown or yellow nodules;
Acral sites favored (head, dorsal hands . elbows)
(Fig. 3.70); 50% have oral or nasopharyngeal lesions; severe destructive arthritis → arthritis mutilans
(45%); no effective treatment
Solitary form: Solitary, asymptomatic , 1 cm yellow-red
nodule; head (#1 site); young adults (M 5 F); no systemic involvement; self-resolving but may excise
massive but asymptomatic bilateral cervical
lymphadenopathy; fever/night sweats/weight loss; ↑
ESR, polyclonal hypergammaglobulinemia; any internal
organ may be involved; 10% have skin lesions
(#1 sites 5 eyelids and malar cheek); p/w multiple
red-brown or xanthomatous papules/plaques; disease
usually self-resolves
Triad: Cutaneous xanthomas, mucosal xanthomas (oral
and upper airway most commonly), diabetes insipidus
p/w 100s of red-brown or yellow papules → coalesce into
oddly patterned xanthoma-like plaques (Fig. 3.71);
symmetric exural/intertriginous involvement
CNS, multiple internal organs; skin involvement in
minority (25%); eyelids and upper half of body; redbrown to yellow indurated nodules/plaques
Spontaneous resolution in 3–6 years; rare visceral le-
sions; 40% of patients with ocular involvement also
have skin involvement
Risk factors for ocular involvement: multiple cuta-
neous JXGs and children , 2 yo
“Triple association” of JXG, NF-1, and .20x ↑ risk
of juvenile myelomonocytic leukemia (JMML)
Histology: Well-circumscribed, dense dermal inltrate of
foamy lipidized histiocytes, Touton giant cells and
eosinophils; loss of rete ridges 1/– ulceration
Self-limited
No internal or mucosal involvement
Historically known for intracytoplasmic “comma
shaped/worm-like” bodies on electron microscopy
(not specic); histology: very similar to JXG but no
Touton giant cells, minimal-to-no lipidized histiocytes
Self-limited; no internal or mucosal involvement
Histology: Same as BCH → clinical distinction required
Rare visceral and bone lesions with occasional fatal cases
S100(1) and CD1a(1) like LCH
Langerin( ) since no Birbeck granules → differentiates
from LCH
Mucous membrane involvement may occur
IgG monoclonal gammopathy (.80%), a/w plasma
cell dyscrasia or multiple myeloma
Histology: See NXG section
Multicentric form: ↑ ESR, fever, anemia; Solid organ
malignancy in 30%
“Coral bead” appearance 5 papules along periungual
region
Histology: Dermal inltrate of mono- and multi-nucle-
ated histiocytes with granular, pink-purple (aka amphophilic, “ground glass”) cytoplasm, often surrounded by empty white spaces (lacunae)
↑ Incidence in West Indians
Histology: pan-dermal inltrate of very large, very foamy
1
/CD681histiocytes with emperipolesis (en-
S100
gulfment of intact lymphocytes and plasma cells),
abundant plasma cells
Skin-limited form: benign; usually pts are older and fe-
male (systemic involvement more often seen in males
and younger pts)
Normolipemic; a/w monoclonal gammopathy,
plasma cell dyscrasia; histology: Dense dermal
infiltrate of many foam cells and occasional Touton
giant cells; chronic course; no effective treatment
High mortality rate
juvenile myelomonocytic leukemia; BCH, benign
162
Fig. 3.68 Juvenile xanthogranuloma, multiple nodules. (From James WD, Berger
TG, Elston DM, Neuhaus IM. Macrophage/Monocyte disorders. In: Andrews’
Diseases of the Skin . 12th ed. Philadelphia: Elsevier; 2016:699–725.)
Fig. 3.69 Infant with benign cephalic histiocytosis. (From Prendiville JS. Lumps,
bumps, and hamartomas. In: Eicheneld LF, Frieden IJ, Mathes EF, Zaenglein
AL, eds. Neonatal and Infant Dermatology. 3rd ed. Philadelphia: Elsevier;
2015:422–442.)
A
C
B
D
E
Fig. 3.70 Clinical manifestations and dermoscopic ndings of the patient with multicentric reticulohistiocytosis. (A) Closely arranged reddish-brown papules (“coral
beads”) were located over the helices and antihelices of the ear. (B) Similar lesions were observed over the perinostril area. (C) and (D) Note the conuent papules and
nodules forming erythematous plaques with a cobblestone surface over the knuckles, mainly involving the metacarpal joints, as well as the presence of periungual
erythema and swelling of the distal phalangeal joints. (E) Diascopy revealed a negative “apple jelly” sign. (F) Delicate thin arborizing vessels within the papules were
observed via gel immersion (contact) dermoscopy. (From Cheng LH, Chiang YY. Multicentric reticulohistiocytosis in Taiwanese woman with Sjögren syndrome. Derma-
tol Sinica. 2016;34[1]:42–45.)
F
163
CHAPTER 3 • General Dermatology
A B
Fig. 3.71 (A) and (B) Cutaneous xanthoma disseminatum with many red-brown papules in the axillae. (From Gong HZ, Zheng HY, Li J. Xanthoma disseminatum.
Lancet. 2018;391(10117):251. [Fig 1ab] Reprinted with permission from Elsevier).
Table 3.24 Monoclonal Gammopathies in Dermatology
Disorder Immunoglobulin Type
Plane xanthoma IgG
Sweet’s syndrome IgA
Primary (AL) amyloidosis IgG
Necrobiotic xanthogranuloma
Scleredema
Scleromyxedema
IgA pemphigus and subcorneal
pustular dermatosis
Pyoderma gangrenosum IgA
Erythema elevatum diutinum IgA
POEMS syndrome IgA and IgG
Schnitzler’s syndrome IgM
Cryoglobulinemia Monoclonal IgM and IgG (type I)
Waldenström macroglobulinemia IgM
■
Lymphoplasmacytic inltration (with IgG41 plasma
IgG
IgG
IgG-
IgA
Monoclonal IgM 1 polyclonal IgG (type II)
Polyclonal IgM and/or IgG (type III)
cells) of various organs (e.g., Mikulicz disease of
lacrimal glands, sclerosing cholangitis, retroperitoneal
brosis, sclerosis sialoadenitis, inammatory
pseudotumor of the orbit, autoimmune pancreatitis)
→ sclerosis and organomegaly/pseudotumors
■
Allergy symptoms, asthenia, weight loss, fever, ↑ IgG4
and IgE in plasma, lymphadenopathy
■
Skin ndings: papulonodules (plasmacytosis) on head/
neck and proximal extremities (histology: brosis w/
storiform pattern and lymphoplasmacytic inltrates w/
IgG41 plasma cells), pseudolymphoma, psoriasis-like
eruption, hypergammaglobulinemic purpura, and
urticarial vasculitis
■
Treatment: prednisone or steroid-sparing agent; rituximab
3.8 XANTHOMAS
• Intracellular and dermal lipid deposition → yellow
appearance of lesions
• Prefer skin, tendons, and eyes
• Due to abnormalities in lipid metabolism (primary or
secondary; may be a/w atherosclerosis) or monoclonal
gammopathy (e.g., MGUS, multiple myeloma, CLL,
Waldenström disease; usually IgG, but can be IgA or
IgM)
■
Lipoproteins: transport plasma lipids to peripheral
cells
Basic structure 5 inner core (triglycerides 1
cholesterol esters) 1 outer shell (phospholipids,
free cholesterol, and apoproteins [bind receptors
and activating enzymes])
Exogenous and endogenous pathways of lipoprotein
synthesis exist
Types of lipoproteins:
♦ Chylomicrons: mainly exogenous production
Central core of mainly triglycerides; outer shell
contains various apoproteins (B-48, E, A-I,
A-II, and C-II)
Becomes chylomicron remnant after most of
the triglyceride content is hydrolyzed
♦ Very-low-density lipoprotein (VLDL): mainly
endogenous production in liver
Central core of mainly triglycerides; outer shell
contains B-100, E and C-II
C-II needed for lipoprotein lipase activation
♦ Intermediate-density lipoprotein (IDL): remnant
of VLDL after hydrolysis of most of triglycerides
by lipoprotein lipase
♦ Low-density lipoprotein (LDL): product of
further triglyceride hydrolysis of IDL (now
164