Michel R. Ibrahim The Dermis- Cutaneous Mucinosis
Michel R. Ibrahim
Board-Certified Dermatologist & Dermatopathologist EBDV, Dip of Dermatopath. Frankfort-Germany Visiting Scientist Sanford-Burnham-Prebys (SBP) Medical Discovery Institute Sanford Consortium for Regenerative Medicine San-Diego, USA Associate Lecturer of Dermatology, STDs & Andrology. Faculty of medicine- Minya University- Egypt.
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Michel R. Ibrahim The Dermis- Cutaneous Mucinosis
MUCINOSES
MUCIN: Protein- hyaluronic acid complex (non-sulfated acid mucopolysaccharide). Appears as wispy, faint blue threads on routine sections.
Staining: H & E 1. H&E: Wispy, faint blue threads. PAS 2. Colloidal iron. CATA 3. Alcian-blue: Positive at pH 2.5. Negative at pH 0.5. 6 4. Toluidine blue At pH 7.0 and 4.0 → metachromasia PH below 2.0 → no metachromasia 5. PAS → negative (indicating absent neutral mucopolysaccharides). 6. Aldehyde-fuchsin → negative (indicating absent sulfated acid mucopolysaccharides).
Six Types 1. Generalized myxedema. 2. Pretibial myxedema. 3. Lichen myxedematosus or papular mucinosis. 6 4. Reticular erythematous mucinosis. 5. Self-healing juvenile cutaneous mucinosis. 6. Scleredema. Easily demonstrable in all cases except: In generalized myxedema → too small. In scleredema → only in the early stage. All are due to ↑ mucin that is normally present in the ground substance of the dermis.
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Michel R. Ibrahim The Dermis- Cutaneous Mucinosis
PRETIBIAL MYXEDEMA
A/E: Thyrotoxicosis. Site: Anterior aspects of the legs → may extend to the dorsa of the feet. Lesion: Raised, nodular, yellow, waxy plaques with prominent follicular openings → peau d'orange appearance. Grave´s disease: diffuse goitre + exophthalmos + pretibial myxedema (patients usually have LATS).
Exophthalmos
Goitre
Pretibial myxedema
Histopathology: Large amounts of mucin in the reticular dermis → ↑ thickness of the dermis → splitting up of collagen bundles into fibers and wide separation of the fibers (thin wisps). Shrinkage of the mucin during the process of fixation and dehydration → empty spaces within the mucin deposits. No ↑ Fibroblasts: stellate shape “mucoblasts”.
Differential Diagnosis: Pretibial mucinosis associated with venous stasis: ↑ mucin in the papillary dermis Angioplasia Siderophages.
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Michel R. Ibrahim The Dermis- Cutaneous Mucinosis
LICHEN MYXEDEMATOSUS
Syn.: Papular Mucinosis, Scleromyxedema
Age: Middle-age adults, M=F. Site: The face and arms. Lesion: Densely grouped “do not coalesce” asymptomatic, soft papules. ± Monoclonal gammopathy.
Scleromyxedema → generalized eruption of papules as in lichen myxedematosus + diffuse thickening of the skin + erythema. Marked accentuation of the skin folds, particularly on the face.
DD: scleroderma clinically by 1. The papular component. 2. No telangiectasias.
Histopathology: Triad of microscopic features: 1. Large amounts of mucin in the upper dermis. 2. Extensive proliferation of fibroblasts throughout the dermis. 3 3. Irregularly arranged bundles of collagen.
NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
Syn.: Nephrogenic fibrosing dermopathy.
All patients have history of exposure to gadolinium MRI contrast dye (highest risk w/ Omniscan, Magnevist, and Optimark) in setting of renal insufficiency (chronic > acute) Site: Legs (> trunk) Lesion: Woody, indurated plaques with “peau d’orange” appearance. Face spared, Yellow papules on palms, Yellow scleral plaques.
Histopathology: 1. ↑CD34+ fibrocytes in dermis and SQ septae. 2. Thickened collagen fibers. 3. ↑dermal mucin. “Lollipop lesion”: Osseous metaplasia. Sclerotic amorphous eosinophilic bodies with entrapped elastic fibers = HIGHLY SPECIFIC for gadolinium exposure.
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Michel R. Ibrahim The Dermis- Cutaneous Mucinosis
RETICULAR ERYTHEMATOUS MUCINOSIS
Site: Center of the chest and of the upper back of women. Lesion: Asymptomatic reticulated macules. It is chronic but usually responds well to small doses of antimalarial drugs such as chloroquine. It may be a presenting sign of SLE.
Histopathology: Two histologic features are usually present: 1. Small amounts of dermal mucin. 2. Mild or moderately mononuclear infiltrate around blood vessels and hair follicles.
Differential Diagnosis: 1. Reticular erythematous mucinosis. Perivascular and perifollicular 2. Jessner's lymphocytic infiltrate of skin. lymphocytic infiltrate and ↑ mucin 3. Lupus erythematosus. among collagen bundles. Jessner's lymphocytic infiltrate → lymphocytic infiltrate ˃ REM. Lupus erythematosus → vacuolar changes in the BCL of the epidermis and follicular units.
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Michel R. Ibrahim The Dermis- Cutaneous Mucinosis
SCLEREDEMA
3rd Type 1st Type 2nd Type (Scleredema Diabeticorum) Obese middle-aged men with Middle-aged women & children IDDM. Prodroma: URTI “strept.”. No prodroma. The skin of the cervicofacial Erythema and induration of the The same clinical region → suddenly hardens with posterior neck and the back → features. extension to the trunk and peau d'orange appearance of Insidious onset. proximal upper limbs. the skin. The face → expressionless. Tongue and pharynx → difficult Ass. with a monoclonal opening of the mouth and gammopathy swallowing. Spontaneous resolution in few Persists for years. months.
Histopathology: Thickened dermis. The collagen bundles → thick and separated by clear spaces → mucin → “fenestration” of the collagen → prominent in the deep dermis. The secretory coils of the sweat glands → in the upper dermis or mid-dermis “normally in the lower dermis or at the junction of the dermis and the subcutaneous fat”. Subcutaneous fat replaced by dense collagenous bundles. No inflammatory infiltrate or ↑ fibroblasts.
Systemic Lesions: Tongue and some skeletal muscles. Muscle bundles → edema and loss of striation.
Differential Diagnosis: Clinically: Scleroderma: Scleredema 1. NO acral involvement. 2. NO Raynaud's phenomenon. 3. NO cuticular and mat telangiectasias.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
Cutaneous Deposits
AMYLOIDOSIS
Amyloid in H&E:
If only large amount.
Amorphous, homogeneous, hyalin, faintly eosinophilic.
Clefts due to shrinkage of the amyloid during fixation & dehydration.
Staining: Congo-red → orange-red in L/M & apple-green birefringence under polarized light. Thioflavine T. → yellow-green fluorescence. Crystal violet → metachromasia.
CLINICAL CLASSIFICATION OF AMYLOIDOSIS Systemic amyloidosis Organ-limited (localized)amyloidosis 1. Primary systemic amyloidosis “AL amyloidosis”: 1. Cutaneous: Plasma cell dyscrasias. Primary: macular, lichen, biphasic, Multiple myeloma. dyschromic, nodular. 2. Secondary systemic amyloidosis “AA amyloidosis”: Secondary: within skin tumors. Chronic inflammation (e.g. rheumatoid arthritis). Chronic infection (TB, Lep Lep & Hidrad. sup).
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
PRIMARY SYSTEMIC AMYLOIDOSIS The oral cavity: The tongue → enlarged and firm ± hemorrhagic papules, plaques and blisters. Xerostomia can result from infiltration of the salivary glands.
Purpura & Echymosis: On the eyelids and neck and in the axillae and anogenital region. Due to infiltration of vessel walls with amyloid. Characteristically → periorbital purpura (the ‘raccoon eyes’ sign) → may be precipitated by coughing, the Valsalva maneuver, or proctoscopy for a rectal biopsy. Pinching or rubbing the skin (pinch purpura).
Skin involvement: Waxy, translucent or purpuric papules, nodules and plaques that resemble nodular amyloidosis.
Macroglossia + carpal tunnel syndrome is a classic presentation → should trigger an investigation for amyloidosis.
Renal involvement → proteinuria → hypoalbuminemia and edema.
Cardiac involvement → CHF → dyspnea, ↑ jugular venous pressure, hepatomegaly and bilateral pedal edema.
Autonomic and sensory neuropathies.
Hepatomegaly.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
Histopathology: 1. Amorphous, homogeneous, hyalin, faintly eosinophilic & fissured masses of amyloid: In the dermis and in the subcutaneous tissues. ❶ Close to the epidermis → ± separated from epidermis by a narrow zone of collagen. Periappendageal. ❷ Perivascular → extravasated erythrocytes. ❸ 2. In the subcutaneous tissue → large aggregates of amyloid with infiltration of the walls of blood vessels and so-called amyloid rings “deposition of amyloid around individual fat cells” ❹ →the fat cells may then appear as if cemented together by the amyloid. 3. Inflammatory cells → abscent. 4. Bullous lesions → uncertain pathogenesis: The formation of clefts within large dermal amyloid deposits. From disruption of basal keratinocytes and the BMZ.
If there are no skin lesions: 1. Fine-needle aspirates of the abdominal fat often are of use in documenting the diagnosis. 2. Normal-appearing skin → positive in 40% of all patients “small deposits in ❹????→ forearm is the recommended area for biopsy. 3. Rectal mucosa. 4. Gingiva.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
SECONDARY SYSTEMIC AMYLOIDOSIS
Histopathology: AA amyloid is deposited in parenchymatous organs such as ❹ the kidneys, liver, spleen, and adrenal. These deposits are found first in the interstitium and blood vessel walls → progression → replace the parenchyma. Deposits within the glomeruli and peritubular tissues result in renal failure.
Fine-needle aspiration biopsy of the subcutaneous fat and staining of the aspirated material by the Congo-red method is the most sensitive method of diagnosis. Tissue biopsy of skin with underlying subcutaneous fat demonstrates deposits of AA amyloid in ❹????.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
PRIMARY LOCALIZED CUTANEOUS AMYLOIDOSIS LICHEN AMYLOIDOSIS & MACULAR AMYLOIDOSIS
Macular amyloidosis Lichen amyloidosis Nodular amyloidosis Description Confluent or rippled (“salt Rippled, hyperpigmented, Pink to yellow waxy nodules and/or and pepper”), pruritic, pruritic papules/plaques on plaques hyperpigmented patches extensor surfaces (esp. Acral. (upper back) shins) Derivation Keratinocyte tonofilaments Keratinocyte tonofilaments Ig light chains (usually keratin 5) (usually keratin 5) Protein Aker Aker AL Other Different but overlaps with Seen in MEN 2A May be a/w Sjogren’s, scleroderma & Facts notalgia paresthetica RA Progression to systemic amyloidosis in 7%
DD:
1. Hypertrophic lichen planus.
2. Lichen simplex chronicus.
3. Lichen amyloidosis.
Histopathology:
Amyloid Sparse pink deposits of amyloid (AK type) in superficial dermis, (Macular/Lichen) melanophages, no inflammation Amyloid Fissured, pale pink amyloid (AL type) material in superficial to mid dermis, (Nodular) and abundant plasma cells (distinguishes from colloid milium)
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
LIPOID PROTEINOSIS
Syn.: Hyalinosis Cutis Et Mucosae, Urbach-Wiethe disease
AR → mutations in the extracellular matrix protein 1 (ECM1) gene; ↑ in South Africa Thickening of BM and deposition of hyaline material in dermis → characteristic thickening of the skin, mucous membranes, and certain viscera
Infiltrated vocal cords → Hoarseness, hoarse cry or weak cry from is the first clinical sign (occurs in infancy and persists for life)
Cutaneous lesions Develop during first few 2 years of life in two overlapping stages First stage: vesicles and hemorrhagic crusts → face, extremities, and oral mucosa develop in association with trauma → “ice-pick” scars Second stage: ↑hyaline deposition within the dermis → yellow, waxy, and coalescing papules/nodules on the face/neck and extremities Beaded eyelid papules → “string of pearls” (50%) Verrucous nodules on elbows/knees/hands
Infiltration of mucosa of pharynx, soft palate, tonsils, and lips by yellow papules/plaques Thickened “woody” tongue; inability to protrude tongue (due to shortened frenulum)
Respiratory difficulty a/w URTIs → may require tracheostomy → major cause of early death Neurologic manifestations → seizures and neuropsychiatric symptoms, a/w pathognomonic sickle or “bean-shaped” calcifcations in temporal lobes or hippocampus
Histopathology: Pink hyaline BMZ material (type IV collagen; PAS-D+) surrounding capillaries, sweat coils, and in the thickened papillary dermis. Focal deposits in the deeper dermis. In verrucous lesions → the homogeneous bundles → oriented perpendicular to the skin surface.
Differential Diagnosis: 1. Porphyria: In lipoid proteinosis: much deeper & more extensive than in porphyria.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
PORPHYRIA
Histopathology: The same in all six types of porphyria.
1. Acral skin with compact orthokeratosis.
2. Solar elastosis: due to patient age and acral location. 3. Homogeneous, eosinophilic PAS positive and diastase resistant material: In & around blood vessels in the papillary dermis “reduplicated BM”. 4. BMZ →thickened. 5. Sclerosis → thick collagen bundles. 6. Cell poor, subepidermal bullae. Some blisters are dermolytic → beneath the PAS-positive BMZ → severe cases → scar. Others form in the lamina lucida → above the PAS-positive BMZ → in mild cases.
Festooning → Characteristic of the bullae of PCT Preservation of the dermal papillae in the floor of the bulla. Explanation: Eosinophilic material within and around the capillary walls in the papillae and the papillary dermis → rigidity of the upper dermis.
Caterpillar bodies → pink BMZ material in blister cavity and epidermis → PAS positive and diastase resistant.
DIF: Negative, may highlight vessels.
Differential Diagnosis: EPP: Hyaline cuff around post-capillary venules. Lipoid proteinosis: Affects superficial & deep vessels and eccrine glands. PCT: much smaller hyaline cuffs around superficial vessels + solar elastosis + caterpillar bodies + subepidermal bullae + festooning.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
Pseudoporphyria Cutanea Tarda (PCT):
In patients with CRF receiving hemodialysis → eruption similar to that of PCT → on
the dorsa of the hands and fingers → during the summer months.
NO Hypertrichosis, sclerodermoid features, and hyperpigmentation. NOrmal porphyrin studies However, in a few patients receiving hemodialysis for CRF, a true PCT coexists. Drug induced Pseudo-PCT: Furosemide, nalidixic acid, tetracycline hydrochloride, and NAPROXEN (#1). Histopathology: As in mild cases of porphyria.
Erythropoietic Protoporphyria (EPP): Most common form of porphyria seen in children. Hyaline cuff around post-capillary venules. No solar elastosis “patients avoid burning sensation associated with sun exposure”. Deficiency of ferrochelatase. The ONLY disorder of porphyrin meta bolism with normal urine porphyrins (EPP: empty pee pee). ↑ Protoporphyrins in the feces & blood.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
Amorphous “Pink Stuff in Dermis” DDx Amyloid Sparse pink deposits of amyloid (AK type) in superficial dermis, (Macular/Lichen) melanophages, no inflammation Amyloid Fissured, pale pink amyloid (AL type) material in superficial to mid (Nodular) dermis, and abundant plasma cells (distinguishes from colloid milium) Colloid Milium Fissured, pale pink deposits completely filling/expanding superficial-mid dermis (deeper than macular/lichen amyloid); extensive solar elastosis (adult form only); no inflammation (vs nodular amyloid) Erythropoietic Hyaline cuff around superficial vessels, no solar elastosis (because Protoporphyria patients diligently avoid sun) Lipoid Pink hyaline BMZ material (type IV collagen; PAS-D+) predominantly Proteinosis centered around superficial and deep (deeper than EPP) vessels and adnexae, with “onion skin” pattern
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
CALCINOSIS CUTIS
Calcinosis Cutis
Four forms 1. Metastatic calcinosis cutis. 2. Dystrophic calcinosis cutis. 3. Idiopathic calcinosis cutis. 4 4. Iatrogenic calcinosis cutis.
1. METASTATIC CALCINOSIS CUTIS
Due to hypercalcemia or hyperphosphatemia.
Hypercalcemia may result from: 1. Primary hyperparathyroidism. 2. ↑ Intake of vitamin D (Hypervitaminosis D). 3. ↑ Intake of milk and alkali (Milk-alkali syndrome). 4. ↑ Destruction of bone through osteomyelitis or metastases of a carcinoma. 5. Sarcoidosis.
Hyperphosphatemia: CRF (#1 cause of metastatic calcification):
Metastatic calcification may take one of two forms: 1. Benign nodular calcification 2. Calciphylaxis.
Benign nodular calcification: In the setting of CRF with prolonged secondary hyperparathyroidism. Large deposits of calcium in the skin and subcutaneous tissue in periarticular sites (# and size correlate with the severity of the hyperphosphatemia. Asymptomatic except for the pressure on surrounding structures. Normalization of serum calcium and phosphate levels may result in resorption of the lesions If larger deposits interfere with function, surgical removal is recommended.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
Calciphylaxis:
Syn: Uremic gangrene syndrome, Calcific uremic arteriolopathy Calcifying panniculitis
Life-threatening condition → progressive calcification of small and medium-sized vessels of the subcutis → necrosis. Most frequently arises in the setting of hyperparathyroidism associated with CRF (usually in patients with diabetes). ± ↑ serum calcium/phosphate product.
Clinically: present as panniculitis or vasculitis.
± Bullae, ulcerations, or a livido reticulosis-like eruption.
F > M
RFs: obesity, DM2, poor nutrition
High mortality (85%) due to gangrene or sepsis
Check protein C activity/function
Histology: thrombotic vasculopathy + vascular calcification + necrosis of skin/soft tissue with a clean background or accompanied by neutrophils.
Treatment: low calcium dialysis, phosphate binders, STS, TPA, parathyroidectomy, surgical debridement, management of tissue infections
Histopathology: Calcium deposits Deep blue → H&E. Black → von Kossa stain. In the subcutaneous fat → massive deposits. In the dermis → granules and small deposits.
Foreign-body reaction: Giant cells, an inflammatory infiltrate, and fibrosis.
Calcification of dermal or subcutaneous arteries or arterioles → infarctive necrosis → the involved vessels → calcification of the walls and intravascular fibrosis.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
2. DYSTROPHIC CALCINOSIS CUTIS
The calcium is deposited in previously damaged tissue. Normal serum calcium and phosphorus. CREST syndrome Spared internal organs. Calcinosis cutis. Raynaud's phenomenon. AICTD: most commonly seen in childhood DM and CREST Esophageal dysfunction. Calcinosis universalis (severe form) in DM > scleroderma. Sclerodactyly. Panniculitis: lobular, particularly pancreatic panniculitis, SC fat Telangiectasia. necrosis of the newborn, lupus profundus. Genodermatoses: PXE (calcification of dermal elastic fibers), Ehlers-Danlos syndrome (spheroids or spherules), PCT (longstanding) Infections: Onchocera volvulus and Taenia solium (Calcified cysts form around larvae or worms) Neoplasms: pilomatricomas (75%), BCCs, epidermal/ pilar cysts.
Histopathology: As in metastatic calcinosis cutis.
Treatment: Low calcium and phosphate diet Aluminum hydroxide and bisphosphonates Colchicine, probenecid and sodium thiosulfate Long-term treatment with diltiazem → ↓ size of calcium deposits (calcium transport into cells). Surgical excision in patients with localized masses that are painful or interfere with function.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
3. IDIOPATHIC CALCINOSIS CUTIS
1. Tumoral calcinosis: Idiopathic. Large subcutaneous calcified masses over large joints in healthy patients → ulceration. Familial. Black races. Associated with hyperphosphatemia (AR: GLANT3 or FGF23) or normophosphatemia (SAMD9).
Histopathology: As in metastatic calcinosis cutis. Discharge of calcium by: Ulceration. Transepidermal elimination.
2. Idiopathic calcified nodules of the scrotum (scrotal calcinosis) Idiopathic vs calcification of epidermoid cyst.
Histopathology: Amorphus masses of calcium. Smooth muscles scattered through the dermis + Rugated epidermis (genital skin).
3. Subepidermal Calcified Nodule
Age & Site: Chin of children & heel of newborn. Lesion: Single small, raised, hard nodule with verrucous or smooth surface. Solitary firm nodule → favors the head and neck region, most commonly the ears. They are also seen on the lateral aspects of the digits.
Histopathology: Pseudoepitheliomatous hyperplasia with transepidermal elimination of calcium. The calcified material → in the uppermost dermis.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
4. IATROGENIC CALCINOSIS CUTIS
1. Extravasation of intravenous solutions containing calcium or phosphate 2. Application of calcium-containing electrode paste for EMGs and EEGs 3. Application of calcium alginate dressings to denuded skin 4. Organ transplantation, especially liver
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
GOUT
Tophi: Site: Helix of the ears, over the bursae of the elbows, and on the fingers and toes. Lesion: When large → discharge a chalky material. Rarely → tophi on the fingertips or as panniculitis on the legs WITHOUT the coexistence of a gouty arthritis.
PODAGRA
1st Metatarsal Joint of Big Toe
Wakes Up Feeling Like Toe on Fire
Histopathology: 1. Tophi → Ethanol is best preservative. Formalin → dissolve the characteristic urate crystals → amorphous material (feathery clefts). 2. Urate crystals → needle-shaped crystals (closely packed → brown bundles). 3. Surrounded by Granulomatous infiltrate. 4. ± Ossification or calcification.
Even if fixed in formalin, the diagnosis of gout can be made without difficulty because of the characteristic rim of foreign-body giant cells and macrophages surrounding the aggregates of amorphous material.
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Michel R. Ibrahim The Dermis- Cutaneous Deposits
OCHRONOSIS
Two types: Endogenous ochronosis (alkaptonuria) → AR “absent homogentisic acid oxidase”. Exogenous ochronosis → topical application of a hydroquinone cream to exposed parts of the skin or contact with phenol (carbolic acid) → macular blue-black hyperpigmentation.
Histopathology: 1. The ochronotic pigment → yellow-brown or ochre color “thus the name ochronosis”. 2. The ochronotic pigment → fine granules free in the tissue and endothelial cells of blood vessels, in the BM and the secretory cells of sweat glands, and within scattered macrophages. 3. The most striking finding is the ochronotic pigment within collagen bundles → homogenization and swelling of the bundles. 4. The collagen bundles appear rigid and tend to fracture transversely with jagged or pointed ends → irregular, homogeneous, light brown clumps lie free in the tissue.
Silver (Argyria): Due to silver in alternative meds/elixirs and silver sulfadiazine on burn wounds Diffuse slate-gray pigmentation, ↑ photo-exposed areas. ± Scleral and nail hyperpigmentation. Deposits of silver in BMZ and membrana propria of eccrine glands (best seen with darkfield microscopy).
NUTRITIONAL DERMATOSES
1. Pellagra. 2. Acrodermatitis enteropathica. 3. Necrolytic acral erythema. 4. Necrolytic migratory erythema (Glucagonoma $).
Histopathology: Pallor of the superficial third of the epidermis ± necrosis. Confluent Parakeratosis and Psoriasiform epidermal hyperplasia.
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Michel R. Ibrahim The Histiocytoses
LANGERHANS CELL DISEASE Letterer-Siwe disease Hand-Schüller- Christian Eosinophilic granuloma Hashimoto-Pritzker disease Acute diffuse LCD chronic multifocal LCD Chronic focal LCD. Congenital self-healing reticulohistiocytosis (CSHRH) 0-2 years 2-6 years 7-12 years At birth Skin Skin Bone Limited to the skin. Bone & & Internal organs. Bone. Skin. Skin: Skin: Bone: Widespread red to brown 1-2mm, pink to skin colored papules, Early → as LSD. Single asymptomatic papulonodule → several pustules &/or vesicles in the scalp, Late → xanthomatous. granulomatous lesion. weeks → crust & involute. flexural areas & trunk. Coalescence → tender. Bone: Cranium, vertebrae, pelvis, Scale & crust with 2ry Triad: scapulae & long bones. impetiginization. Bone lesion. 3 Exophthalmos. Spontaneous fracture & Petechia & purpura. st Palmoplanter involvement + Nail. Diabetus insipidus. Osteomylitis may be the 1 DD: Seb D, Ecz., Scab., Intertrigo. sign. DI: Bone: Infiltration of post pit by LC. Osteolytic tender → uncommon TTT: vasopressin. except in the mastoid region → clinical picture of otitis media. Exophthalmos: Cranium → map appearance. Retro-ocular bone involvement. Organs: → prognosis. Lung. Premature loss of teeth → Liver. 2ry to gingival lesion. LNs. Low RBCs & platlets. Aggressive with organ failure. Chronic progressive. Indolent Self healing
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Michel R. Ibrahim The Histiocytoses
LANGERHANS CELL DISEASE
Histopathology: Perivascular or lichenoid infiltrates of Langerhans cells confined to the papillary and upper reticular dermis (may be follicular-centered). Cells → abundant eosinophilic or pale cytoplasms and longitudinally grooved or reniform “folded or lobulated, kidney-shaped ‘coffee-bean’” nuclei with small nucleoli. ± Epidermotropism. Eosinophils. S100, CD1a, Langerin (CD207; stains Birbeck granules→ most specific > CD1a) Birbeck granules by electron microscopy.
Acute disseminated LCD can reasonably be argued to be a malignancy because it is progressive, destructive, potentially fatal, and shows clonality. Some cases have been identified with marked cytologic atypia, including mitoses, and a poor clinical outcome.
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Michel R. Ibrahim The Histiocytoses
CONGENITAL SELF HEALING RETICULOHISTIOCYTOSIS
Histopathology: Numerous multinucleate giant cells and oncocytic macrophages showing abundant eosinophilic, finely granular cytoplasm → “ground-glass” appearance. Langerhans cells (abundant eosinophilic or pale cytoplasms and longitudinally grooved or reniform “folded or lobulated, kidney-shaped ‘coffee-bean’” nuclei with small nucleoli.) occupy the papillary and upper reticular dermis. ± Epidermotropism. Eosinophils. S100, CD1a, Langerin (CD207; stains Birbeck granules→ most specific > CD1a) Birbeck granules by electron microscopy. Extensive areas of dermal necrosis (possibly indicative of involution) may be more common in congenital self-healing disease than in the systemic variety of Langerhans cell histiocytosis.
Differential Diagnosis: Clinical workup to rule out extracutaneous involvement is mandatory because the histopathology of the skin-limited form of the disease can be virtually identical to the systemic type. Some cases of CSHRH may be clinically confused with: 1. The blueberry muffin syndrome. 2. Congenital leukemic infiltrates. 3. Mast cell disease.
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Michel R. Ibrahim The Histiocytoses
XANTHOGRANULOMA FAMILY
JUVENILE XANTHOGRANULOMA (JXG)
Age: During the first year of life; 20% → at birth. Because the lesions are also seen in adults, JXG is an imperfect term. Site: Face, neck, or upper trunk. Lesion: One or several red to yellow papules and nodules. In children → the lesions grow rapidly → regress within a year. In adults → solitary and persistent.
Clinical forms: 1. The micronodular variant → most common → infants with many small nodules. 2. The macronodular variant: few lesions, but → several centimeters in diameter. 3. The solitary giant xanthogranuloma > 5 cm. 4. Plaques, prominent nasal involvement (the Cyrano sign). 5. A lichenoid variant. 6. Subcutaneous or deep JXG. 7. JXG develop in LCD→ reflects the similar bone marrow origin of macrophages and LC.
Systemic complications: 1. Ocular involvement → glaucoma and bleeding into the anterior chamber is the most common “in < 10% of young patients”. 2. Oral lesions may occur. 3. An association between JXG, café-au-lait macules, neurofibromatosis I, and juvenile chronic myelogenous leukemia “rare”. 4. Other systems, including the CNS, kidney, lungs, liver, testes, and pericardium.
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Michel R. Ibrahim The Histiocytoses
Histopathology:
In mature lesions → granulomatous infiltrate containing foamy cells, FB giant cells, and Touton giant cells + macrophages, lymphocytes, and eosinophils.
The presence of giant cells, most of them Touton giant cells, showing a wreath of nuclei surrounded by foamy cytoplasm is quite typical for JXG, but not diagnostic as wreath- shaped giant cells can be seen in other disorders including some melanocytic nevi.
Immunohistochemistry: CD68, factor XIIIa, fascin.
The histologic features of: 1. Xanthogranuloma. 2. Benign cephalic histiocytosis. 3. Generalized eruptive histiocytosis. 4. Xanthoma disseminatum. Are nearly identical.
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Michel R. Ibrahim The Histiocytoses
RETICULOHISTIOCYTOSIS
1. Giant cell reticulohistiocytoma (GCRH). 2. Multicentric reticulohistiocytosis (MRH) “Lipoid dermatoarthritis”.
Both disorders occur almost exclusively in adults. The histologic picture is very similar in the two types but everything else is different.
GCRH: Diagnosed as a JXG or dermatofibroma. The clinical features, distribution, and course are identical to JXG. In > 90% of cases → the lesion is single. No systemic involvement.
MRH: “Lipoid dermatoarthritis”. Female. Female. Fifth. Fifth or sixth decade of life. Face. Nodules → on the extremities. Finger. Papules along the nail fold → “coral bead sign”. Papules on the Face (ears & perinasal) → leonine Facies. Nodules on the oral or nasal mucosa (in 50% of patients). Xanthelasmata (in25% of patients). Polyarthritis → mutilating, especially on the hands. Hyperlipidemia (30%-50%), internal malignancies (15%- 30%) & autoimmune diseases (5%-15%).
Histopathology: Sea of multinucleate giant cells and oncocytic macrophages with abundant eosinophilic, finely granular cytoplasm “two-toned” “ground-glass” appearance. Each histiocyte sits in a punched-out lacuna.
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Michel R. Ibrahim The Histiocytoses
ROSAI-DORFMAN DISEASE
Syn.: Sinus Histiocytosis with Massive Lymphadenopathy
Massive cervical lymphadenopathy “most common manifestation” → bilateral & painless. Benign disorder. Resolve spontaneously (few have persistent problems, and very few die). 10% have skin lesions (#1 sites = eyelids and malar cheek) → multiple red-brown or xanthomatous papules.
Histopathology: The skin lesions: The low-power view has been compared to that of a “lymph node in the skin”. Polymorphous infiltrate → lymphocytes, plasma cells and macrophages with clear cytoplasm “multinucleated or have a foamy cytoplasm”. Emperipolesis → lymphocytes & plasma cells are taken up by macrophages but not attacked and digested by enzymes → appear intact.
In the lymph nodes: The sinuses are greatly dilated and crowded with inflammatory cells, particularly macrophages. Abundant foamy cytoplasm and also display emperipolesis.
The cells are S-100 positive but CD1a negative, and NO Birbeck granules.
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Michel R. Ibrahim Xanthomas
XANTHOMAS
Histopathology:
Foamy cells → macrophages engulfed lipid. ± Giant cells, especially Touton type with a wreath of nuclei. Free lipids not yet taken up by macrophages (xanthoma with underlying lipid abnormality). The lipid droplets can be better seen if frozen or formalin-fixed sections are stained with fat stains such as scarlet red or Sudan red. Fixation artifact → formalin fixation and paraffin embedding → remove lipids → only their shadows are left behind. Larger extracellular deposits of cholesterol and other sterols leave behind clefts. Polarized light → Cholesterol esters are doubly refractile, whereas other lipids are not. Thus, tendon and tuberous xanthomas tend to be doubly refractile, whereas other xanthomas are not. Chronic lesions → fibrosis.
Foamy macrophages. Free lipids
Fat stains
Fixation artifact.
Fibrosis
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Michel R. Ibrahim Mastocytosis
MASTOCYTOSIS
Childhood Forms Adult Forms ❶Solitary mastocytoma: ❶Reddish-brown macules/papules: Single tan/yellow-tan plaque/nodule. Most common presentation in adults. Distal extremities. On trunk/proximal extremities. Self-resolves over 1-3 years. ↑ in # over time. Hyperpigmented. ❷Urticaria pigmentosa: Most common presentation in children. ❷Telangiectasia macularis eruptive Multiple light brown to red-brown perstans (TMEP): macules and papules. Telangiectatic macules and patches. Anywhere; start on trunk; spare No hyperpigmentation palms/soles/face. ❸Diffuse cutaneous mastocytosis ± Pruritus and flushing; blistering (bullous
mastocytosis) in about 1/4 patients. Symptoms improve by early adolescence, but skin lesions may not completely resolve. Systemic Mastocytoses More lesions → more likely to have ❶Indolent systemic mastocytosis. systemic symptoms: ❷Aggressive systemic mastocytosis. . Diarrhea, abdominal pain, and ❸Mast cell leukemia. wheezing/ dyspnea. . Anaphylaxis is rare, but possible.
❸Diffuse cutaneous mastocytosis: Infiltrated, red-brown, leathery plaques with peau d’orange appearance that can involve large areas of body Blister → erosions ↑incidence of systemic symptoms and progression to systemic mastocytosis
Darier’s sign (local erythema or urticarial wheal after friction or rubbing) → in all forms.
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Michel R. Ibrahim Mastocytosis
Histopathology: Uniformly spaced “fried-egg” mast cells → characterized by the presence of metachromatic granules in their cytoplasm → fill the papillary dermis and extend into reticular dermis in nodular lesions: . Not visible with routine stains. . Giemsa stain, toluidine blue (granules → purple) or tryptase. . Leder's stain (cytoplasm → red, NOT dependent on presence of granules). . CD117.
In the maculopapular type and TMEP → the mast cells are limited to a superficial perivascular infiltrate. In some mast cells, the nuclei may be round or oval, but in most mast cells, they are spindle shaped. The presence of > 5 perivascular mast cells around each vessel is suggestive of mastocytosis.
Eosinophils may be present in small numbers in all types with the exception of TMEP, → NO eosinophils because of the small numbers of mast cells within the lesions.
If a biopsy is taken shortly after the lesion has been stroked → ↑ number of eosinophils and extracellular mast cell granules.
The bullae: Subepidermal with mast cells & eosinophils.
The pigmentation is due to: . Hyperpigmentation of BCL. . Melanophages in the upper dermis.
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