: Pattern diagnosis of a not-so- difficult group of entities Hawaii 2019 Victor G. Prieto, MD, PhD Professor Depts of Pathology and Dermatology University of Texas-MD Anderson Cancer Center Houston TX, USA Sunset in Maui Outline •Introduction •Histologic examination •Septal vs. lobular •Illustrative seminar cases •Summary •(Presentation will be available) Introduction •Structure: –Lobules separated by fibrous septa –Within the septa run the vessels and nerves •Upper portion of panniculus contains eccrine and apocrine glands, and hair follicles Type of specimen

•Punches should be discouraged. Most sizes (5 mm) will result in very little adipose tissue •Skin ellipses are best Histologic analysis •Perpendicular sections •Systematic approach •Septal vs lobular •Type of infiltrate •Vascular involvement •(Special stains) Panniculitis •Vessel size and type (artery vs. vein) •Inflammatory infiltrate (neutrophils, eosinophils, macrophages, multinucleated giant cells, and granulomas) •Life of lesions •Clinical-pathologic correlation! Panniculitis • Usually no involvement of dermis • Septal: fibrosis and widening of the septa, with relatively little involving the lobules • Lobular: involvement of adipocytes, with relatively normal septa Clinical features

•56-yo woman •6-month history •Subcutaneous nodules on lower extremity Unremarkable overlying epidermis Widened and fibrotic septa Widened and fibrotic septa Histiocytes, lymphocytes Scattered foreign body giant cells and eosinophils Histiocytes, lymphocytes Scattered foreign body giant cells and eosinophils is not identified Clinical features: Acute form •Sudden •Tender, bright red or dusky red-purple nodules (1 to 5 cm in diameter) •Anterior surfaces lower legs (also calves, thighs, forearms, hands, and face) Clinical features: Acute form

•Usually no ulceration •Involution of individual lesions within a few weeks •Intermittent appearance of new lesions (several months) Clinical features: Acute form •Fever, malaise, leukocytosis, and arthropathy •Bilateral hilar adenopathy (pulmonary infections) •10% to 20% of patients with sarcoidosis (good prognosis) Chronic Form: Histologic features •Edema of septa •Lymphohistiocytic infiltrate (Neutrophils, eosinophils) •Fibrin deposition and extravasation of erythrocytes (rare vasculitis - estrogenic oral contraceptives) Histologic features

•Periphery of lobules •No necrosis of fat •Macrophages around small blood vessels or a slit-like space (Miescher radial nodules) Differential diagnosis

• • •Panarteritis nodosa •Superficial migratory thrombophlebitis •Other granulomatous processes Associations •Strep, Mycobact, Yersinia, Brucella, Leptospira, and Chlamydia •Coccidioidis, Histoplasma, dermatophytes, and Blasto •Toxoplasmosis •Herpes simplex, infectious mononucleosis •Lymphogranuloma venereum, ornithosis, and psittacosis Associations •Leukemia and Hodgkin disease •Other carcinomas •Adjuvant therapy •Crohn disease •Sarcoidosis Etiology

•Type IV delayed hypersensitivity reaction •Trauma or sluggish blood flow Key points •Wide septa •Predominantly chronic infiltrate •Multinucleated giant cells •Granulomas Clinical history

•30-yo man •Skin nodules •Right thigh Superficial and deep dermis Extensive necrosis Mixed infiltrate Extensive necrosis Extensive necrosis Bacterial colonies Birefringent material (Energy dispersive spectrometry - magnesium silicate, consistent with talc) Factitious Panniculitis (Webster’s New Universal Unabridged Dictionary) Clinical features •Munchausen syndrome •Mentally ill persons, drug addicts •“Woody” induration •Blunt trauma: Blue edema (hematoma in subcutaneous tissue) •Medications, silicone, feces, talk, or milk AAD Histologic features •Mixed lobular and septal •Mixed acute and chronic infiltrate •Sclerosing lipogranulomas or “Swiss- cheese” (oily substances) •Superimposed bacterial infection •Polarized light, electron microscopy and spectrophotometry Differential diagnosis

•Infection Key points

•Suspect the diagnosis •Also dermal infiltrate •Polarization Clinical history

•73-yo female •Left ankle •Very painful ulcerated lesion •Rolled base Pale upper epidermis Clusters of thick-walled vessels Fibrosis, thick vessels Pale upper epidermis Clusters of thick-walled vessels Focal fibrin and neutrophils Fibrosis, thick vessels, and focal lipomembranous change Clinical features •Synonyms: Sclerosing panniculitis, hypodermatitis sclerodermiformis, and membranous •Indurated, inflammatory plaques on lower extremities •Ischemia •Mottled hyperpigmentation of skin Histology

•Stasis dermatitis •Adipose tissue: fibrosis and lipomembranous change Etiology •Ischemia •Low fibrinolytic activity •Low proteins C and S Key points

•Thick vessels •Fibrosis •Lipomembranous change Clinical History 19-yo woman Several month history Painful nodules on abdomen, arms, and buttocks “T-cell lymphoma Dx”

Unremarkable epidermis Dense infiltrate (dermis/SCT) Lobular pattern Dense infiltrate Mixed lymphocytes, plasma cells Aggregates of lymphocytes Focal fat necrosis Lymphocytes, plasma cells Rimming of lymphocytes Lymphocytes, plasma cells Rimming of lymphocytes CD4 CD8 Additional Studies

1:640 ANA EBER - TCR (PCR) - Lupus Profundus Mimicking Panniculitis T-cell Lymphoma Key Points •Histologic examination •Immunoperoxidase (mixed CD4 / CD8 infiltrate) •(Usually) Absence of re-arrangement of TCR •Rimming is not pathognomonic! Clinical features •Deep firm nodules •Overlying skin may be abnormal (discoid lupus) or unremarkable •Trunk and proximal extremities, (lateral aspects of upper arms, thighs, and buttocks) Clinical features •Painful lesions •Ulceration and depressed scarring •Loss of hair, erythema, poikiloderma, and epidermal atrophy •“Lupus profundus” •70% also have discoid lupus •50% have systemic lupus Histologic features •Deep lymphocytic infiltrate with plasma cells •Germinal centers •Fibrinoid necrosis •Increased mucin •Deep vasculitis Histologic features •50% positive IF (DEJ) (IgM and C3) •Also blood vessel walls •Trauma may be involved (increased vascular permeability with leakage of circulating ANA or immune complexes) Differential Diagnosis

• Subcutaneous T-cell lymphoma (CD4-/ CD8+ proliferation with “rimming”) • Other lymphomas • “Histiocytic cytophagic panniculitis” (not accepted by everybody, possibly a reaction pattern to lymphomas and viral infections) Clinical history

•33-yo woman •Left leg nodule •Clinical diagnosis: granuloma annulare Lobular panniculitis (slight thickening of septa) No sparing areas Vasculitis Mixed infiltrate, giant cells Normal amount of mucin Special stains negative for organisms Nodular vasculitis Clinical features •Young to middle-aged women •Painful nodules •Calf •Several weeks •Common recurrences •(Drainage and ulceration) Histologic features •Lobular panniculitis •Necrosis of adipose tissue •Neutrophils (early) and in necrosis •Macrophages, lipophages, and granulomas Etiology •Nodular vasculitis = erythema induratum of Bazin (?) •Clinical features of mycobacterial infection (Mantoux test or active TB) •(rarely hepatitis C) •Necrosis due to ischemia (vasculitis of small to medium-sized vessels) Differential diagnosis •Erythema induratum of Bazin (?) •Other infections •Angiocentric T-cell lymphoma •Erythema nodosum •Cold panniculitis Clinical history

•11-day-old girl •Multiple, hard, erythematous subcutaneous nodules •Scalp, trunk, and extremities Unremarkable epidermis and dermis Lobular panniculitis Small and clustered glands Mostly lobular panniculitis “Empty” spaces Neutrophils and macrophages Fine, needle-like crystalline structures in a radial arrangement No vasculitis Subcutaneous fat necrosis of the newborn Clinical features • Premature or full-term infants • Delivery with forceps • Hypothermia (cardiac surgery) • Indurated nodules and plaques • Days after birth • Caseous material rarely • Spontaneous resolution (death) Clinical features •Defect in composition and metabolism of fat (greater saturation of lipids) •Newborn infants and 40% infants (<6 mo), application of ice cubes to the skin produces panniculitis •Trauma (?) Histologic features •Fat necrosis •Macrophages and giant cells •Crystalline fat (needle-shaped clefts in a radial arrangement) •Frozen sections, doubly refractile •Small calcium deposits Differential diagnosis

• •Steroid treatment •Traumatic fact necrosis •Infectious panniculitis Key points

•Age •Crystals Clinical history

•31-year-old woman •Questionable history of “surgery” to this area Dermal and SCT fibrosis Mixed septal/lobular Dermal and SCT fibrosis Irregular size and shape of adipocytes Lymphocytes and macrophages Lipogranulomas Expression of lysozyme Histology

•Fibrosis •Lymphocytes and macrophages •Lipogranulomas •Expression of lysozyme Traumatic fat necrosis Clinical features •Physical: pressure, cold, heat, or electricity •Chemical: insulin, demerol, pentazocine, etc •Oily substances: paraffin or silicone Histologic features •Liquefaction and ulceration •Thick oily fluid •Healing by depressed scarring •Cold-induced lesions usually do not ulcerate (except pernio or cryoglobulinemia Histologic features •Early: Acute inflammation and aggregation of neutrophils and focal fat necrosis with hemorrhage •Late: Lymphocytes and macrophages with fibrosis •Vasculitis usually is absent Histologic features

•“Fat cysts” •Osmium tetroxide: unsaturated double bonds in endogenous lipids •Polarized light Differential diagnosis

•Infection •Factitious Key points •Suspect it! •Polarization Clinical history

•50-yo man •Tender nodules on the left leg •History of melanoma on the let with prior metastasis. Tx: Pembrolizumab Anti PD-1/PD-L1. Other

• Panniculitis mimicking recurrence • Tetzlaff et al. JCP 2017 Anti PD-1/PD-L1: Other Reactions

• Metastatic SCC, Nivolumab • Pruritic vesicles and blisters on the neck, trunk, extremities Jour et al. JCP 2016; 43 (8): 688-696 Anti PD-1/PD-L1

• Subepidermal blister with mixed infiltrate of neutrophils, lymphocytes and eosinophils in the blister cavity Anti PD-1/PD-L1

• PAS floor of the blister. DIF heavy, linear IgG and C3 immune deposits on the blister roof • Bullous pemphigoid Panniculitis associated with Immunecheckpoint Inhibitors Clinical history •59-yo woman •2-week history •Large nodules on the lower extremities and abdomen •Tender Predominantly lobular infiltrate Homogenized adipose tissue Focal calcification Saponification Pancreatic adenocarcinoma Pancreatic Fat Necrosis Clinical features •Tender, ill-defined, red-brown nodules •Lower extremities (abdomen) •Ulceration •Drainage of oily substance Clinical features (II) •Associated with pancreatic disease (pancreatitis or neoplasm) •Release of pancreatic enzymes may induce permeability of the microcirculation and cause fat necrosis •Treatment of underlying disease Histologic features •Mostly lobular panniculitis •No vasculitis •Ghost cells (necrotic and calcified adipocytes) •Saponification (yellowish material with calcification) Differential Diagnosis •Factitious panniculitis •Local injections (interferon) Key Points •Saponification of fat •Calcification •Underlying disease •Rarely other causes Banyan Tree. Lahaina Summary •Lobular vs. septal •Septal: Erythema nodosum •Lobular: Erythema induratum •Vasculitis: Systemic? •Neutrophils, dermal infiltrate: special stains •Polarized light (foreign material) •Newer therapies Thank you