4. Updates in inflammatory dermatopathology.pdf

Seminars in Diagnostic Pathology 39 (2022) 288–297 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Review article Updates in inflammatory dermatopathology Sam Wu *, Collin-Jamal Smith, Jayson R Miedema, Paul B Googe Universit...

Seminars in Diagnostic Pathology 39 (2022) 288–297 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Review article Updates in inflammatory dermatopathology Sam Wu *, Collin-Jamal Smith, Jayson R Miedema, Paul B Googe University of North Carolina at Chapel Hill School of Medicine, 410 Market Street Suite 400, Chapel Hill, NC 27516, United States Introduction The interpretation of biopsy specimens of inflammatory disorders of the skin is challenging in that the microscopic findings must be considered in the context of the clinical presentation of the patient in order to render an informative and accurate diagnosis. This reality is reflected in the organization of inflammatory dermatopathology into categories known as “tissue reaction patterns”, each of which encom­ passes multiple clinical entities. As distinction between these specific entities within a reaction pattern cannot always be reliably performed solely on the basis of histopathologic findings and inflammatory der­ matoses may on occasion exhibit non-classic histology, sign-out of in­ flammatory dermatopathology may at times result in a descriptive report and a differential diagnosis. Effective communication with the clinician is critical in synthesizing biopsy findings with clinical data to further refine the diagnosis or to recognize when clinicopathologic correlation is lacking and further investigations may be warranted. This article will review the features of the major reaction patterns, discuss the common entities that reside within each category, and highlight the histopathologic findings that may assist in discrimination with a focus on recent updates in the literature. Spongiotic dermatitis Spongiosis refers to the presence of intercellular edema between epidermal (or follicular) keratinocytes resulting in an increase in the space between adjacent keratinocytes in which the intercellular des­ mosomes may be visualized. Additional features of spongiotic dermatitis include intraepidermal vesicle formation, exocytosis of lymphocytes (or at times, neutrophils, eosinophils, or histiocytes) into the epidermis, dermal inflammation, and changes of the stratum corneum including parakeratosis and collections of serum. Spongiotic dermatitis may be further classified into acute, subacute, and chronic phases, in which intraepidermal vesiculation is seen in acute form (Fig. 1A), the pro­ gressive development of epidermal acanthosis and parakeratosis occurring in the subacute and chronic forms (Fig. 1B), and the presence of papillary dermal fibrosis seen in chronic cases (Fig. 1C) [1,2]. Clinical entities exhibiting a spongiotic pattern include but are not limited to atopic dermatitis, irritant and allergic contact dermatitis, id reaction * Corresponding author. E-mail address: [email protected] (S. Wu). https://doi.org/10.1053/j.semdp.2022.02.003 Available online 24 February 2022 0740-2570/© 2022 Elsevier Inc. All rights reserved. (‘autoeczematization’), nummular dermatitis, stasis dermatitis, pityri­ asis rosea, seborrheic dermatitis, and eczematous medication reactions. The presence of intraepidermal clusters of Langerhans’ cells has been shown to be associated with allergic contact dermatitis. Ves­ iculobullous disorders such as bullous pemphigoid and pemphigus and arthropod bite reaction should be considered in addition to primary spongiotic disorders in the presence of eosinophilic spongiosis. The presence of multifocal parakeratotic mounds and the “lifting” or “tilting” of individual mounds in which only one side of the mound is attached to the stratum corneum has been described as a feature of pityriasis rosea [5,6]. (Fig. 2) Psoriasiform dermatitis Psoriasiform hyperplasia describes a pattern of regular acanthosis of the epidermis with elongation of rete ridges. The prototypical example of a psoriasiform dermatitis is psoriasis of which classic diagnostic fea­ tures include intracorneal neutrophils, diminution or loss of the granular layer, thinning of the suprapapillary epidermis, dilated capillaries in dermal papillae, and the presence of neutrophilic spongiosis [1,7]. (Fig. 3A) It should be noted that non-classic features such as vacuolar changes, dyskeratosis, and eosinophilia may be seen with some fre­ quency in cases of psoriasis and do not reliably exclude this diagnosis. Other entities exhibiting a primarily psoriasiform reaction pattern include lichen simplex chronicus/prurigo nodularis, and pityriasis rubra pilaris. Lichen simplex chronicus (LSC) and prurigo nodularis are characterized by compact hyperkeratosis with formation of a stratum lucidum, hypergranulosis, and vertically oriented collagen fibers within dermal papillae. As these epidermal changes resemble those seen in volar skin, albeit with preserved pilosebaceous units, this constellation of findings has been termed the “hairy palm sign”. (Fig. 3B) Clini­ cally, lichen simplex chronicus and prurigo nodularis present as thick­ ened, often hyperpigmented plaques and nodules respectively and arise as a consequence of chronic scratching/rubbing of the skin. Pityriasis rubra pilaris (PRP) presents as erythematous, scaly plaques often asso­ ciated with keratoderma and is characterized histologically by vertically and horizontally alternating parakeratosis in a “checkerboard” pattern and on occasion may demonstrate epidermal acantholysis [10,11,12, 13]. (Fig. 3C) Some recently-described entities with histopathologic S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 Fig. 1. A) Intraepidermal spongiotic vesicle with an unaltered stratum corneum displaying basket-woven orthokeratosis in acute spongiotic dermatitis. (H&E, 100x) B) Development of epidermal acanthosis and parakeratosis in association with intracorneal serum (arrow) occurs in subacute spongiotic dermatitis. (H&E, 200x) C) Prominent, psoriasiform epidermal acanthosis in chronic spongiotic dermatitis. Papillary dermal fibrosis may also be seen. (H&E 40x). psoriasis or PRP. These lesions are recalcitrant to conventional therapies for psoriasis but respond well to ustekinumab [17,18]. Nutritional de­ ficiencies such as acrodermatitis enteropathica or glucagonoma syn­ drome also exhibit psoriasiform epidermal changes with superficial epidermal pallor and keratinocyte dysmaturation [19,20,21,22]. A frequent challenge in interpreting biopsies with psoriasiform changes is the distinction of psoriasis from other conditions with over­ lapping histopathologic features such as chronic spongiotic dermatitis or mycosis fungoides. Recent literature suggests strong and diffuse expression of IL-36 throughout the upper epidermis is a feature of pso­ riasis and may assist in distinction from forms of eczema, mycosis fun­ goides, LSC, and syphilis but not from acute generalized exanthematous pustulosis, PRP, or lichen planus [23,24,25]. Fig. 2. Delicate mound of “lifted” or “tilted” parakeratosis attached to the stratum corneum at one end in pityriasis rosea (H&E, 40x). Interface dermatitis Interface dermatitis may present with vacuolar alterations of the dermoepidermal junction in association with dyskeratotic keratinocytes and a sparse inflammatory infiltrate (termed vacuolar interface derma­ titis) or alternatively exhibit additional findings of a dense band-like inflammatory infiltrate (termed lichenoid interface dermatitis) which may obscure the dermoepidermal junction. Melanin pigment inconti­ nence is often observed in the dermis as a consequence of damage to the features of PRP but distinct clinical presentations include facial discoid dermatosis and CARD14 -associated papulosquamous eruption (CAPE). Facial discoid dermatosis presents with recalcitrant scaly erythematous plaques on the face and has been proposed to represent a subtype of PRP [14,15,16]. CAPE presents with early onset of psoriasiform lesions with prominent facial involvement in the context of a strong family history of Fig. 3. A) Psoriasis is characterized by regular acanthosis of the epidermis with elongation of rete ridges, loss of the granular layer, thinning of the epidermis overlying dermal papillae, dilation of dermal capillaries, and parakeratosis with collections of intracorneal neutrophils (arrow). (H&E 100x) B) Lichen simplex chronicus demonstrates epidermal acanthosis with compact hyperkeratosis, hypergranulosis, and formation of a stratum lucidum (arrow) (H&E 40x) with C) vertically oriented collagen bundles in the dermis. (H&E, 100x) D) Pityriasis rubra pilaris exhibits mounds of parakeratosis alternating vertically and horizontally in a “checkerboard” pattern. (H&E 100x). 289 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 Fig. 4. A) Lichen planus demonstrates epidermal acanthosis with squamatization of the basal keratinocytes and a “saw-tooth” configuration of the rete ridges overlying a band-like lymphocytic infiltrate in the dermis (H&E 100x) B) Vacuolization of the dermo-epidermal junction is accompanied by colloid bodies (arrows) and melanin pigment incontinence within the dermis. (H&E 400x). C) Hypertrophic lichen planus additionally exhibits pseudoepitheliomatous hyperplasia that must be distinguished from well-differentiated squamous cell carcinoma. (H&E, 40x) D) In lichen sclerosus, the lichenoid infiltrate is separated from the atrophic epidermis by a zone of homogenized dermis. (H&E, 40x). dermoepidermal junction. In practice, the density of inflammation often exists along a spectrum and vacuolar and lichenoid interface dermatitis should not be conceptualized as mutually exclusive categories [26,27]. Lichenoid interface dermatitis is typified by lichen planus (LP), which additionally exhibits irregular epidermal acanthosis with a ‘sawtooth’ configuration of the rete ridges, wedge-shaped zones of hyper­ granulosis, squamatization of basal keratinocytes, colloid bodies, and formation of clefts between the epidermis and dermis (‘Max-Joseph space’) which can occasionally coalesce to form vesicles. (Fig. 4A) A variant of lichen planus known as hypertrophic lichen planus (HLP) exhibits prominent pseudoepitheliomatous hyperplasia and variable dermal eosinophilia. (Fig. 4B) HLP may mimic well-differentiated squamous cell carcinoma or keratoacanthoma; the presence of transepidermal elimination of elastic fibers has been described to occur in keratoacanthomas and squamous cell carcinomas but not in hyper­ trophic lichen planus [30,31]. Lichenoid medication eruption should be considered in the differential diagnosis of LP, and while histopatholog­ ical clues such as parakeratosis, interruption of the granular layer, and tissue eosinophilia may suggest a medication-induced lichenoid dermatitis, correlation with medication history is necessary to establish the diagnosis. In the oral mucosa, the possibility of contact allergy due to amalgam should be considered as a cause of lichenoid mucositis. It should be noted that lichenoid inflammation may be associated with benign and malignant cutaneous neoplasms such as benign lichenoid keratoses, lichenoid actinic keratoses, and melanomas among others. On occasion, nests of cells at the dermoepidermal junction demonstrating immunoreactivity to multiple melanocytic markers can be seen associated with lichenoid inflammation in the clinical context of a rash, underscoring the need for clinicopathologic correlation to avoid misdiagnosis of a melanocytic neoplasm [34,35,36]. Other lichenoid interface dermatitides include lichen sclerosus, lichen nitidus, and lichen striatus. In lichen sclerosus, the inflammatory infiltrate is often more sparse than in lichen planus, and separated from the epidermis by a homogenized superficial dermis. Dermal Fig. 5. A) Erythema multiforme is the prototypical vascuolar interface dermatitis. In this image it is presenting on acral skin with necrotic keratino­ cytes along the basal layer and minimal alteration of the stratum corneum reflecting an acute onset. (H&E 40x) B) Stevens Johnson syndrome/Toxic epidermal necrolysis is characterized by a vacuolar interface dermatitis, clas­ sically paucicellular, with full thickness epidermal necrosis and basket-woven orthokeratosis. At stages in their evolution, significant overlap exists between the histological pictures of erythema multiforme and SJS/TEN. (H&E, 40x). eosinophilia, elastophagocytosis and increase of deeper dermal elastic fibers may be also be seen [37,38,39,40,41]. The infiltrate in lichen nitidus often forms nodular aggregates encircled by the surrounding rete ridges in a “ball-in-claw” configuration. Lichen striatus can exhibit in addition to lichenoid inflammation a superficial and deep perivascular 290 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 Fig. 6. Discoid lupus erythematosus (the prototypical chronic cutaneous lupus erythematosus) is characterized by epidermal atrophy, follicular plugging, basement membrane thickening (arrow), superficial and deep inflammation, vascular ectasia, and dermal mucin deposition. (A, H&E 40x; B, H&E 200x). and periadnexal infiltrate. Erythema multiforme is a prototypical vacuolar interface dermatitis with sparse/minimal inflammation, vacuolar changes of the dermoepi­ dermal junction, and prominent scattered dyskeratotic keratinocytes. (Fig. 5A) Keratinocyte necrosis may become confluent leading to zones of full-thickness epidermal necrosis and secondary vesicle formation. The stratum corneum usually exhibits basket-woven orthokeratosis, reflecting the acute nature of the process. It should be noted that erythema multiforme and Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN), while clinically distinct entities, are indistin­ guishable histologically. (Fig. 5B) As the latter can be associated with significant morbidity and mortality, assessment of the clinical presen­ tation of the patient is important when evaluating a biopsy with these findings. Loss of desmoplakin staining on immunohistochemistry is seen in erythema multiforme and SJS/TEN and may assist in the critically important distinction of these entities from their histopathologic mimics. Cutaneous acute graft versus host disease (aGVHD) exhibits overall similar features, although findings of lymphocytes adjacent to necrotic keratinocytes (“satellite cell necrosis”) and involvement of the adnexal epithelium are associated with aGVHD. Histopathologic grading of cutaneous aGVHD is graded according to the Lerner criteria, but is of unclear prognostic significance in contrast to clinical grading [44,45]. Connective tissue disorders such as cutaneous lupus erythematosus and dermatomyositis also exhibit primarily a vacuolar interface pattern of inflammation. The findings are most subtle in acute cutaneous lupus erythematosus which demonstrates vacuolar alterations with sparse inflammation. In contrast, discoid lupus erythematous exhibits more prominent epidermal changes (atrophy, follicular plugging, basement membrane zone thickening) and inflammation which adopts a superficial and deep perivascular and periadnexal pattern. (Fig. 6) Subacute cutaneous lupus erythematosus exhibits features intermediate between those of acute cutaneous lupus erythematosus and discoid lupus erythematosus. Some forms of chronic cutaneous lupus ery­ thematosus such as tumid lupus erythematosus and lupus panniculitis may lack epidermal changes in a subset of cases. The former pre­ sents as superficial and deep perivascular and periadnexal lymphocytic inflammation while the latter is a lymphocytic lobular panniculitis with hyalinization of the subcutaneous fat associated with lymphoid aggre­ gates and plasma cells [47,48]. Reticular dermal mucin deposition is a frequent feature of all forms of cutaneous lupus and dermatomyositis. The histopathologic features of dermatomyositis are similar to those of acute cutaneous lupus erythematosus and distinction may be difficult on histopathological grounds alone. Clusters of CD123+ plasmacytoid dendritic cells in a perivascular and periadnexal pattern within the dermis has been reported as a feature of various forms of cutaneous lupus erythematosus that may be helpful in distinguishing this condition from histopathological mimics, while localization of plasmacytoid dendritic cells to the epidermis is associated with dermatomyositis [50, 51,52,53,54,55]. Immunofluorescence studies may also be helpful in the evaluation of connective tissue disorders. The lupus band test assesses for the deposition of immunoglobulins IgA, IgG, and IgM as well as complement in a granular pattern along the dermoepidermal junction. The rate of positive lupus band tests varies among subtypes of lupus erythematosus, with lesional versus non-lesional skin, and with sun-protected or sun-exposed skin and is further complicated by the variability in the definition of a positive test. One proposed criteria for a positive lupus band test is the presence of IgM in a continuous band of at least moderate intensity involving at least 50% of in sun-exposed skin or an interrupted band of IgM of at least moderate intensity in Fig. 7. Pityriasis lichenoides exists as an acute form and a chronic form. In the acute form (shown), there is a wedge-shaped inflammatory infiltrate with interface changes, prominent lymphocytic scattering into the epidermis (exocytosis), and erythrocyte extravasation into the dermis. While the acute form is most common in children, both forms can be seen in all ages. (A, H&E 40x; B, H&E 100x). 291 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 Fig. 9. Bullous pemphigoid is an autoimmune disorder which demonstrates subepidermal vesicle formation associated with blister cavity (inset) and dermal eosinophilia (H&E 100x; inset: H&E 400x). epidermal hyperplasia, prominent lymphocyte exocytosis, dense dermal inflammation and erythrocyte extravasation within the dermis and epidermis. The degree of inflammation and interface changes may be less pronounced in PLC. While pityriasis lichenoides is typically classified as a benign inflammatory dermatosis, the presence of T-lymphocyte clonality is well-documented in this condition [64,65]. This serves as an illustration of the fact that lymphocyte clonality in isolation is insufficient grounds to warrant a diagnosis of lymphoma as clonal populations of lymphocytes have been identified in a variety of benign inflammatory dermatoses in addition to pityriasis lichenoides. Positive clonality studies in cutaneous lymphoid infiltrates must be interpreted in the context of histopathological, immunohistochemical, and clinical findings. Fig. 8. A) Pemphigus foliaceus shows superficial acantholysis and vesicle for­ mation beneath the stratum corneum/within the upper epidermis due to im­ mune mediated loss of intercellular desmosomal attachements. (H&E, 100x) B) Pemphigus vulgaris demonstrates acantholysis of the suprabasilar keratino­ cytes. Some of likened the appearance of the remaining basal keratinocytes to rows of “tombstones”. Extension of acantholysis down hair follicles (arrow) is characteristic of this condition. (H&E, 100x). Vesiculobullous dermatoses sun-protected skin, with the presence of additional immunoreactants further enhancing the specificity of the test [46,56]. Positive staining in epidermal keratinocytes is also strongly suggestive of connective tissue disease, with a nuclear pattern suggesting systemic lupus erythematosus or mixed connective tissue disease and a “dust-like” cytoplasmic pattern suggesting subacute cutaneous lupus erythematosus or systemic lupus erythematosus [57,58]. Finally, the presence of C5b-9 deposition along the dermoepidermal junction and within dermal vessels in the absence of a positive lupus band test supports a diagnosis of dermatomyositis over lupus erythematosus. While there is tremendous diversity in the reaction patterns that medication eruptions may produce, interface dermatitis (whether lichenoid or vacuolar) has been reported as the most common histologic presentation of medication eruptions including in cases of morbilliform (exanthematous) medication eruptions in which the vacuolar interface alterations are subtle and accompanied by perivascular and interstitial inflammation [60,61]. The histopathologic features of morbilliform medication eruptions may overlap with those of viral exanthems. Fixed drug eruptions represents another clinically distinct entity pre­ senting with round to oval lesions that recur at the same site with each episode of medication exposure which exhibits an interface dermatitis on histology, in which dermal melanin pigment incontinence may be prominent especially in recurrent cases. The existence of multiple patterns of inflammation within a biopsy specimen is suggestive of a medication eruption and is common in the severe cutaneous adverse reaction known as drug rash with eosinophilia and systemic symptoms (DRESS). Another entity sometimes classified as an interface dermatitis that exhibits features of other reaction patterns is pityriasis lichenoides comprised of clinically distinct subtypes pityriasis lichenoides vari­ oliformis et acuta (PLEVA) and pityriasis lichenoides chronica (PLC). (Fig. 7) The former presents clinically as vesicular and ulcerated papules whereas the latter presents as scaly, erythematous and hyperpigmented plaques. In PLEVA, interface changes are accompanied by psoriasiform Vesicle or bullae formation within the skin may occur as a sequela of an inflammatory process classified in another section of this article (i.e. acute vesicular contact dermatitis, bullous lichen planus), as a conse­ quence of infection, exogenous injury, ischemia, genodermatosis, or as an autoimmune disorder which is the focus of this section. Vesicle formation beneath the stratum corneum/within the upper epidermis can be seen in pemphigus foliaceus which is associated with acantholysis or separation of adjacent keratinocytes due to loss of intercellular desmosomal attachments. (Fig. 8A) Staphylococcal scalded skin syndrome and bullous impetigo comprise the primary dif­ ferential diagnostic considerations. The presence of neutrophilic inflammation forming a subcorneal/intraepidermal pustule should raise consideration of IgA pemphigus as well as other non-immunobullous conditions such as pustular psoriasis, acute generalized exanthematous pustulosis, bullous impetigo, candidiasis, dermatophytosis, and sub­ corneal pustular dermatosis. Immunofluorescence demonstrates inter­ cellular deposits of IgG and C3 in the upper epidermis in pemphigus foliaceus and IgA in IgA pemphigus. Pemphigus vulgaris demonstrates acantholysis in a suprabasilar distribution, with the remnant basilar keratinocytes along the floor of the blister cavity likened to tombstones. (Fig. 8B) In both PF and PV, the acantholytic changes may extend along follicular epithelium and are associated with miniaturization of sebaceous glands [69,70]. Immunofluorescence in pemphigus vulgaris demonstrates intercellular IgG and C3 along the lower epidermis. The presence of nuclear molding, multinucleation, and/or chromatin margination in addition to acan­ tholysis would suggest herpesvirus infection. Additional differential diagnostic considerations would include the genodermatoses Darier’s disease with characteristic dyskeratotic keratinocytes comprising corp ronds and corp grains and Hailey-Hailey disease which typically exhibits acantholysis at all levels of the epidermis. Grover’s disease, or transient acantholytic dermatosis, is an acquired condition which may histologi­ cally resemble pemphigus vulgaris, Darier’s disease, or Hailey-Hailey 292 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 are localized to dermal papillae in dermatitis herpetiformis in contrast to a more diffuse distribution in linear IgA bullous dermatosis and bullous lupus erythematosus. Cell-poor subepidermal vesiculobullous dermato­ ses include epidermolysis bullosa acquisita and porphyria cutanea tarda. The immunofluorescence findings of subepidermal ves­ iculobullous dermatoses are listed in Table 1. Direct immunofluores­ cence should be performed on perilesional skin within 1 cm of vesicles/bullae as immunoreactants may be difficult to detect and localize in lesions skin due to degradation and/or re-epithelialization with the exception of porphyria in which sampling of lesional skin is recommended [77,78]. Indirect immunofluorescence on salt-split skin further localizes the deposition of immunoreactants in the skin and helps distinguish among various subepidermal blistering disorders. Table 1 Direct and indirect immunofluorescence findings in various subepidermal autoimmune blistering disorders [77,112]. BMZ: basement membrane zone. Disease Direct Immunofluorescence Indirect Immunofluorescence on salt-split skin Bullous pemphigoid Mucous membrane pemphigoid Linear IgA bullous dermatosis Dermatitis herpetiformis Bullous lupus erythematosus Linear IgG and C3, nserrated pattern along BMZ Linear IgG and C3 along BMZ Epidermal Epidermolysis bullosa acquisita Porphyria cutanea tarda Linear IgA +/- C3 along BMZ Epidermal (dermal in antiepiligrin mucous membrane pemphigoid) Epidermal Granular IgA in dermal papillae Granular/linear IgG, IgM, IgA, C3, fibrinogen along BMZ Linear IgG and C3, userrated pattern along BMZ N/A Linear IgG, IgA > C3 along BMZ and around dermal vessels N/A Vasculitis and vasculopathy Dermal Vasculitis of the skin may be classified by the caliber of vessels involved and the nature of the associated inflammatory infiltrate. Leu­ kocytoclastic vasculitis involves small, capillary-caliber vessels, presents as palpable purpura and demonstrates signs of vascular injury including endothelial swelling and fibrinoid necrosis with neutrophilic inflam­ mation, karrhyorectic debris, and dermal hemorrhage. (Fig. 10A) Biopsy timing is an important consideration and sampling of lesions present for 24–72 h is recommended as diagnostic findings may be less prominent in very early or late lesions. Leukocytoclastic vasculitis is most often idiopathic but may also be associated with infections, medication exposure, autoimmune disorders, or malignancy [80,81]. Immunofluorescence may be helpful as an adjunctive study and dem­ onstrates immunoglobulin, complement, and fibrinogen deposition in vessel walls with the presence of IgA suggesting a more specific diag­ nosis of Henoch-Schonlein purpura/IgA vasculitis [82,83]. Polyarteritis nodosa is a medium vessel vasculitis involving small to medium arteries and may present in skin-limited or systemic forms. Early lesions of polyarteritis nodosa demonstrates neutrophilic inflam­ mation within the walls of muscular arteries, progressing to a chronic inflammatory infiltrate of lymphocytes and histiocytes associated with fibrosis in later lesions. (Fig. 10B) The medium-caliber arteries Dermal disease [67,71]. Subepidermal vesicle formation may be associated with eosinophilic, neutrophilic, or sparse/minimal inflammation. Abundant intravesicular and dermal eosinophils are typical of bullous pemphigoid, though some cases of cell-poor bullous pemphigoid lack significant inflammation. (Fig. 9) Occasionally, bullous pemphigoid may present with eosinophilic spongiosis and/or dermal eosinophilia without clinically and/or microscopically apparent vesicles or bullae [73,74]. Mucous membrane pemphigoid typically shares histopathologic and immuno­ fluorescence features with bullous pemphigoid with the additional findings of plasmacellular inflammation in mucosal lesions and the presence of subepithelial fibrosis. Neutrophil-rich immunobullous dermatoses included dermatitis herpetiformis, linear IgA bullous dermatosis, and bullous lupus erythematosus. Collections of neutrophils Fig. 10. A) Leukocytoclastic vasculitis has many causes but the histology of all causes shows common features: fibrinoid vessel wall change/necrosis with peri­ vascular neutrophils, cellular debris, and hemorrhage, involving small dermal vessels. (H&E 200x) B) In contrast polyarteritis nodosa is a vasculitis involving medium sized muscular arteries. (H&E 100x) C) Calciphylaxis also affects blood vessels, but is a thrombotic rather than an inflammatory process with stippled calcium deposition around small subcutaneous vessels. (H&E 200x. 293 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 Fig. 11. A) Sarcoidosis shows tight well-formed granulomas with minimal peripheral lymphocytes. (H&E 100x) B) The granulomas of granuloma annulare are more loosely formed and palisade around central necrobiosis (collagen degeneration) with mucin. (H&E 100x) C) The granulomas of necrobiosis lipoidica diabeticorum are also loosely formed with collagen degeneration but give a “layered” appearance at low power with background plasma cells and fibrosis which results in a square configuration of the specimen. (H&E 20x). involved by cutaneous polyarteritis nodosa (cPAN) are located within the subcutaneous fat, and a biopsy of sufficient depth is required to adequately evaluate for this condition. Furthermore, the inflammatory changes may exist in discontiguous foci and evaluation of multiple serial sections may be required. The relationship between cPAN and macular lymphocytic arteritis/lymphocytic thrombophilic arteritis is the subject of debate, with some authors advocating that the latter represents a later phase of the former in which the lymphocytic in­ flammatory infiltrate predominates [84,85,86,87]. Distinction of poly­ arteritis nodosa from thrombophlebitis is important given the treatment implications and may be difficult on the lower extremities where thick-walled veins resembling arteries can be seen. In addition to the identification of venous valves on serial sections, assessment of smooth muscle morphology and elastin distribution within the vessel walls can aid in this distinction, wherein the medial muscular layer of thick-walled veins are comprised of discontiguous bundles of smooth muscle with interspersed elastin fibers while the medical muscular layer of arteries are comprised of a continuous layer of smooth muscle without inter­ spersed elastin fibers [88,89]. Vasculopathy refers to vessel injury that may result from thrombotic or embolic causes and manifests as intravascular thrombi that may be accompanied by ischemic changes in the subcutaneous, dermal, and epidermal tissue. A notable example of vasculopathy is calcific uremic arteriolopathy (calciphylaxis) which is associated with significant morbidity and mortality. Calciphylaxis demonstrates vascular calcifi­ cation and thrombosis of the small vessels within the subcutaneous fat, but in practice, these findings may be focal and their absence does not preclude the diagnosis. (Fig. 10C) Additional findings of calci­ phylaxis have been described including periadnexal calcification, pseudoxanthoma elasticum-like changes, and dermal angiomatosis [91, 92,93,94,95]. including foreign body reactions and infections. (Fig. 11A) The granulomas of sarcoidosis may be associated with significant lympho­ cytic inflammation and may demonstrate transepidermal elimination [97,98]. Necrobiosis (degenerating dermal collagen bundles which appear swollen and more eosinophilic) may be seen in association with granulomatous inflammation in granuloma annulare, necrobiosis lip­ oidica, necrobiotic xanthogranuloma, and reactive granulomatous dermatitis [96,99]. Granuloma annulare may exhibit either an intersti­ tial pattern of histiocytic inflammation intercalating among collagen bundles, or a palisaded pattern in which the infiltrate surrounds an area of necrobiosis associated with mucin deposition. (Fig. 11B) The zones of necrobiosis in necrobiosis lipoidica are broader and alternate with the inflammatory infiltrate in a layered fashion. (Fig. 11C) Nec­ robiotic xanthogranulomas, which are associated with monoclonal gammopathies, may additionally demonstrate extracellular cholesterol clefts. Other necrobiotic granulomatous dermatitides include palisaded neutrophilic granulomatous dermatitis in which leukocyto­ clastic vasculitis and dermal fibrin deposition may be seen, interstitial granulomatous dermatitis in which the histiocytic infiltrate is separated from the degenerating collagen fiber it surrounds by empty space (“floating sign”), and interstitial granulomatous drug eruption which may be associated with vacuolar changes in the epidermis [102,103, 104]. While there are some distinctive clinical and histopathologic features of each of these conditions, there can also be substantial overlap and therefore some authors have proposed classifying these entities under the umbrella of “reactive granulomatous dermatitis” [105,106]. Neutrophilic dermatoses Sweet syndrome (acute febrile neutrophilic dermatosis) is an example of a neutrophilic dermatosis and may be non-malignancy associated, paraneoplastic, or medication-induced. Histologically, Sweet syndrome demonstrates dense dermal neutrophilic inflammation with leukocytoclasia and papillary dermal edema. (Fig. 12) A subset of cases may demonstrate secondary leukocytoclastic vasculitis. Variants in which the inflammatory cells resemble histiocytoid mononuclear cells (histiocytoid Sweet syndrome, which has been Granulomatous dermatitis Granulomatous dermal inflammation can exhibit a spectrum of morphologies. Well-formed, tightly-knit epithelioid granulomas should raise the consideration of sarcoidosis, with differential diagnoses 294 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 7 Biswas A. Psoriasiform Dermatitis. Pearls and Pitfalls in Inflammatory Dermatopathology. Press: Cambridge University; 2016. 8 Chau T, Parsi KK, Ogawa T, et al. Psoriasis or not? Review of 51 clinically confirmed cases reveals an expanded histopathologic spectrum of psoriasis. J Cutan Pathol. 2017;44(12):1018–1026, 10.1111/cup.13033. 9 Weigelt N, Metze D, Ständer S. Prurigo nodularis: systematic analysis of 58 histological criteria in 136 patients. J Cutan Pathol. 2010;37(5):578–586. https:// doi.org/10.1111/j.1600-0560.2009.01484.x. 10 Ko CJ, Milstone LM, Choi J, McNiff JM. Pityriasis rubra pilaris: the clinical context of acantholysis and other histologic features. Int J Dermatol. 2011;50(12): 1480–1485. https://doi.org/10.1111/j.1365-4632.2011.04990.x. 11 Sebastian A, Koff AB, Goldberg LJ. PRP with subcorneal acantholysis: case report and review. J Cutan Pathol. 2010;37(1):99–101. https://doi.org/10.1111/j.16000560.2009.01279.x. 12 Avitan-Hersh E, Bergman R. The incidence of acantholysis in pityriasis rubra pilaris-histopathological study using multiple-step sections and clinicopathologic correlations. Am J Dermatopathol. 2015;37(10):755–758, 10.1097/ DAD.0000000000000346. 13 Soeprono FF. Histologic criteria for the diagnosis of pityriasis rubra pilaris. Am J Dermatopathol. 1986;8(4):277–283. https://doi.org/10.1097/00000372198608000-00001. 14 Facial discoid dermatosis: a new subtype of pityriasis rubra pilaris? J Am Acad Dermatol. 2014;70(5). AB169. 10.1016/j.jaad.2014.01.704. 15 Ko CJ, Heald P, Antaya RJ, Bolognia JL. Facial discoid dermatosis. Int J Dermatol. 2010;49(2):189–192, 10.1111/j.1365-4632.2009.04206.x. 16 Gan EY, Ng SK, Goh CL, Lee SSJ. Recalcitrant psoriasiform dermatosis of the face: is it related to pityriasis rubra pilaris? J Cutan Pathol. 2018;45(7):491–497. https:// doi.org/10.1111/cup.13148. 17 Craiglow BG, Boyden LM, Hu R, et al. CARD14-associated papulosquamous eruption: a spectrum including features of psoriasis and pityriasis rubra pilaris. J Am Acad Dermatol. 2018;79(3):487–494. https://doi.org/10.1016/j. jaad.2018.02.034. 18 Ring NG, Craiglow BG, Panse G, et al. Histopathologic findings characteristic of CARD14-associated papulosquamous eruption. J Cutan Pathol. 2020;47(5): 425–430, 10.1111/cup.13633. 19 Garcia D, Nielson CB, Gillihan R, Schoch J, Auerbach J, Motaparthi K. Xerotic eruption and purpura: answer. Am J Dermatopathol. 2020;42(3):221–223. https:// doi.org/10.1097/DAD.0000000000001323. 20 White Jm, Higgins E, du Vivier A, Creamer D. Desquamating migratory erythema caused by nutritional deficiency-4 cases. J Am Acad Dermatol. 2004;50(3). P40. 10.1016/j.jaad.2003.10.163. 21 Corbo MD, Lam J. Zinc deficiency and its management in the pediatric population: a literature review and proposed etiologic classification. J Am Acad Dermatol. 2013; 69(4):616–624. e1. 10.1016/j.jaad.2013.04.028. 22 Toberer F, Hartschuh W, Wiedemeyer K. Glucagonoma-associated necrolytic migratory erythema: the broad spectrum of the clinical and histopathological findings and clues to the diagnosis. Am J Dermatopathol. 2019;41(3):e29–e32, 10.1097/DAD.0000000000001219. 23 Cohen JN, Bowman S, Laszik ZG, North JP. Clinicopathologic overlap of psoriasis, eczema, and psoriasiform dermatoses: a retrospective study of T helper type 2 and 17 subsets, interleukin 36, and β-defensin 2 in spongiotic psoriasiform dermatitis, sebopsoriasis, and tumor necrosis factor α inhibitor-associated dermatitis. J Am Acad Dermatol. 2020;82(2):430–439, 10.1016/j.jaad.2019.08.023. 24 Aquino TM, Calvarido MG, North JP. Interleukin 36 expression in psoriasis variants and other dermatologic diseases with psoriasis-like histopathologic features. J Cutan Pathol. 2021. Published online August 410.1111/cup.14115. 25 Erdem O, Leblebici C, Koku Aksu AE, Erdil D, Kara Polat A, Gürel MS. IL-36α and IL36γ expressions in the differential diagnosis of palmoplantar psoriasis and palmoplantar eczema: a retrospective histopathologic and immunohistochemical study. J Cutan Pathol. 2021. Published online July 2110.1111/cup.14105. 26 Calonje MD, Dip RC, Path JE, et al. Lichenoid and interface dermatitis. McKee’s Pathology of the Skin: Expert Consult -. 4th ed. Saunders: Online and Print 2 Vol Set; 2011:1906. 27 Biswas A. Interface Dermatitis. Pearls and Pitfalls in Inflammatory Dermatopathology. Press: Cambridge University; 2016. 28 Alomari A, McNiff JM. The significance of eosinophils in hypertrophic lichen planus. J Cutan Pathol. 2014;41(4):347–352. https://doi.org/10.1111/cup.12275. 29 Astudillo MG, Hoang MP, Nazarian RM, Foreman RK. Distinction between hypertrophic lichen planus and squamous cell carcinoma requires clinicopathologic correlation in difficult cases. Am J Dermatopathol. 2021;43(5):349–355. https://doi. org/10.1097/DAD.0000000000001776. 30 Shah K, Kazlouskaya V, Lal K, Molina D, Elston DM. Perforating elastic fibers (’elastic fiber trapping’) in the differentiation of keratoacanthoma, conventional squamous cell carcinoma and pseudocarcinomatous epithelial hyperplasia. J Cutan Pathol. 2014;41(2):108–112, 10.1111/cup.12247. 31 Bowen AR, Burt L, Boucher K, Tristani-Firouzi P, Florell SR. Use of proliferation rate, p53 staining and perforating elastic fibers in distinguishing keratoacanthoma from hypertrophic lichen planus: a pilot study. J Cutan Pathol. 2012;39(2):243–250. https://doi.org/10.1111/j.1600-0560.2011.01834.x. 32 Lage D, Juliano PB, Metze K, de Souza EM, Cintra ML. Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study. Int J Dermatol. 2012;51(10):1199–1205. https://doi.org/10.1111/j.13654632.2011.05113.x. 33 Thornhill M.H., Pemberton M.N., Simmons R.K., Theaker E.D. Amalgam-contact hypersensitivity lesions and oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95(3):291–299. 10.1067/moe.2003.115. Fig. 12. Sweet syndrome is the classic neutrophilic dermatosis, showing a dense dermal neutrophilic infiltrate with cellular debris (leukocytoclasia) and papillary dermal edema. (H&E 100x, inset: H&E 200x). reported to be more strongly associated with malignancies) or yeast forms (cryptococcoid Sweet syndrome) have been described [109,110, 111]. The histopathologic features of other neutrophilic dermatoses such as rheumatoid neutrophilic dermatosis and bowel-associated derma­ tosis-arthritis syndrome are overall similar. Findings in pyoderma gan­ grenosum vary depending on the stage at which the lesion is biopsied and the region of the lesion that is sampled and may show findings of a neutrophilic dermatosis or non-specific findings of an ulcer. Studies to exclude infectious etiologies are recommended in evaluating biopsies of neutrophilic dermatoses. Conclusion Interpretation of biopsies of inflammatory dermatopathology can be challenging for a variety of reasons. Histopathologic features often point to a reaction pattern rather than a discrete diagnosis (i.e. “spongiotic dermatitis”). A given clinical entity can exhibit multiple patterns of inflammation and be difficult to classify into a reaction pattern (i.e. syphilis). Mimickers and masqueraders abound (i.e. benign dermatoses exhibiting clonality simulating cutaneous lymphoma) and non-classic findings of inflammatory dermatoses may confound the diagnosis (i.e. cell-poor bullous pemphigoid). The presence or absence of diagnostic findings may depend on the site selection and the timing of the biopsy (i. e. vasculitis). While existing and new histopathologic clues may assist in diagnosis and distinction, the collaborative dialog between pathologist and clinician remains critically important in integrating microscopic findings with the clinical context to produce a meaningful diagnosis and inform management. Declaration of Competing Interest The authors have no relevant conflicts of interests to disclose References 1 Calonje MD, Dip RC, Path JE, et al. Spongiotic, psoriasiform, and pustular dermatoses. McKee’s Pathology of the Skin: Expert Consult - Online and Print 2 Vol Set. Saunders: 4th ed; 2011:1906. 2 Biswas A. Spongiotic Dermatitis. In: Pearls and Pitfalls in Inflammatory Dermatopathology. Press: Cambridge University; 2016. 3 Rosa G, Fernandez AP, Vij A, et al. Langerhans cell collections, but not eosinophils, are clues to a diagnosis of allergic contact dermatitis in appropriate skin biopsies. J Cutan Pathol. 2016;43(6):498–504. https://doi.org/10.1111/cup.12707. 4 Crotty C, Pittelkow M, Muller SA. Eosinophilic spongiosis: a clinicopathologic review of seventy-one cases. J Am Acad Dermatol. 1983;8(3):337–343. https://doi. org/10.1016/s0190-9622(83)70036-8. 5 Cardoso JC, Veraitch O, Gianotti R, et al. Hints” in the horn: diagnostic clues in the stratum corneum. J Cutan Pathol. 2017;44(3):256–278. https://doi.org/10.1111/ cup.12839. 6 Brady SP. Parakeratosis. J Am Acad Dermatol. 2004;50(1):77–84, 10.1016/S01909622(03)02801-9. 295 S. Wu et al. Seminars in Diagnostic Pathology 39 (2022) 288–297 59 Magro CM, Crowson AN. The immunofluorescent profile of dermatomyositis: a comparative study with lupus erythematosus. J Cutan Pathol. 1997;24(9):543–552, 10.1111/j.1600-0560.1997.tb01458.x. 60 Naim M, Weyers W, Metze D. Histopathologic features of exanthematous drug eruptions of the macular and papular type. Am J Dermatopathol. 2011;33(7): 695–704. https://doi.org/10.1097/DAD.0b013e31820a285d. 61 Weyers W, Metze D. Histopathology of drug eruptions - general criteria, common patterns, and differential diagnosis. Dermatol Pract Concept. 2011;1(1):33–47. https://doi.org/10.5826/dpc.0101a09. 62 Singh S, Khandpur S, Arava S, et al. Assessment of histopathological features of maculopapular viral exanthem and drug-induced exanthem. J Cutan Pathol. 2017; 44(12):1038–1048, 10.1111/cup.13047. 63 Ortonne N, Valeyrie-Allanore L, Bastuji-Garin S, et al. Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study. Br J Dermatol. 2015;173(1):50–58. https://doi.org/10.1111/ bjd.13683. 64 Weinberg JM, Kristal L, Chooback L, Honig PJ, Kramer EM, Lessin SR. The clonal nature of pityriasis lichenoides. Arch Dermatol. 2002;138(8):1063–1067. https:// doi.org/10.1001/archderm.138.8.1063. 65 Dereure O, Levi E, Kadin ME. T-Cell clonality in pityriasis lichenoides et varioliformis acuta: a heteroduplex analysis of 20 cases. Arch Dermatol. 2000;136 (12):1483–1486. https://doi.org/10.1001/archderm.136.12.1483. 66 Sproul AM, Goodlad JR. Clonality testing of cutaneous lymphoid infiltrates: practicalities, pitfalls and potential uses. J Hematop. 2012;5(1–2):69–82. https:// doi.org/10.1007/s12308-012-0145-9. 67 Biswas A. Intraepidermal Vesiculobullous Dermatitis. In: Pearls and Pitfalls in Inflammatory Dermatopathology. Cambridge University Press. 2016. 68 Porro AM, Caetano L, de VN, et al. Non-classical forms of pemphigus: pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus. An Bras Dermatol. 2014;89(1):96–106. https://doi.org/10.1590/abd18064841.20142459. 69 Manocha A, Tirumalae R. Histopathology of pemphigus vulgaris revisited. Am J Dermatopathol. 2021;43(6):429–437. https://doi.org/10.1097/ DAD.0000000000001838. 70 Sar-Pomian M, Czuwara J, Rudnicka L, Olszewska M. Miniaturization of sebaceous glands: a novel histopathological finding in pemphigus vulgaris and pemphigus foliaceus of the scalp. J Cutan Pathol. 2017;44(10):835–842, 10.1111/cup.12994. 71 Calonje MD, Dip RC, Path JE, et al. Acantholytic disorders. In: McKee’s Pathology of the Skin: Expert Consult - Online and Print 2 Vol Set. Saunders: 4th ed; 2011:1906. 72 Biswas A. Subepidermal Vesiculobullous Dermatitis. Pearls and Pitfalls in Inflammatory Dermatopathology. Press: Cambridge University; 2016. 73 Merton A, Wu Y-H. Spongiform pemphigoid: a case series of an uncommon histopathologic pattern. J Cutan Pathol. 2020;47(4):339–345. https://doi.org/ 10.1111/cup.13627. 74 Hodge BD, Roach J, Reserva JL, et al. The spectrum of histopathologic findings in pemphigoid: avoiding diagnostic pitfalls. J Cutan Pathol. 2018;45(11):831–838. https://doi.org/10.1111/cup.13343. 75 Rose C, Schmidt E, Kerstan A, et al. Histopathology of anti-laminin 5 mucous membrane pemphigoid. J Am Acad Dermatol. 2009;61(3):433–440. https://doi.org/ 10.1016/j.jaad.2009.02.012. 76 PhD FRC Calonje MD, Dip RC, Path JE, Brenn MD, Path T. Inherited and autoimmune subepidermal blistering diseases. In: McKee’s Pathology of the Skin: Expert Consult - Online and Print 2 Vol Set. 4th ed. Saunders. 2011:1906. 77 Mutasim DF, Adams BB. Immunofluorescence in dermatology. J Am Acad Dermatol. 2001;45(6):803–822. quiz 822. 10.1067/mjd.2001.117518. 78 Elston DM, Stratman EJ, Miller SJ. Skin biopsy: biopsy issues in specific diseases. J Am Acad Dermatol. 2016;74(1):1–16. quiz 17. 10.1016/j.jaad.2015.06.033. 79 Biswas A. Vasculitis. Pearls and Pitfalls in Inflammatory Dermatopathology. Press: Cambridge University; 2016. 80 Goeser MR, Laniosz V, Wetter DA. A practical approach to the diagnosis, evaluation, and management of cutaneous small-vessel vasculitis. Am J Clin Dermatol. 2014;15(4):299–306. https://doi.org/10.1007/s40257-014-0076-6. 81 Micheletti RG, Werth VP. Small vessel vasculitis of the skin. Rheum Dis Clin North Am. 2015;41(1):21–32. vii. 10.1016/j.rdc.2014.09.006. 82 Lath K, Chatterjee D, Saikia UN, et al. Role of Direct Immunofluorescence in Cutaneous Small-Vessel Vasculitis: experience From a Tertiary Center. Am J Dermatopathol. 2018;40(9):661–666. https://doi.org/10.1097/ DAD.0000000000001170. 83 Alalwani M, Billings SD, Gota CE. Clinical significance of immunoglobulin deposition in leukocytoclastic vasculitis: a 5-year retrospective study of 88 patients at cleveland clinic. Am J Dermatopathol. 2014;36(9):723–729, 10.1097/ DAD.0000000000000122. 84 Morimoto A, Chen K-R. Reappraisal of histopathology of cutaneous polyarteritis nodosa. J Cutan Pathol. 2016;43(12):1131–1138. https://doi.org/10.1111/ cup.12809. 85 Buffiere-Morgado A, Battistella M, Vignon-Pennamen M-D, et al. Relationship between cutaneous polyarteritis nodosa (cPAN) and macular lymphocytic arteritis (MLA): blinded histologic assessment of 35 cPAN cases. J Am Acad Dermatol. 2015; 73(6):1013–1020, 10.1016/j.jaad.2015.09.010. 86 Kelly RI, Wee E, Balta S, Williams RA. Lymphocytic thrombophilic arteritis and cutaneous polyarteritis nodosa: clinicopathologic comparison with blinded histologic assessment. J Am Acad Dermatol. 2020;83(2):501–508. https://doi.org/ 10.1016/j.jaad.2019.10.068. 87 Macarenco RS, Galan A, Simoni PM, et al. Cutaneous lymphocytic thrombophilic (macular) arteritis: a distinct entity or an indolent (reparative) stage of cutaneous polyarteritis nodosa? Report of 2 cases of cutaneous arteritis and review of the 34 Beltraminelli H, Shabrawi-Caelen LE, Kerl H, Cerroni L. Melan-a-positive “pseudomelanocytic nests”: a pitfall in the histopathologic and immunohistochemical diagnosis of pigmented lesions on sun-damaged skin. Am J Dermatopathol. 2009;31(3):305–308. https://doi.org/10.1097/ DAD.0b013e31819d3769. 35 Silva CY, Goldberg LJ, Mahalingam M, Bhawan J, Wolpowitz D. Nests with numerous SOX10 and MiTF-positive cells in lichenoid inflammation: pseudomelanocytic nests or authentic melanocytic proliferation? J Cutan Pathol. 2011;38(10):797–800, 10.1111/j.1600-0560.2011.01756.x. 36 Chung HJ, Simkin AD, Bhawan J, Wolpowitz D. melanocytic nests arising in lichenoid inflammation”: reappraisal of the terminology “melanocytic pseudonests. Am J Dermatopathol. 2015;37(12):940–943. https://doi.org/10.1097/ DAD.0000000000000305. 37 Abbas O, Chatrath V, Goldberg LJ. Elastophagocytosis in extragenital lichen sclerosus. J Cutan Pathol. 2010;37(10):1032–1037, 10.1111/j.16000560.2010.01575.x. 38 Shiba Y, Ono K, Akiyama M, Fujimoto N, Tajima S. Increase of elastic fibers in lichen sclerosus et atrophicus. J Cutan Pathol. 2014;41(8):646–649. https://doi. org/10.1111/cup.12342. 39 Lester EB, Swick BL. Eosinophils in biopsy specimens of lichen sclerosus: a not uncommon finding. J Cutan Pathol. 2015;42(1):16–21. https://doi.org/10.1111/ cup.12445. 40 Keith PJ, Wolz MM, Peters MS. Eosinophils in lichen sclerosus et atrophicus. J Cutan Pathol. 2015;42(10):693–698. https://doi.org/10.1111/cup.12556. 41 Fancher K, Gardner JM, Shalin SC. Elastophagocytosis and interstitial granulomatous infiltrate are more common in extragenital vs genital lichen sclerosus. J Cutan Pathol. 2020;47(10):903–912. https://doi.org/10.1111/ cup.13741. 42 Forrester VJ, Tran B, Hein SC, Wick MR. Pattern-Specific Loss of Desmoplakin I and II Immunoreactivity in Erythema Multiforme and its Variants: a Possible Aid in Histologic Diagnosis. Am J Dermatopathol. 2020;42(2):111–116. https://doi.org/ 10.1097/DAD.0000000000001545. 43 Fischer A, Jakubowski AA, Lacouture ME, et al. Histopathologic Features of Cutaneous Acute Graft-Versus-Host Disease in T-Cell-Depleted Peripheral Blood Stem Cell Transplant Recipients. Am J Dermatopathol. 2015;37(7):523–529. https:// doi.org/10.1097/DAD.0000000000000357. 44 Hogenes MCH, Te Boome LCJ, van der Valk DC, et al. Clinical versus histological grading in the assessment of cutaneous graft versus host disease. Eur J Med Res. 2019;24(1):19, 10.1186/s40001-019-0377-6. 45 Narkhede M, Rybicki L, Abounader D, et al. The association of histologic grade with acute graft-versus-host disease response and outcomes. Am J Hematol. 2017;92(7): 683–688. https://doi.org/10.1002/ajh.24749. 46 Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol. 2001;28(1):1–23, 10.1034/j.1600-0560.2001.280101.x. 47 Rodriguez-Caruncho C, Bielsa I, Fernández-Figueras MT, Roca J, Carrascosa JM, Ferrándiz C. Lupus erythematosus tumidus: a clinical and histological study of 25 cases. Lupus. 2015;24(7):751–755, 10.1177/0961203314560204. 48 Sánchez NP, Peters MS, Winkelmann RK. The histopathology of lupus erythematosus panniculitis. J Am Acad Dermatol. 1981;5(6):673–680, 10.1016/ s0190-9622(81)70129-4. 49 Smith ES, Hallman JR, DeLuca AM, Goldenberg G, Jorizzo JL, Sangueza OP. Dermatomyositis: a clinicopathological study of 40 patients. Am J Dermatopathol. 2009;31(1):61–67. https://doi.org/10.1097/DAD.0b013e31818520e1. 50 Tomasini D, Mentzel T, Hantschke M, et al. Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner’s lymphocytic infiltrate of the skin and cutaneous lupus erythematosus. J Cutan Pathol. 2010;37(11):1132–1139, 10.1111/j.16000560.2010.01587.x. 51 McNiff JM, Kaplan DH. Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus. J Cutan Pathol. 2008;35(5):452–456. https://doi.org/10.1111/j.1600-0560.2007.00848.x. 52 Chen SJT, Tse JY, Harms PW, Hristov AC, Chan MP. Utility of CD123 immunohistochemistry in differentiating lupus erythematosus from cutaneous T cell lymphoma. Histopathology. 2019;74(6):908–916. https://doi.org/10.1111/ his.13817. 53 Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis. J Cutan Pathol. 2010;37(6):659–671. https://doi.org/10.1111/j.1600-0560.2009.01443.x. 54 Ko CJ, Srivastava B, Braverman I, Antaya RJ, McNiff JM. Hypertrophic lupus erythematosus: the diagnostic utility of CD123 staining. J Cutan Pathol. 2011;38 (11):889–892. https://doi.org/10.1111/j.1600-0560.2011.01779.x. 55 Walsh NM, Lai J, Hanly JG, et al. Plasmacytoid dendritic cells in hypertrophic discoid lupus erythematosus: an objective evaluation of their diagnostic value. J Cutan Pathol. 2015;42(1):32–38. https://doi.org/10.1111/cup.12416. 56 Reich A, Marcinow K, Bialynicki-Birula R. The lupus band test in systemic lupus erythematosus patients. Ther Clin Risk Manag. 2011;7:27–32. https://doi.org/ 10.2147/TCRM.S10145. 57 Koelle MS, Kumar V, Beutner EH, Chorzelski TP. In-vivo epidermal nuclear reactions: a selective process. Br J Dermatol. 1991;125(1):48–52, 10.1111/j.13652133.1991.tb06038.x. 58 Burrows NP, Bhogal BS, Russell Jones R, Black MM. Clinicopathological significance of cutaneous epidermal nuclear staining by direct immunofluorescence. J Cutan Pathol. 1993;20(2):159–162. https://doi.org/ 10.1111/j.1600-0560.1993.tb00234.x. 296 S. Wu et al. 88 89 90 91 92 93 94 95 96 97 98 99 100 Seminars in Diagnostic Pathology 39 (2022) 288–297 101 Finan MC, Winkelmann RK. Histopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol. 1987;14(2):92–99, 10.1111/j.1600-0560.1987. tb00479.x. 102 Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol. 1998;25(2):72–78, 10.1111/j.1600-0560.1998.tb01693.x. 103 Peroni A, Colato C, Schena D, Gisondi P, Girolomoni G. Interstitial granulomatous dermatitis: a distinct entity with characteristic histological and clinical pattern. Br J Dermatol. 2012;166(4):775–783, 10.1111/j.1365-2133.2011.10727.x. 104 Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular disease. Arch Dermatol. 1994;130(10):1278–1283, 10.1001/ archderm.1994.01690100062010. 105 Rodríguez-Garijo N, Bielsa I, Mascaró JM, et al. Reactive granulomatous dermatitis as a histological pattern including manifestations of interstitial granulomatous dermatitis and palisaded neutrophilic and granulomatous dermatitis: a study of 52 patients. J Eur Acad Dermatol Venereol. 2021;35(4):988–994. https://doi.org/ 10.1111/jdv.17010. 106 Rosenbach M, English JC. Reactive granulomatous dermatitis: a review of palisaded neutrophilic and granulomatous dermatitis, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, and a proposed reclassification. Dermatol Clin. 2015;33(3):373–387. https://doi.org/10.1016/j.det.2015.03.005. 107 PhD FRC Calonje MD, Dip RC, Path JE, Brenn MD, Path T, Lazar MD. Neutrophilic and eosinophilic dermatoses. McKee’s Pathology of the Skin: Expert Consult -. 4th ed. Saunders: Online and Print 2 Vol Set; 2011:1906. 108 Malone JC, Slone SP, Wills-Frank LA, et al. Vascular inflammation (vasculitis) in sweet syndrome. Arch Dermatol. 2002;138(3). https://doi.org/10.1001/ archderm.138.3.345. 109 Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes. Arch Dermatol. 2005;141(7): 834–842. https://doi.org/10.1001/archderm.141.7.834. 110 Wilson J, Gleghorn K, Kelly B. Cryptococcoid Sweet’s syndrome: two reports of Sweet’s syndrome mimicking cutaneous cryptococcosis. J Cutan Pathol. 2017;44(5): 413–419. https://doi.org/10.1111/cup.12921. 111 Haber R, Feghali J, El Gemayel M. Risk of malignancy in histiocytoid Sweet syndrome: a systematic review and reappraisal. J Am Acad Dermatol. 2020;83(2): 661–663. https://doi.org/10.1016/j.jaad.2020.02.048. 112 Terra JB, Meijer JM, Jonkman MF, Diercks GFH. The n- vs. u-serration is a learnable criterion to differentiate pemphigoid from epidermolysis bullosa acquisita in direct immunofluorescence serration pattern analysis. Br J Dermatol. 2013;169(1): 100–105. https://doi.org/10.1111/bjd.12308. literature. Am J Dermatopathol. 2013;35(2):213–219. https://doi.org/10.1097/ DAD.0b013e31825ba0ec. Dalton SR, Fillman EP, Ferringer T, Tyler W, Elston DM. Smooth muscle pattern is more reliable than the presence or absence of an internal elastic lamina in distinguishing an artery from a vein. J Cutan Pathol. 2006;33(3):216–219, 10.1111/ j.0303-6987.2006.00419.x. Chen K-R. The misdiagnosis of superficial thrombophlebitis as cutaneous polyarteritis nodosa: features of the internal elastic lamina and the compact concentric muscular layer as diagnostic pitfalls. Am J Dermatopathol. 2010;32(7): 688–693. https://doi.org/10.1097/DAD.0b013e3181d7759d. Calonje MD, Dip RC, Path JE. Vascular diseases. In: McKee’s Pathology of the Skin: Expert Consult - Online and Print 2 Vol Set. 4th ed. Saunders. 2011:1906. Dutta P, Chaudet KM, Nazarian RM, Kroshinsky D, Nigwekar SU. Correlation between clinical and pathological features of cutaneous calciphylaxis. PLoS ONE. 2019;14(6). e0218155. 10.1371/journal.pone.0218155. Prinz Vavricka BM, Barry C, Victor T, Guitart J. Diffuse dermal angiomatosis associated with calciphylaxis. Am J Dermatopathol. 2009;31(7):653–657. https:// doi.org/10.1097/DAD.0b013e3181a59ba9. Penn LA, Brinster N. Calciphylaxis with pseudoxanthoma elasticum-like changes: a case series. J Cutan Pathol. 2018;45(2):118–121, 10.1111/cup.13075. O’Connor HM, Wu Q, Lauzon SD, Forcucci JA. Diffuse dermal angiomatosis associated with calciphylaxis: a 5-year retrospective institutional review. J Cutan Pathol. 2020;47(1):27–30, 10.1111/cup.13585. Bahrani E, Perkins IU, North JP. Diagnosing calciphylaxis: a review with emphasis on histopathology. Am J Dermatopathol. 2020;42(7):471–480, 10.1097/ DAD.0000000000001526. Calonje MD, Dip RC, Path JE. Granulomatous, necrobiotic, and perforating dermatoses. In: McKee’s Pathology of the Skin: Expert Consult - Online and Print 2 Vol Set. Saunders: 4th ed; 2011:1906. Ismail A, Beckum K, McKay K. Transepithelial elimination in sarcoidosis: a frequent finding. J Cutan Pathol. 2014;41(1):22–27. https://doi.org/10.1111/cup.12253. Cardoso JC, Cravo M, Reis JP, Tellechea O. Cutaneous sarcoidosis: a histopathological study. J Eur Acad Dermatol Venereol. 2009;23(6):678–682, 10.1111/j.1468-3083.2009.03153.x. Biswas A. Nodular and Diffuse Dermatitis. In: Pearls and Pitfalls in Inflammatory Dermatopathology. Press: Cambridge University; 2016. Ronen S, Rothschild M, Suster S. The interstitial variant of granuloma annulare: clinicopathologic study of 69 cases with a comparison with conventional granuloma annulare. J Cutan Pathol. 2019;46(7):471–478. https://doi.org/10.1111/ cup.13455. 297