What’s new in the fifth edition

The purpose of this chapter is to provide selected highlights of new information (or, in some cases, revitalized old information) that has become available in the realm of dermatopathology, along with the page number where each one (and its references) can be found in this volume. It is not intended to be a comprehensive summation of all such information, and of course individual readers may disagree on the choices made, but at least this will give some indication of the depth and breadth of new knowledge that has been generated by colleagues throughout the world since the previous edition.

Chapter 4 : the Lichenoid Reaction Pattern (“Interface Dermatitis”)

In the microscopic differential diagnosis between lichen planus and lupus erythematosus , CD34 has the highest specificity and positive predictive value for the diagnosis of lichen planus, whereas CD3 shows the highest sensitivity and negative predictive value for that diagnosis ( p. 55 ).

Immunostaining for cytokeratin 903 can be helpful in the rapid diagnosis of lichen planopilaris by allowing identification of colloid bodies, even in foci of intense inflammation ( p. 60 ).

High intraepidermal apoptotic keratinocytes favor lichenoid keratosis over lichenoid drug eruption and lupus erythematosus ( p. 66 ).

Fixed sunlight eruption may show features of a lichenoid dermatitis but more often is characterized by spongiosis and papillary dermal edema ( p. 70 ).

Chapter 5 : the Psoriasiform Reaction Pattern

The classic microscopic changes of psoriasis are associated with CD3 + T-cell infiltrates and epidermotropism of CD8 + cells ( p. 102 ).

Mounds of parakeratosis with neutrophils, spongiform pustules, and clubbed and evenly elongated rete ridges are more common in psoriasis , whereas follicular plugging, shouldered parakeratosis, and prominent lymphocyte exocytosis are more common in seborrheic dermatitis ( p. 108 ).

Nutritional deficiency disorders can have microscopic similarities to psoriasis, but they can also complicate psoriasis. This was shown in a case of pellagra that occurred in the setting of psoriasis; improvement followed treatment of psoriasis along with niacin supplementation ( p. 108 ).

Some patients have features of both pityriasis rubra pilaris and psoriasis and tend to be resistant to conventional psoriasis therapies. These patients have an early age of onset, prominent involvement of face and ears, and a family history of psoriasis or pityriasis rubra pilaris. The term CARD14-associated papulosquamous eruption (CAPE) has been proposed for these cases ( p. 112 ).

A series of cases of pityriasis rubra pilaris demonstrated microscopic features of lichen nitidus surrounded by more typical changes of pityriasis rubra pilaris ( p. 112 ).

Among the other microscopic findings in lichen simplex chronicus and prurigo nodularis are subepidermal band-like vascular proliferation resembling acquired elastotic hemangioma, eccrine ductal metaplasia, and milia-like changes involving eccrine ducts with intraluminal calcification ( p. 116 ).

Chapter 6 : the Spongiotic Reaction Pattern

An eruption similar to eosinophilic, polymorphic, and pruritic eruption has been reported in patients with cervical cancer and after radiation therapy in a patient with primary nodal Merkel cell carcinoma ( p. 126 ).

A recently described clinical subtype of irritant contact dermatitis is recurrent flexural pellagroid dermatitis . It is most common in women and presents as well-demarcated erythema that evolves to rust-brown plaques with cigarette paper–like wrinkling. The suspected cause is soapless cleansing bars containing 44% sodium laurel sulfate ( p. 132 ). The microscopic features can resemble pityriasis rubra pilaris ( p. 132 ).

The microscopic differentiation between nonpustular palmoplantar psoriasis and allergic contact dermatitis can be difficult, and the two can occur together—a situation termed eczema in psoriatico (EIP) . The latter has histopathological features of both disorders. Immunohistochemistry can be of value, in that there is reduced expression of CK17 in allergic contact dermatitis compared with psoriasis and EIP, and there are higher numbers of CD8 + cells in EIP compared with either allergic contact dermatitis or psoriasis alone ( p. 137 ).

In the differential diagnosis of seborrheic dermatitis and psoriasis of the scalp, the most helpful microscopic features are follicular plugging, shouldered parakeratosis, and prominent lymphocyte exocytosis (seborrheic dermatitis), or parakeratotic mounds with neutrophils, spongiform pustules, clubbed and evenly elongated rete ridges, and increased numbers of mitoses (psoriasis) ( p. 141 ).

Chapter 7 : the Vesiculobullous Reaction Pattern

There are at least six types of immunoglobulin A (IgA) pemphigus, with overlapping features but also with clinical, microscopic, immunofluorescence, and target antigen findings that differ in some respects. The six types are subcorneal pustular dermatosis type, intraepidermal neutrophilic IgA dermatosis, IgA pemphigus vegetans, IgA pemphigus foliaceus, IgA pemphigus vulgaris, and unclassified intercellular IgA dermatosis ( p. 164 ).

IgG/IgA pemphigus differs minimally from traditional IgG pemphigus but does show several differences from IgA pemphigus ( p. 164 ). Microscopically, this form of pemphigus shows a lesser degree of pustule formation and more acantholysis compared with IgA pemphigus, but subcorneal pustules or acantholytic mid-epidermal blisters with neutrophilic and eosinophilic spongiosis can occur. Direct immunofluorescence findings differ from IgA pemphigus in that there are deposits of C3 as well as IgA and IgG ( p. 164 ).

Intracytoplasmic granular deposits of collagen VII can be seen in bullous dermolysis of the newborn , a rare dominant or recessive variant of dystrophic epidermolysis bullosa , and may be a specific finding for that entity ( p. 183 ).

In a recent direct immunofluorescence study of paraneoplastic pemphigus , staining for C3 and/or IgG showed intercellular fluorescence in 9 cases, and 3 of these also had basement membrane zone fluorescence in either a linear or granular pattern. One showed only linear basement membrane zone deposition ( p. 189 ).

When using direct immunofluorescence in the differentiation of bullous pemphigoid and epidermolysis bullosa acquisita (EBA), a useful technique can be double staining with antibody to IgG and either type VII collagen (they overlap in EBA but not in pemphigoid) or type XVII collagen (they overlap in pemphigoid but not in EBA) ( p. 195 ).

In circumstances where frozen tissue is not available for direct immunofluorescence study, C3d or C4d can be used on formalin-fixed, paraffin-embedded tissue as a screening test for mucous membrane pemphigoid , though a negative result does not exclude the diagnosis and an additional biopsy for direct immunofluorescence study should be obtained ( p. 204 ).

Chapter 8 : the Granulomatous Reaction Pattern

One study of sarcoidosis has shown perineural granulomas in 62% of patients and 55% of biopsies. The predominant anatomical distribution of this finding (face, proximal extremities, trunk) was found to be similar to that of a condition called sarcoidosis small fiber neuropathy —a condition associated with sensory disturbances ( p. 214 ).

Microscopic features with predictive value for tuberculoid leprosy are a predominance of tuberculoid granulomas, in an adnexal and neural distribution, and granulomas replacing nerves within sweat gland glomeruli. Those predictive of sarcoidosis are dermal fibrosis, back-to-back granulomas, atypical giant cells and plasma cells, greater numbers of conventional giant cells, and spared nerves beside granulomas. An analysis of reticulin fiber density did not discriminate between the two diseases in this study, but there was support for the impression of fiber fragmentation within the granulomas of tuberculoid leprosy ( p. 216 ).

Chapter 9 : the Vasculopathic Reaction Pattern

Lower extremity inflammatory lymphedema , an exquisitely tender condition that develops in otherwise healthy military trainees during the first 72 hours of basic training, features leukocytoclastic vasculitis involving the deep dermal vascular plexus. It has been associated with prolonged standing at attention ( p. 256 ).

In Henoch–Schönlein purpura , renal involvement is significantly associated with papillary dermal edema on histopathology and with perivascular C3 deposition on direct immunofluorescence. IgM deposition may be associated with articular involvement ( p. 259 ).

Recurrent cutaneous eosinophilic vasculitis appears to be an entity separate from those with systemic aspects. It is more common among women. Peripheral eosinophilia may be absent and when present, is typically not as pronounced as it would be in hypereosinophilic syndrome or eosinophilic angioedema. In eosinophilic vasculitis, there is little or no leukocytoclasis ( p. 259 ).

There has been debate over a possible special link between histiocytoid Sweet's syndrome and hematological disorders, including myelodysplastic syndromes. Several papers have suggested this relationship, but a recent detailed study found that histiocytoid Sweet's syndrome is not more commonly related to hematological malignancy than classic Sweet's syndrome ( p. 273 ).

In a recent study, varicella zoster virus glycoprotein E was found in endothelial cells and eccrine epithelium in five of six cases of pityriasis lichenoides acuta . Interestingly, it was found in only one of seven patients with pityriasis lichenoides chronica ( p. 284 ).

Chapter 10 : Disorders of Epidermal Maturation and Keratinization

Compared with X-linked ichthyosis , autosomal recessive congenital ichthyosis with transglutaminase 1 mutation has the following distinguishing microscopic features: a thicker granular cell layer, a greater degree of acanthosis, mildly to markedly tortuous and dilated vessels, and more frequent mitoses ( p. 310 ).

The following features have been found to be characteristics of the ichthyosis in Netherton's syndrome: psoriasiform hyperplasia, with compact parakeratosis and without thinning of suprapapillary plates, intracorneal or subcorneal splitting, dyskeratotic cells in the upper spinous layers, dilated blood vessels in the superficial dermis, and a dermal infiltrate containing neutrophils and eosinophils. Definitive diagnosis depends on immunohistochemistry for LEKT1—absent in Netherton's syndrome ( p. 313 ).

Gain-of-function mutations in the TRPM4 gene (which encodes TRPM4, a calcium-activated monovalent cation channel) are a cause of progressive symmetrical erythrokeratodermia ( p. 314 ).

Pachyonychia congenita is inherited as an autosomal dominant trait. In the past, several presumed autosomal recessive cases had been reported. However, the author of that paper recently noted that the individuals involved had loss-of-function mutations in the CAST gene and, along with a group of Chinese and Nepalese patients, were shown to have a newly described syndrome called the PLACK syndrome (peeling skin, leukonychia, acral punctate keratoses, and angular cheilitis) ( p. 324 ).

A number of examples of acrokeratosis verruciformis not associated with Darier's disease have shown foci of acantholytic dyskeratosis. Several of these patients were found to have the P602L mutation ( p. 339 ).

Chapter 11 : Disorders of Pigmentation

A significant mode of melanin transfer consists of exocytosis of polymerized melanin (melanocores) by fusion of melanosomes with the melanocyte plasma membrane, followed by release into the extracellular space and ingestion by adjacent keratinocytes. This process may be controlled by Rab11b, one of the small guanosine triphosphates (GTPases) that regulate intracellular membrane trafficking ( p. 348 ).

In a variant of vitiligo known as marginal vitiligo , in which depigmented patches are surrounded by elevated, erythematous borders, these margins show changes of spongiotic dermatitis, with superficial dermal lymphocytic and eosinophilic infiltrates ( pp. 349, 352 ).

Pseudo Chédiak–Higashi granules (PCH) can be present in the blast cells of acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndromes, and acute monoblastic leukemia, creating difficulty when attempting to diagnose Chédiak–Higashi syndrome . Microscopic differentiation is possible by recognizing the frequent pink color of PCH granules or the detection of other structures, such as Auer rods, that were found together with the PCH granules in a case of acute T/myeloid leukemia ( p. 357 ).

In idiopathic eruptive macular pigmentation , the current opinion is that the presence of numerous dermal melanophages is a negative finding that argues against the diagnosis; an absence of interface changes and normal mast cell counts remain accepted diagnostic criteria ( p. 362 ).

Keratin globules, or whorls, in the stratum corneum appear to be common features in biopsy specimens of terra firma-forme dermatosis ( p. 373 ).

Chapter 12 : Disorders of Collagen

The T helper 1 (Th1) and Th17 polarized infiltrates in eosinophilic fasciitis can be exploited to aid in the differentiation from morphea . The percentage of Th17 cells is significantly higher in eosinophilic fasciitis, whereas the CD4/CD8 ratio is significantly greater, and the Th1/Th2 ratio significantly lower, in morphea ( p. 387 ).

The microscopic diagnosis of atrophoderma of Pasini and Pierini is a difficult one. A recent study of the histopathology of this lesion using multiphoton microscopy and second harmonic generation revealed organizational changes in connective tissues not seen with ordinary methods: increasing horizontal collagen fiber organization toward the lower dermis, and greater disorganization of elastic fibers in the upper dermis ( p. 387 ).

Fibroblastic connective tissue nevus is a relatively newly described entity. It usually presents as painless plaques or nodules in children. The main microscopic features include papillomatosis and a proliferation of bland spindled cells arranged in short, intersecting fascicles in the deep reticular dermis and superficial subcutis, sometimes with entrapment of appendages or adipocytes. Though there is usually positive CD34 staining, it may be weak and focal and is sometimes negative ( p. 396 ).

Herovici's collagen stain is a method by which type III collagen stains blue and type I collagen stains red. It proved to be useful, for example, in evaluating a case of focal dermal hypoplasia treated with ablative fractional laser resurfacing, in which a shift in collagen predominance from type III collagen (characteristic of fetal or early wound connective tissue) to type I (mature) collagen could be demonstrated ( p. 404 ).

Reactive perforating collagenosis may be difficult to distinguish from the “pseudo-perforation” that can occur in prurigo , likely a result of vigorous scratching. Findings favoring pseudo-perforation include an absence of altered collagen, the presence of full-thickness epidermal necrosis, and the associated elimination of elastic fibers ( p. 407 ).

Chapter 13 : Disorders of Elastic Tissue

In a photomicrograph of a recent case of elastoderma , elastic fibers displayed lumpy-bumpy, or “railroad track,” deposits closely resembling the changes in penicillamine dermopathy, yet with no history of penicillamine treatment. This may suggest a similar mechanism at work in elastoderma, related to inhibition of lysyl oxidase activity and decreased cross-linking of elastin ( p. 417 ).

A disorder with a phenotype similar to pseudoxanthoma elasticum is associated with mutations in the GGCX gene for γ-glutamyl carboxylase. Clinical features include loose redundant skin and sometimes retinitis pigmentosa or coagulation factor deficiencies. Microscopic findings include thin, fragmented elastic fibers with limited mineralization in the superficial and mid-dermis but more prominent mineralization in the deep dermis. There is positive immunostaining with antibodies to the uncarboxylated matrix gla protein (MGP) in a clumped configuration (the carboxylated form of MGP is an inhibitor of pathological mineralization) ( p. 420 ).

The bullae in erythema ab igne are subepidermal, associated with dilated vessels and sparse superficial perivascular lymphocytic inflammation. In one case, bulla formation was associated with a lichenoid tissue reaction. Direct immunofluorescence is negative for basement membrane zone staining, but there has been weak vascular positivity for IgG and C3 in one case ( p. 428 ).

There has been a suggestion of a triad of disorders under the term fibroelastolytic papulosis of the neck. These include papillary dermal elastolysis , white fibrous papulosis of the neck (fibroelastolytic papulosis of the neck) , and a rare condition, papillary dermal elastosis . Papillary dermal elastolysis features a marked reduction in, or complete loss of, oxytalan and elaunin elastic fibers in the papillary dermis; remaining fibers are neither calcified nor fragmented. White fibrous papulosis of the neck features haphazardly arranged reticular dermal collagen bundles, in which elastic fibers are reduced in number but structurally normal. Papillary dermal elastosis shows numerous clumped and curled elastic fibers in the papillary dermis that may alternate with foci lacking oxytalan and elaunin fibers ( p. 433 ).

Chapter 14 : Cutaneous Mucinoses

The interstitial granulomatous variant of scleromyxedema closely resembles interstitial granuloma annulare. Additional skin biopsies may or may not show more typical areas of scleromyxedema. When present, the finding of necrobiosis favors granuloma annulare ( p. 441 ).

Two sets of microscopic findings are seen in the subcutaneous nodules of self-healing juvenile cutaneous mucinosis . One consists of spindled and stellate fibroblast-like cells and ganglion-like cells in a mucinous matrix, resembling proliferative fasciitis. The other is described as a chronic lobular panniculitis and features thickened interlobular septa, mild lymphocytic inflammation, small capillaries, and partial replacement of adipose tissue by fibrosis. Again, fibroblastic and ganglion-like cells can be identified ( p. 442 ).

A comparative histopathological study of reticular erythematous mucinosis and tumid lupus erythematosus shows that the former has a less dense and deep infiltrate, more superficial mucin deposition, less frequent junctional complement and immunoglobulin deposition, and a lower percentage of cases showing plasmacytoid dendritic cells with less clustering of these cells. The results suggest that different pathogenetic mechanisms may be involved in the two conditions ( p. 445 ).

Several changes involving follicular structures have been described in focal mucinosis , including “perifollicular mucinosis,” follicular induction with surrounding clefts mimicking superficial basal cell carcinoma, and follicular distortion that resembles fibrofolliculoma ( p. 448 ).

Chapter 15 : Cutaneous Deposits

In amyloidosis cutis dyschromica , there is reticulated hyperpigmentation with hypopigmented spots that may be widespread. The GPNMB gene that is mutated in this disorder encodes a transmembrane glycoprotein, NMB, that is implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation. Staining for GPNMB is markedly reduced in lesional skin in this condition. Other histopathological findings include increased amounts of amyloid in papillary dermis and infiltrating macrophages in hyperpigmented areas and loss of melanocytes in depigmented areas ( p. 472 ).

Calcium hydoxylapatite (CaHa) is a soft tissue filler that consists of 35-mm diameter microspheres suspended in a gel carrier. The material persists for at least 6 months in humans, and changes may last for at least 12 to 18 months. At 1 month after injection, CaHa microspherules (appearing as smooth, slightly irregular pink spherules) can be seen with little inflammatory response or fibrosis. At 6 months, the spherules are no longer as regular or smooth, and they are surrounded by thick collagen and multinucleated giant cells ( p. 488 ).

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