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What’s New in Dermatopathology

Inflammatory Dermatoses

Penn, Lauren, MD*; Rothman, Lisa, MD*; Sutton, Angela M., DO; Brinster, Nooshin K., MD*; Vidal, Claudia I., MD, PhD†,‡

Advances in Anatomic Pathology: January 2019 - Volume 26 - Issue 1 - p 40–55
doi: 10.1097/PAP.0000000000000210
Review Articles

Inflammatory skin diseases encompass a vast array of conditions. The field continues to expand and evolve with resurgence of conditions, through newly recognized medication adverse effects, and via more detailed descriptions of known dermatoses. The importance of clinicopathologic correlation and an up to date knowledge of dermatologic conditions cannot be overstated. This review focuses on an array of recent important developments in the histologic diagnosis of inflammatory conditions that affect the skin.

*The Ronald O. Perelman Department of Dermatology, New York University, New York, NY

Departments of Dermatology

Pathology, Saint Louis University, St. Louis, MO

L.P., L.R., A.M.S. contributed equally to the work.

N.K.B.: senior author.

C.I.V.: invited and senior author.

The authors have no funding or conflicts of interest to disclose.

Reprints: Claudia I. Vidal, MD, PhD, 1755 S. Grand Blvd., St. Louis, MO 63104 (e-mail: vidalcmd@gmail.com).All figures can be viewed online in color at www.anatomicpathology.com.

The inflammatory dermatoses encompass a vast array of conditions with varied, often subtle, and in many instances challenging histologic findings. The importance of clinicopathologic correlation and an up to date knowledge of dermatologic conditions cannot be overstated. Within this ever-changing field, well-known conditions, once thought scarce, have experienced a recent resurgence. Also, given the current revolutionary landscape of oncologic treatment with targeted therapy, as well as treatment advances within other fields of medicine, newly recognized medication adverse effects have emerged. In addition, newly documented histologic findings and novel use of immunohistochemistry have refined the diagnosis of various conditions within dermatology with significant clinical implications. In this review, we seek to provide an update on reemerging and new conditions within dermatopathology, and also inform the audience on recent advances pertaining known inflammatory dermatoses. The review will highlight the histologic findings unique and characteristic to these conditions.

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SYPHILIS—NOT NEW BUT REEMERGING

Syphilis is a sexually transmitted disease that occurs worldwide, caused by infection with Treponema pallidum. The incidence of syphilis has experienced resurgence in recent years. In 2001, the reported national rate of primary and secondary syphilis was 2.1 cases per 100,000 population, which was the lowest incidence rate since the start of reporting in 1941.1 However, since that time, the rate has increased every year. In 2016, the rate had increased to 8.7 cases per 100,000 population, the highest since 1993 (2017 CDC). This rise in reported cases is thought in part to be due to an increase in cases occurring in men who have sex with men, as well as increased rates of oral intercourse. Rates have increased in both men and women. In 2015 to 2016, the rate increased 14.7% in men and 35.7% in women.1 Of particular concern regarding this increase in women, is the subsequent concomitant increase in congenital syphilis cases. In 2016, the national rate of congenital syphilis was reported as 15.7 cases per 100,000 population, a 27.6% increase from 2015 and a 86.9% increase since 2012.1

This chronic infection has a well-known natural progression, which transitions through active and latent stages, including a primary stage, secondary stage, latent stage, and tertiary stage. The primary stage manifests after an average of 3 weeks postexposure as a papule that evolves into a painless ulcer. Regional lymphadenopathy may also occur. This lesion then typically self resolves over a period of weeks. The secondary stage may occur weeks to months after resolution of the primary lesion, and is characterized by a vast array of clinical manifestations due to hematogenous and lymphatic spread of treponemes. This stage may be preceded by prodromal systemic symptoms including fever, malaise, and generalized lymphadenopathy, among others. Often touted as the “Great Mimicker,” the cutaneous manifestations of secondary syphilis are heterogenous, and may include condyloma lata (Fig. 1A), a papulosquamous eruption (Fig. 1B), papules and plaques on the palms and soles, hypopigmented macules, mucosal patches and plaques, and a patchy alopecia. A latent period then ensues after resolution of clinical lesions from secondary stage infection, and can last for many years. Tertiary stage or late syphilis, occurs in 15% to 40% of untreated individuals, and is characterized by severe cardiac, neurological, skin, visceral or bony involvement.2 A congenital form may also occur via vertical transmission during pregnancy or delivery (Fig. 1C). In parallel with these varied clinical findings, the histologic findings of syphilis can also demonstrate a wide variety of manifestations.

FIGURE 1

FIGURE 1

The histologic findings associated with cutaneous eruptions of secondary syphilis may encompass several different inflammatory reaction patterns including spongiosis, psoriasiform hyperplasia, lichenoid inflammatory reaction, and a granulomatous dermatitis, or a combination of these.3 In a recent review article by Flamm and colleagues, the histologic findings of the papulosquamous eruption of secondary syphilis were further characterized. Histologic features known to occur in secondary syphilis were examined within multiple specimens from various institutions. Included in this were interstitial inflammation, endothelial swelling (Fig. 2A), irregular acanthosis, elongated rete ridges, vacuolar interface dermatitis (Fig. 2B), the presence of plasma cells (Fig. 2C), lymphocytes with ample cytoplasm, neutrophils within the stratum corneum (Fig. 2D), a lichenoid infiltrate, effacement, and psoriasiform acanthosis.4 In some instances, as few as 2 of these distinguishing features were present, which speaks to the challenge of an accurate diagnosis of this entity.4 In this study, the most common findings overall were an interstitial inflammatory infiltrate, endothelial swelling, irregular acanthosis, and elongated slender rete ridges.4 Plasma cells, often thought of as a characteristic histologic finding, were only noted in ∼70% of cases studied.4 In specimens where 5 or fewer features were present, interstitial inflammation and endothelial cell swelling were the most commonly represented, and found to be helpful diagnostic features in otherwise histologically subtle cases.4 Given the spectrum of pathologic findings of this entity, a high level of suspicion must be applied. Another frequently encountered situation in which syphilis should remain high in the differential is in biopsies of oral or genital mucosa.

FIGURE 2

FIGURE 2

The primary chancre is the initial presenting symptom, and while the genitalia is the most common location, other sites of involvement are becoming more prevalent, including the oral mucosa. Clinically painless ulceration will be the most common presentation, although red or white patches, as well as mass like lesions have also been reported.5 In this location, the clinical differential diagnosis may include a malignancy or an inflammatory dermatosis, including immunobullous disorders, contact dermatitis, and lichen planus. Syphilis may not be an initial diagnostic consideration, and therefore a high index of suspicion must once again be applied. In a recent report by Tse and colleagues, the histologic manifestations of syphilis of the aerodigestive tract were characterized. They classified the histologic findings into 3 patterns: plasma cell-rich, lymphohistiocytic with or without granulomas, and lymphoma-like with large atypical lymphoid cells.5 The most commonly observed pattern was the plasma cell rich, including those from the oral mucosa.5 The lymphohistiocytic pattern was observed in cases from the lower gastrointestinal tract, and the lymphoma-like pattern was observed in both the upper and lower aerodigestive tracts.5 Granulomas were also identified in half of the cases studied.5 The epithelial surface was eroded or ulcerated in the vast majority of cases, but may also appear hyperplastic.5 A distinct finding in the majority of specimens was perineural plasma cells, and this can be a helpful clue to this at times challenging diagnosis.5 In addition, the use of special and immunohistochemical stains can further aid in the diagnostic work up.

Historically silver impregnated stains have been used for treponema identification, including the Levaditi or Warthin-Starry stain. However, potential diagnostic pitfalls include a relatively low sensitivity and background artifactual staining, which may make interpretation difficult.6 Immunohistochemistry using antibodies to T. pallidum offers a more sensitive method of detection (Fig. 3). In a study by Martin-Ezquerra and colleagues, the patterns of antitreponema immunohistochemical staining were examined. In this study, immunohistochemistry identified spirochetes in 80% of specimens, in comparison to Warthin-Starry, which identified spirochetes in only 50% of specimens. In the majority of cases in which spirochetes were not identified by immunohistochemistry, the patients had recently been treated, or had long-standing disease.6 This rate of detection is similar to previously reported sensitivities, of 74% to 94% for immunohistochemistry and 31% to 71% for Warthin-Starry.6 In lesions of primary syphilis, the distribution of spirochetes often appeared perivascular in nature, which they defined as a “vasculotropic pattern.”6 In some cases, spirochetes were also present in an intercellular distribution in the lower epithelium, in particular in areas adjacent to an ulceration.6 In lesions of secondary syphilis, spirochetes were seen more often within the epidermis in an intercellular distribution, particularly in the lower levels of the epidermis.6 However, in some cases spirochetes were located in the upper levels of the epidermis, within the papillary dermis, and within follicular or sweat gland epithelium.6 One word of caution regarding application of immunohistochemistry for detection of T. pallidum, is that although sensitivity is superior to that of Warthin-Starry, it is not specific to T. pallidum species, and cross reactivity has been noted between other spirochetes, including Brachyspira sp., which is implicated as a cause of human intestinal spirochetosis.7

FIGURE 3

FIGURE 3

In sum, syphilis is a reemerging infection, affecting all ages and sexes, and can present in a wide variety of appearances. A high index of suspicion and knowledge of the varied and sometimes subtle histologic features is imperative for accurate diagnosis of this infection. The use of immunohistochemistry has improved detection rates of spirochetes within tissue sections, although not all cases will have positive staining. A low threshold for clinical correlation and correlation with serologic studies may be warranted in these cases in which the diagnosis is suspected.

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MEDICATION ADVERSE REACTIONS—SOURCES OF EMERGING INFLAMMATORY REACTIONS

Cutaneous Reactions Caused by Immune Checkpoint Inhibitors

Immune checkpoint pathways, which include the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programed death receptor-1/programed death receptor ligand-1 (PD-1/PD-L1) pathways, are designed to reduce immune activation and limit self-damage. Studies have shown that tumors are able to manipulate these pathways to dampen immune clearance and enhance tumor survival. Immune activation with ipilimumab, an anti-CTLA-4 antibody, as well as the PD-1 inhibitors pembrolizumab and nivolumab, has been demonstrated to induce a long lasting antitumor immune response in melanoma, lung, renal, and bladder cancers in various clinical trials.8–13 Other immune therapeutics in this class includes tremelimumab, another anti-CTLA-4 antibody, and the PD-L1 antibodies atezolizumab and durvalumab. Adverse events from these drugs are mainly immune related given their mechanism. Cutaneous toxicity is one of the most commonly recognized side effects of the immune checkpoint inhibitors, occurring in 47% to 68% of patients treated with ipilimumab and about 13% to 40% of patients treated with nivolumab.14,15 Not surprisingly, given the role of the immune system in many dermatologic disorders, dermatologic toxicity has yielded adverse reactions that mimic many known inflammatory dermatoses.

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Cutaneous Toxicity Associated With CTLA-4 Antibody Therapy

CTLA-4 is a protein receptor found on T cells that inhibits the priming phase of T-cell activation. Ipilimumab is a fully human monoclonal antibody that blocks the CTLA-4 receptor on T cells, removing the inhibitory function that results in an increase in the number of CD4+ and CD8+T cells.10,16 It was the first agent to receive Food and Drug Administration (FDA) approval for advanced stage melanoma following a large double blind, double dummy clinical trial showing improved survival.8,16 Cutaneous toxicity is frequent, occurs early in the course of treatment (occurring on average 21 to 42 d following initiation), and is dose dependent.14,17 A maculopapular eruption is the most common manifestation and mirrors other hypersensitivity medication-induced eruptions.18–20 Studies with histologic data describe a pattern that resembles an eczematous drug eruption with spongiosis of the epidermis and a perivascular lymphocytic infiltrate with eosinophils (Fig. 4).18 An elevated peripheral eosinophil count has also been described with the eruption.21 Rare reports suggest that the maculopapular eruption can also manifest histologically as a lichenoid dermatitis.22 Vitiligo, another adverse event, occurs in ∼1% to 3% of patients treated with anti-CTLA-4 antibodies. It typically develops months after treatment initiation and does not appear to be dose related.20,23 Infrequent inflammatory dermatoses reported in the literature with anti-CTLA-4 immunotherapy include cases that clinically and histologically appear as Stevens-Johnson syndrome/toxic epidermal necrolysis,8,18 acute generalized exanthematous pustulosis,24 papules and plaques that histologically show a CD30+ lymphomatoid reaction,20 neutrophilic dermatoses (including Sweet syndrome and pyoderma gangrenosum),25–28 granulomatous eruptions,29 dermatitis herpetiformis,30 and papulokeratotic eruptions that histologically resemble Grover disease.31,32 Alopecia of the scalp and other regions of the body that histologically mimics alopecia areata has also been described.21 In addition, acneiform lesions,22 dermatomyositis,33,34 and radiation-associated dermatitis22 have been diagnosed clinically in patients receiving anti-CTLA-4 therapy. Tremelimumab, another anti-CTLA-4 antibody, shows a similar toxicity profile that includes a skin rash and pruritus, occurring in 33% and 31% of patients, respectively.35,36

FIGURE 4

FIGURE 4

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Cutaneous Toxicity Associated With PD-1/PD-L1 Antibody Therapy

PD-1 is expressed on T, B, and NK cells and its ligand is present on antigen presenting cells. The pathway is involved in the effector phase of T-cell activation in the tumor microenvironment. Blockade results in increased CD8+T cells (in relation to CD4+T cells) and enhanced antitumor immune activation.10 Cutaneous toxicities associated with PD-1 and PD-L1 antibody therapy are similar to those seen with anti-CTLA-4 therapy, with the range of cutaneous toxicity reported with anti-PD-L1 therapy slightly more limited, possibly due in part to the fact that literature is still emerging. Skin rash not otherwise specified, pruritus, and vitiligo are the most commonly associated dermatologic reactions associated with ant-PD-1/PD-L1 therapy. These tend to occur slightly later in the course of treatment (weeks to months) when compared with the dermatologic toxicity associated with anti-CTLA-4 antibody (eg, ipilimumab) therapy.9,14,20,37,38 In a large meta-analysis of the cutaneous toxicities with the anti-PD-1 agents pembrolizumab and nivolumab, Belum and colleagues reported the incidence of all grade rash to be 16.7% and 14.3% (relative risk 2.6 and 2.5), respectively. Pruritus had an incidence of 20.2% and 13.2% (relative risk 49.9 and 34.5), respectively. Vitiligo had an incidence of 8.3% and 7.5% (relative risk 17.5 and 17.6), respectively. Similar to the rash seen with anti-CTLA-4 agents, the most common presentation of the rash associated with the anti-PD-1 agents is a maculopapular eruption, which on histology shows a lichenoid/interface pattern with a perivascular infiltrate that includes eosinophils (Fig. 5).37,39,40 A mucosal lichenoid eruption has also been reported with anti-PD-L1 agents.41 Interestingly, vitiligo from anti-PD-1 agents tends to occur more commonly in patients treated for melanoma37 presumably secondary to activation of the immune response against melanocytes. Early studies suggest a more favorable outcome in melanoma patients that develop vitiligo following anti-PD-1 therapy.42,43 Inflammatory lesions have been reported to precede depigmentation in some cases.44 Fascinating is the fact that treatment with anti-PD-1 and anti-PD-L1 for lung carcinoma can lead to hair repigmentation in some cases, inferring the complexity of these agents in different tumors.45 Unique adverse events with anti-PD-1 therapy that do not appear to be seen with anti-CTLA-4 therapy include a psoriasiform eruption,37,46,47 an immunobullous eruption that mimics bullous pemphigoid,30,48,49 and a vasculopathic reaction.37

FIGURE 5

FIGURE 5

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Combination Therapy With the Checkpoint Inhibitors

While therapy with CTLA-4 and PD-1 blockade has been shown to be synergistic it is not surprising that the combination leads to a higher rate of skin toxicity than when each agent is used alone (42% to 55% for single agent therapy compared with 59% to 71% for combination therapy).50,51

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Cutaneous Reactions Associated With Epidermal Growth Factor Receptor (EGFR) Inhibitors

EGFR inhibitors are used frequently in the treatment of solid organ malignancy. These medications are broadly divided into 2 categories, monoclonal antibodies and tyrosine kinase inhibitors, and include cetuximab, panitumumab, gefitinib, and erlotinib, among others. Cutaneous adverse effects of this medication class are well-documented, frequently encountered, and can create a large impact on the quality of life of patients. In addition, the presence of some of these cutaneous side effects has been shown to correlate with treatment response and prognosis, ensuing an even greater interest to clinicians. Among these are the well-known acneiform (papulopustular) eruptions, paronychia, xerosis, hyperpigmentation, trichomegaly, telangiectasia, and a newer recognized purpuric drug eruption.

The acneiform eruption secondary to EGFR inhibitors occurs in approximately half of the recipients of these drugs, and in up to 75% to 100% of individuals taking cetuximab specifically.52 This eruption typically begins within 1 week of treatment, and is characterized by erythematous papules and pustules without comedones on the head/neck, upper trunk, and shoulders.52 The eruption may be pruritic, and there appears to be a dose-related response to the severity. Interestingly, the presence and severity of the eruption does appear to correlate with treatment response and overall survival, with improved rates within those individuals with this cutaneous eruption.52,53 Histopathology typically reveals a neutrophilic infiltrate within the dermis and surrounding the follicular infundibulum, with typical sparing of sebaceous lobules.52 The pathogenesis of this eruption remains not well understood.52

Paronychia has been estimated to occur in ∼10% to 15% of individuals treated with cetuximab and gefitinib, and typically occurs months after initiation of treatment.52 This paronychia may involve multiple fingers and toes, and can cause significant functional impairment.52 Histopathology demonstrates a marked dermal inflammatory infiltrate, composed of plasma cells, lymphocytes, and neutrophils.52 Cultures have failed to identify causative infectious organisms, except for reports of secondary infection with Staphylococcus aureus. 52 Subungual lobular capillary hemangiomas (pyogenic granulomas) have also been reported.52

The other known cutaneous side effects reported in this class of medications occur less frequently, but are well recognized. They include xerosis, hyperpigmentation, trichomegaly, and telangiectasia.52 More recently, a newly recognized purpuric drug eruption has been documented, with unique clinical and histologic features.

Cho et al54 recently characterized this purpuric eruption. In their retrospective study, the onset of symptoms varied significantly between patients, but the mean onset was 3.5 months. Clinically, patients presented with purpuric macules or papules coalescing into plaques, primarily on the lower extremities, some in an annular configuration.54 Nonfollicular pustules were also identified in 56% of individuals, many of which were culture positive for S. aureus.54 Histopathology revealed epidermal dysmaturation, neutrophilic aggregation, erythrocyte extravasation, and endothelial cell swelling.54 A leukocytoclastic vasculitis was seen in a minority (9%) of patients.54 Tissue cultures performed revealed a high incidence of infectious organisms, the most common of which was S. aureus. 54 Other, less commonly reported infectious organisms included Candida species, Pseudomonas aeruginosa, and Serratia species.54 In their review, the majority of patients improved with systemic antibiotics.54 In addition to the reported cutaneous effects from targeted oncologic therapy, other distinct medication reactions have recently been characterized with distinct clinical and histologic presentations, including exenatide-induced panniculitis.

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Cutaneous Reactions to BRAF Inhibitors

Over 80% of cutaneous melanoma demonstrates mutations in the MAPK pathway (RAS-RAF-MEK-ERK mitogen-activated protein kinase pathway), which functions in cell differentiation, proliferation, survival, stress response and apoptosis. BRAF V600E is one of the most common mutations seen in melanoma involving this pathway. Vemurafenib and dabrafenib are medications both approved for the treatment of V600E BRAF positive metastatic melanoma and work by inhibiting melanoma tumorigenesis through inhibition of the MAPK pathway. While these medications are generally well-tolerated, adverse reactions exist with cutaneous reactions affecting 74% of patients taking these inhibitors.55,56 Cutaneous reactions include an exanthematous/maculopapular or papulopustular rash that affects the face, truck and arms, and is dose dependent. Histology of the maculopapular rash can appear as a perivascular dermatitis or a dermal hypersensitivity eruption.19,57–59 A well-reported cutaneous effect of these medication is the development of keratotic lesions. These lesions occur in 12% of patients taking vemurafenib and 8% of patients taking dabrafenib and may appear clinically and histologically as squamous cell carcinoma and keratoacanthoma. These lesions can be treated with simple excision and typically do not require dose modification. Other keratotic lesions that can be seen include verrucous keratoses (seborrheic keratosis and verruca vulgaris) and hypertrophic actinic keratoses.57,60,61 The use of a MEK inhibitor, trametinib, which also targets this pathway, and is approved for metastatic or unrespectable melanoma with V600E or V600K mutations, has been shown to decrease the incidence of these keratotic lesions when used in combination with the BRAF inhibitors.56,62,63 Photosensitivity has additionally been reported in 7% to 12% of patients taking BRAF inhibitors and is more common in patients taking vemurafenib; thus, counseling on sun protection practices is helpful in the management of these patients.64 Other cutaneous reactions in patients taking BRAF inhibitors include xerosis (dry skin), pruritus (itchy skin), and paronychia (nail infection, where the nail and skin meet) all of which are observed with administration >3 months. Alopecia, plantar hyperkeratosis and panniculitis have also been reported with BRAF inhibitors.55

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Cutaneous Reactions Associated With Exenatide-induced Panniculitis

Exenatide is a glucagon-like peptide-1 receptor agonist, used in the treatment of type II diabetes. This medication is injected subcutaneously, typically in the abdomen, thigh, or arm and can be dosed either twice a day or once per week in an extended release formulation. The extended release formulation consists of poly (DL-lactic-co-glycolic acid) (PLGA) microspheres, which contain exenatide both on their surface and within. During clinical trials of this medication, subcutaneous nodules were reported in patients using the extended release formulation, which spontaneously resolved within 3 to 6 weeks. Recent reports have further characterized this phenomenon as an eosinophil-rich granulomatous panniculitis.65–68 The pathologic findings reported are that of a mixed lobular and septal panniculitis, with an associated granulomatous infiltrate composed of lymphocytes, histiocytes, eosinophils, and often multinucleated giant cells (Fig. 6A).65–69 In some reports, these microspheres have been visualized, and described as round structures that are birefringent and nonpolarizable.69 Interestingly, these microspheres have been found to be highlighted by Acid fast (Fig. 6B) and Fite Stains. This positive staining pattern has been postulated to be due to the lipid quality and content of the PLGA used in these extended release microspheres, but further studies are needed to elucidate this further.69 This characteristic reaction is one that pathologists should be aware of, given the unique and distinct histologic features.

FIGURE 6

FIGURE 6

In sum, mediation-induced cutaneous reactions including those resulting from therapy with immune checkpoint inhibitors and EGFR inhibitors can cause cutaneous manifestations that mimic a variety of inflammatory dermatoses. Likewise, new staining patterns such as that seen with microsphere formulations can aid in identification of drug reactions. A thorough history, including obtaining a medication list, is often helpful in making an accurate diagnosis. In addition, awareness of these toxicities is important and can lead to better management of these patients.

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UPDATES IN NEUTROPHILIC DERMATOSES

Histiocytoid Sweet Syndrome

Sweet syndrome, or acute febrile neutrophilic dermatosis, was first described by Douglas Sweet in 1964.70 A reactive disorder of poorly understood etiology, Sweet syndrome tends to arise in the following clinical scenarios: idiopathic; associated with underlying inflammatory conditions or infections; associated with underlying hematologic dyscrasia or malignancy, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); or associated with solid tumors. The majority of cases fall into the idiopathic or inflammatory category.71 Clinically, patients with Sweet syndrome rapidly develop tender erythematous plaques and nodules, often accompanied by fever, leukocytosis, and in particular, neutrophilia (Fig. 7). The typical histopathologic findings are an interstitial inflammatory infiltrate comprised predominantly of neutrophils with leukocytoclasia and papillary dermal edema (Fig. 8).72 As such, Sweet syndrome is classified as a neutrophilic dermatosis.

FIGURE 7

FIGURE 7

FIGURE 8

FIGURE 8

More recently there has been the introduction of a histologic subtype of Sweet syndrome, characterized by a predominance of mononuclear cells in the dermis with the morphology of histiocytes (Fig. 9). In 2005, Requena and colleagues reported 41 patients with Sweet syndrome in which the inflammatory infiltrate was atypical: it was predominantly comprised of histiocytoid-appearing mononuclear cells with large kidney-shaped, vesicular nuclei, single nucleoli, and scant eosinophilic cytoplasm.73 In some cases, the infiltrate reached deeply into the dermis and subcutis. Neutrophils were present, but were vastly outnumbered. Strong myeloperoxidase (MPO) immunoreactivity demonstrated that, in spite of their histiocytoid morphology, these cells were in fact immature myeloid cells. Requena and colleagues termed this uncommon variant of Sweet syndromehistiocytoid Sweet syndrome.”

FIGURE 9

FIGURE 9

Histiocytoid Sweet syndrome is an increasingly recognized variant of Sweet syndrome, although not without controversy. The nature of the histiocytoid cells has generated significant debate in the literature. While some authors favor that the histiocytoid cells are immature neutrophils, others contend that they represent leukemic cells in patients with underlying hematologic dyscrasias and malignancy.74,75 In a description of Sweet syndrome that predates Requena and colleagues’ report, Jordaan74 describe 3 sequential stages of the infiltrate in Sweet syndrome: lymphocytic, neutrophilic, and histiocytic. Requena and colleagues disagreed with the assertion that histiocytoid Sweet syndrome is a late histiocyte-rich stage of classic Sweet syndrome. In their series, they observed the histiocytoid mononuclear infiltrate in very early lesions, biopsied within 24 hours of development. In addition, the histiocytoid mononuclear cells were strongly reactive for MPO, a reliable marker for myeloid cells, in particular immature neutrophils.73,76,77

The assertion by some, that the histiocytoid cells are in fact a manifestation of leukemia cutis, has sparked significant debate since Requena and colleagues’ original report. As leukemia cutis heralds death within 1 year for 88% of patients with AML and CML, the origin of these cells is critical.78,79 The infiltrate in leukemia cutis can be histopathologically indistinguishable from the aforedescribed infiltrate in histiocytoid Sweet syndrome, making this determination difficult.80 Requena and colleagues note that peripheral blood smears in 27 of their patients with histiocytoid Sweet syndrome did not demonstrate circulating leukemic cells, and the bcr/abl fusion gene was not identified by fluorescent in situ hybridization (FISH) in the dermal infiltrate. In addition, clinical follow-up over several years did not eventuate in any acute or chronic myelogenous leukemia. Thus, Requena and colleagues assert in their original publication that the histiocytoid cells are not leukemic and, furthermore, are not seen in association with underlying hematologic abnormalities in any higher frequency than classic Sweet Syndrome; 24% of their cases of histiocytoid Sweet syndrome were associated with an underlying hematologic dyscrasia, whereas 21% of classic Sweet syndrome are associated with any type of underlying malignancy.81

A report by Alegría-Landa et al82 in 2017 further examined this question by performing comprehensive immunohistochemical profiling of the infiltrate in 33 patients with histiocytoid Sweet syndrome. The histiocytoid cells were again found to express MPO, as well as myeloid nuclear differentiation antigen, further supportive of myelomonocytic lineage. In addition, they performed CD163/MPO dual staining and found minimal co-expression of CD163 and MPO, excluding the possibility that the cells represent histiocytes with aberrant MPO expression. The authors also found a similar lack of the bcr/abl fusion gene, with the exception of one patient who was known to harbor the bcr/abl chromosomal abnormality in the bone marrow. They concluded that the patients studied were no more likely to have or go on to develop hematologic dyscrasias compared with patients with classic Sweet syndrome.

Over the 12 years between the foundational description of histiocytoid Sweet syndrome by Requena and colleagues and the follow-up study by Alegría-Landa and colleagues, multiple case reports, small case series, and letters have debated the assertion that histiocytoid Sweet syndrome is simply a benign variant of Sweet syndrome. Detractors note that FISH is only useful when there is a known underlying hematologic disorder with an identifiable chromosomal abnormality, as a malignancy-specific probe is necessary to characterize the infiltrate.83 In a study by Osio and colleagues’s, FISH performed on the histiocytoid infiltrate on 6 patients with histiocytoid Sweet syndrome and underlying MDS with a known associated bone marrow abnormality revealed the same genetic aberration in the infiltrate in 4 of 6 patients (a finding the authors termed “myelodysplasia cutis”).84

Another contentious issue is whether histiocytoid Sweet syndrome has a stronger association with hematologic malignancy as compared with classic Sweet syndrome, with many authors disputing Requena and colleagues’ and Alegría-Landa and colleagues’ interpretation of the existing data. A series of 62 patients with Sweet syndrome reported by Ghoufi et al85 demonstrated that histiocytoid Sweet syndrome is indeed more frequently associated with hematologic malignancies, with MDS drawing the strongest association. A total of 55.5% of patients with histiocytoid Sweet syndrome in their cohort had underlying hematologic dyscrasias (compared with 25% with classic Sweet syndrome). A significant proportion of these patients with histiocytoid Sweet syndrome had MDS. Bush and Wick86 found a similar association rate of histiocytoid Sweet syndrome with hematologic malignancy (53%) in their meta-analysis when they excluded the data from Requena and colleagues’ initial report, which they felt to underrepresent the association.

While the association with underlying hematologic malignancy remains controversial, a novel immunohistochemical marker to distinguish the infiltrates in histiocytoid Sweet syndrome and leukemia cutis may bring clarity to the histopathologic diagnosis and its clinical implications. Previous attempts to identify leukemic cells in the skin with blast markers CD34 and CD117 have been challenging, as these markers are often negative in leukemia cutis. Missense mutations in erythroblast transformation-specific regulated gene-1 (ERG), a regulator of cell proliferation, differentiation, angiogenesis, and apoptosis, have been reported in a subset of patients with AML and subsequently in patients with a variety of leukemias.87,88 Xu et al89 recently report that ERG is a strong and specific immunomarker for leukemia cutis, with a sensitivity of 81.4% and specificity of 100%, based on a cohort of 32 patients, 16 with known leukemia cutis (with bone marrow biopsy-proven malignancy) and 16 with reactive myeloid infiltrates (a broad category of inflammatory disorders that included Sweet syndrome but also other reactive dermatitides). Given the potentially similar appearance of the infiltrates in histiocytoid Sweet syndrome and leukemia cutis, and the extremely different prognosis of the 2 conditions, a reliable immunohistochemical marker such as ERG may be of value.

Since the formal introduction of the concept of histiocytoid Sweet syndrome in 2005, both the histopathologic diagnosis as well as its underlying association with hematologic malignancy has been vigorously debated. Morphology, immunohistochemistry, FISH, clinical history, and long-term follow-up are sometimes insufficient. However, the course for patients with histiocytoid Sweet syndrome and leukemia cutis is markedly different, and discerning these 2 conditions is not merely a matter of nomenclature. Histiocytoid Sweet syndrome is a work in progress, and close surveillance of these patients is required.

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Autoimmune Neutrophilic Dermatosis

In addition to Sweet syndrome, there are other cutaneous neutrophilic disorders that herald systemic conditions. In the past decade there has been extensive study of neutrophils in the setting of autoimmune diseases. In 2006, Gleason and colleagues formally introduced the concept of neutrophilic dermatosis of lupus erythematosus (LE) in their description of 4 patients who presented with acute systemic symptoms consistent with LE and a nonbullous, erythematous cutaneous eruption with the following histopathologic findings: a superficial perivascular and interstitial neutrophil-rich infiltrate with notable leukocytoclasia, but no vasculitis or significant papillary dermal edema.90 These 4 cases had subtle features of LE, such as vacuolar interface and dermal mucin (in one case). Subsequently, Brinster et al91 reported an additional 4 cases of nonbullous neutrophilic dermatosis in the setting of LE; these cases were clinically and histopathologically similar to those described above. Gleason and colleagues’ and Brinster and colleagues’ reports add 8 cases to 6 previously reported cases of a “Sweet-like syndrome” in the setting of LE, all of which share the clinical features of erythematous, edematous papules and plaques without bulla formation (Fig. 10) and the pathologic features of a neutrophil-predominant infiltrate of dermis with leukocytoclasia, a lack of significant dermal edema, an absence of vasculitis and variable vacuolar interface alteration (Fig. 11).92–94 In some patients there may be complement and immunoglobulin deposition at the dermal-epidermal junction with direct immunofluorescence, particularly in those patients with systemic LE. There is insufficient data to determine the precise number, but in our experience up to 50% of those patients with underlying lupus have positive direct immunofluorescence findings (Fig. 12).

FIGURE 10

FIGURE 10

FIGURE 11

FIGURE 11

FIGURE 12

FIGURE 12

The “neutrophilic dermatoses of lupus erythematosus,” and the prior reported cases of “Sweet-like syndrome” of LE, fit into a larger category of neutrophilic dermatoses that are observed in the setting of a variety of autoimmune connective tissue diseases (AICTDs), including rheumatoid arthritis, Sjögren syndrome, and Still disease.95 It is now widely accepted that neutrophil-rich dermatoses resembling SS, with a neutrophil-rich infiltrate, leukocytoclasia and lack of primary vasculitis may occur in the setting of a variety of AICTDs, and “autoimmune neutrophilic dermatosis” is an appropriate description for the entity.96 Distinguishing the 2 patterns is essential to arrive at the correct diagnosis (Table 1).

TABLE 1

TABLE 1

The more recently described entity, neutrophilic urticarial dermatosis, also falls into the spectrum of autoimmune neutrophilic dermatosis,97,98 neutrophilic urticarial dermatosis is a transient eruption that commonly presents with urticarial lesions lasting <48 hours, leaving no purpura, and systemic symptoms in patients with AICTDs and autoinflammatory disorders. Histopathologically, there is a perivascular and interstitial neutrophilic infiltrate with prominent leukocytoclasia, but lacking dermal edema or vasculitis. Distinguishing features are (1) neutrophilic epitheliotropism, whereby neutrophils are located within and around hair follicles, sebaceous glands and most commonly, eccrine glands and ducts; and (2) basophilic degeneration of collagen bundles, most prominent in biopsies with denser neutrophilic infiltrates (Fig. 13).

FIGURE 13

FIGURE 13

The role of neutrophils in autoimmune and autoinflammatory diseases has long been overlooked, with the emphasis instead being on autoreactive T lymphocytes that develop after an “immunization” phase, and then activate a variety of cell types that damage host tissue (“effector” phase). However, neutrophils are capable of contributing to autoimmunity, both in the “immunization” phase by exposing autoantigens when involved in a vasculitic process, during apoptosis, or as mediators of cell damage in the “effector” phase.99,100 In lesional skin of neutrophilic dermatoses, cytokines that recruit neutrophils and amplify the inflammatory response are known to be overexpressed.101 In addition, aberrant expression and/or activation of adhesion and migration molecules that assist in neutrophil migration to local tissues (such as intercellular adhesion molecule-1) has been observed in the eruption of dermatomyositis.102 The specific mechanism of the neutrophilic dermatoses in AICTD is poorly understood, but neutrophils appear to play a role in pathogenesis.

It is essential for pathologists to recognize the role of neutrophils in the spectrum of cutaneous manifestations of hematologic dyscrasias and connective tissue disorders and be familiar with the histologic features.

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UPDATES IN CALCIPHYLAXIS

Calciphylaxis is a rare, life-threatening condition that is characterized by calcification of the microvasculature and cutaneous soft tissue.103

There are 2 main subtypes of calciphylaxis, uremic, and nonuremic. Uremic calciphylaxis, the most common, occurs in patients with end-stage renal disease, whereas cases of nonuremic calciphylaxis, which are not associated with renal disease, are well-documented and found to be associated with many different conditions, such as primary hyperparathyroidism, alcoholic liver disease, malignancy, and connective tissue disease.104

Our current understanding of the pathophysiology of calciphylaxis is complex and evolving. Dysregulation of systemic mineralization involving calcium, phosphate, and parathyroid hormone levels was once thought to be the primary process behind the development of calciphylaxis, but it is now understood that medial calcification of arterioles followed by thrombotic occlusion are the key features required for the development of calciphylaxis lesions.105–107

Calcification of the arteriole media is the result of downstream effects of dysregulation of systemic mineralization leading to an imbalance of procalcification and anticalcification factors in both the circulation and local tissue environment. Elevations in circulating calcium-phosphate product (CaXP) and upregulation of procalcifying products in the extracellular matrix occur in the setting of decreased levels of anticalcification products, namely Fetuin-A and matrix gla protein, found in the systemic circulation and extracellular matrix, respectively.94,96 As a result of this procalcification milieu and the presence of various osteogenic factors, such as bone morphogenic protein-4 and osteopontin, vascular smooth muscle cells transform from a contractile phenotype to an osteoblast-like phenotype that results in calcification of the smooth muscle of the arteriole media.105,107 Transformed vascular smooth muscle cells not only promote calcification, but may also trigger intimal hyperplasia and vascular sloughing resulting in nonthrombotic vascular occlusion.107

Thrombotic occlusion and hypercoagulability are also gaining appreciation for their role in the development in calciphylaxis lesions. Systemic hypercoagulability, including protein C and S deficiencies have been reported in cases of calciphylaxis, and it is also believed that inflammatory cytokines and reactive oxygen species, triggered by vascular injury, may induce a local hypercoagulable reaction with subsequent areas of focal thrombosis and necrosis. It is this appreciation of an underlying prothrombotic state that helps to explain cases of calciphylaxis in nonuremic patients.105,106

Early in the development of calciphylaxis, clinical findings are most notable for livedo racemose, persistent, net-like, reticulated, and erythematous to purpuric patches. There may be underlying erythematous to violaceous, tender, indurated subcutaneous plaques and nodules. These lesions are most commonly seen in adipose-rich areas of the trunk and extremities, with the legs being the most common site of involvement. Less commonly, penile and digital involvement has been reported. As the disease progresses, these cutaneous lesions deteriorate to exquisitely painful, nonhealing, stellate ulcers with an overlying black eschar (Fig. 14).105

FIGURE 14

FIGURE 14

For both uremic and nonuremic patients, the diagnosis of calciphylaxis can be more elusive given its clinical similarities to many other entities, such as systemic infections, hypercoagulable states, autoimmune diseases, vasculitis, and malignancies.105 In these cases, histologic confirmation is a vital diagnostic tool. Unfortunately, acquiring an adequate tissue sample can prove challenging. In one retrospective review of 56 biopsies from confirmed calciphylaxis patients, classic features of calcification in arterioles were noted in only 18% of samples.108

It has been nearly 60 years since calciphylaxis was first described in the medical literature,109 yet the literature addressing its histologic features is largely comprised of case reports and series. Only 3 retrospective studies examining the histologic features of calciphylaxis have been published, all within the last 5 years.108,110,111

Skin biopsy remains the gold standard in the diagnosis of calciphylaxis given the clinical similarities to many other entities.105,112 Calcium deposition within the tunica media of small to medium sized arteries and arterioles in the subcutaneous fat is the most diagnostic histologic feature,46,61 but obtaining an adequate tissue sample is often compromised by various clinical factors, which can render a skin biopsy specimen nondiagnostic (Fig. 15). These challenges have lead many clinicians to rely on clinical features alone for the diagnosis.105,109,111,113 Fortunately, other histologic features have been found to be significantly associated with calciphylaxis, including intimal hyperplasia, microthrombi, and extravascular soft tissue calcification.108,110,111

FIGURE 15

FIGURE 15

Chen and colleagues recently demonstrated that a skin biopsy can be especially useful in patients with end-stage chronic kidney disease (CKD), as significant histologic differences have been demonstrated in CKD patients with and without calciphylaxis. The authors found that CKD patients with calciphylaxis were significantly more likely to demonstrate thrombi and vessel wall calcification in the dermis and superficial fat, thrombi within calcified vessels, and dermal angioplasia compared with CKD patients without calciphylaxis. The authors also demonstrated that there were no significant histopathologic changes in calciphylaxis patients with and without renal disease.110

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Perieccrine Calcification

Calcification of extravascular structures, such as dermal collagen and subcutaneous fat are helpful histologic features, but its specificity is attenuated by conditions that can demonstrate similar features, such as lupus and pancreatic panniculitides.108 Perieccrine calcification (Fig. 16), however, is one form of extravascular calcification that is a subtle, but potentially valuable feature. In a retrospective case-control study by Mochel et al,108 perieccrine calcification, detectable only with von Kossa and Alizarin red calcium stains, was found to be highly specific, having been identified in 11% (n=6/55) of cases and no controls. Notably, perieccrine calcification was the only form of calcium deposition identified in 4 of the 6 cases. While this finding was not statistically significant (P=0.33) likely due to the small sample size, it is potentially instrumental in histologically challenging cases. Since this study was published, perieccrine calcification in calciphylaxis has been addressed in 2 publications. A case report by Dookhan et al114 confirmed the presence of this feature in a 44-year-old male with uremic calciphylaxis. Similar to the aforementioned case-control study, perieccrine calcification was not identifiable with hematoxylin and eosin staining and was only visualized with von Kossa calcium staining. A retrospective case-control study by Chen and colleagues did not identify perieccrine calcification in any of their 57 calciphylaxis subjects; however, calcium stains were not utilized in the analysis of these histologic specimens.11

FIGURE 16

FIGURE 16

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Pseudoxanthoma Elasticum-like Changes

Another histologic feature noted to be associated with calciphylaxis in recent years in the presence of pseudoxanthoma elasticum-like changes. Briefly, pseudoxanthoma elasticum (PXE) is a rare, clinically distinct, genetic disorder that shares with calciphylaxis the common feature of cutaneous calcification. It is, however, markedly distinct from calciphylaxis in both its cutaneous and histologic presentation. It is caused by an autosomal recessive mutation in the ABCC6 (ATP-binding cassette subfamily C member 6) gene, normally expressed in the liver and the kidney.115 While the exact function of this gene remains unknown, ABCC6-knockout mouse models demonstrate progressive mineralization of connective tissue.115 Clinically, PXE manifests as yellowish, coalescing papules and redundant folds in flexural skin, angioid streaks of the retina, and cardiovascular claudication and infarctions (Fig. 17). Histopathology of the skin reveals curled, frayed, and calcified elastic fibers in the mid reticular dermis.115–118

FIGURE 17

FIGURE 17

Cutaneous PXE-like histopathologic features in the absence of systemic involvement have been described in association with various autoimmune and metabolic disorders,119–128 in addition to 3 case reports and 2 case series of uremic and nonuremic calciphylaxis.104,129–132 These cases demonstrate histologic features of calciphylaxis in conjunction with the curled, frayed and calcified elastic fibers known to PXE, which can be localized to either the reticular dermis or septae of the subcutaneous fat (Fig. 18).104,129–132 This finding is identifiable with hematoxylin and eosin staining, but may be better visualized with special calcium stains (ie, von Kossa) and elastic fiber stains (ie, Verhoeff-Van Gieson stain). The mechanism for the development of PXE-like features in calciphylaxis is unclear, but given the frequent difficulty in demonstrating vascular calcium deposition, it has been proposed as a feature that may heighten suspicion for an underlying diagnosis of calciphylaxis in the appropriate clinical setting.

FIGURE 18

FIGURE 18

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CONCLUSIONS

In conclusion, inflammatory dermatopathology is an evolving field, with an ever-changing landscape. Changing trends in infectious diseases, medication advances, and refined characterization of various dermatologic conditions have accounted for recent updates within the field. This complex subject demands a high index of suspicion, and vigilance to maintaining up to date knowledge of dermatology to ensure an accurate diagnosis.

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REFERENCES

1. Syphilis. 2017. Available at: cdc.gov.
2. Peeling RW, Mabey D, Kamb ML, et al. Syphilis. Nat Rev Dis Primers. 2017;3:17073.
3. Weedon D. Skin Pathology, 2nd ed. London: Churchill-Livingstone; 1998.
4. Flamm A, Parikh K, Xie Q, et al. Histologic features of secondary syphilis: a multicenter retrospective review. J Am Acad Dermatol. 2015;73:1025–1030.
5. Tse JY, Chan MP, Ferry JA, et al. Syphilis of the aerodigestive tract. Am J Surg Pathol. 2017;42:472–478.
6. Martin-Ezquerra G, Fernandez-Casado A, Barco D, et al. Treponema pallidum distribution patterns in mucocutaneous lesions of primary and secondary syphilis: an immunohistochemical and ultrastructural study. Hum Pathol. 2009;40:624–630.
7. Ruiz SJ, Procop GW. Cross-reactivity of anti-Treponema immunohistochemistry with non-Treponema spirochetes: a simple call for caution. Arch Pathol Lab Med. 2016;140:1021–1022.
8. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
9. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–330.
10. Massari F, Santoni M, Ciccarese C, et al. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015;41:114–121.
11. McDermott DF, Drake CG, Sznol M, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33:2013–2020.
12. Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33:2004–2012.
13. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–562.
14. Ciccarese C, Alfieri S, Santoni M, et al. New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors. Expert Opin Drug Metab Toxicol. 2016;12:57–75.
15. Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28:254–263.
16. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3:611–618.
17. Wolchok JD, Weber JS, Hamid O, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 2010;10:9.
18. Lacouture ME, Wolchok JD, Yosipovitch G, et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71:161–169.
19. Curry JL, Torres-Cabala CA, Kim KB, et al. Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol. 2014;53:376–384.
20. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44:158–176.
21. Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol. 2006;142:166–172.
22. Voskens CJ, Goldinger SM, Loquai C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8:e53745.
23. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 2015;11:2471–2484.
24. Hwang SJ, Carlos G, Wakade D, et al. Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma. Melanoma Res. 2016;26:417–420.
25. Gormley R, Wanat K, Elenitsas R, et al. Ipilimumab-associated Sweet syndrome in a melanoma patient. J Am Acad Dermatol. 2014;71:e211–e213.
26. Kyllo RL, Parker MK, Rosman I, et al. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma. J Am Acad Dermatol. 2014;70:e85–e86.
27. Pintova S, Sidhu H, Friedlander PA, et al. Sweet’s syndrome in a patient with metastatic melanoma after ipilimumab therapy. Melanoma Res. 2013;23:498–501.
28. Rudolph BM, Staib F, Von Stebut E, et al. Neutrophilic disease of the skin and intestines after ipilimumab treatment for malignant melanoma-simultaneous occurrence of pyoderma gangrenosum and colitis. Eur J Dermatol. 2014;24:268–269.
29. Reule RB, North JP. Cutaneous and pulmonary sarcoidosis-like reaction associated with ipilimumab. J Am Acad Dermatol. 2013;69:e272–e273.
30. Mochel MC, Ming ME, Imadojemu S, et al. Cutaneous autoimmune effects in the setting of therapeutic immune checkpoint inhibition for metastatic melanoma. J Cutan Pathol. 2016;43:787–791.
31. Munoz J, Guillot B, Girard C, et al. First report of ipilimumab-induced Grover disease. Br J Dermatol. 2014;171:1236–1237.
32. Uemura M, Faisal F, Haymaker C, et al. A case report of Grover’s disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1. J Immunother Cancer. 2016;4:55.
33. Sheik Ali S, Goddard AL, Luke JJ, et al. Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade. JAMA Dermatol. 2015;151:195–199.
34. Yamaguchi Y, Abe R, Haga N, et al. A case of drug-associated dermatomyositis following ipilimumab therapy. Eur J Dermatol. 2016;26:320–321.
35. Ribas A, Chesney JA, Gordon MS, et al. Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion. J Transl Med. 2012;10:236.
36. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616–622.
37. Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.
38. Minkis K, Garden BC, Wu S, et al. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013;69:e121–e128.
39. Joseph RW, Cappel M, Goedjen B, et al. Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy. Cancer Immunol Res. 2015;3:18–22.
40. Tetzlaff MT, Nagarajan P, Chon S, et al. Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features. Am J Dermatopathol. 2017;39:121–129.
41. Sibaud V, Eid C, Belum VR, et al. Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings. J Eur Acad Dermatol Venereol. 2017;31:e464–e469.
42. Sanlorenzo M, Vujic I, Daud A, et al. Cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151:1206–1212.
43. Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–894.
44. Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45–51.
45. Rivera N, Boada A, Bielsa MI, et al. Hair repigmentation during immunotherapy treatment with an anti-programmed cell death 1 and anti-programmed cell death ligand 1 agent for lung cancer. JAMA Dermatol. 2017;153:1162–1165.
46. Totonchy MB, Ezaldein HH, Ko CJ, et al. Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatol. 2016;152:590–592.
47. Ohtsuka M, Miura T, Mori T, et al. Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma. JAMA Dermatol. 2015;151:797–799.
48. Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43:688–696.
49. Carlos G, Anforth R, Chou S, et al. A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. Melanoma Res. 2015;25:265–268.
50. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.
51. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–2017.
52. Hu JC, Sadeghi P, Pinter-Brown LC, et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007;56:317–326.
53. Abdel-Rahman O, Fouad M. Correlation of cetuximab-induced skin rash and outcomes of solid tumor patients treated cetuximab: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015;93:127–135.
54. Cho Y-T, Chen K-L, Sheen Y-S, et al. Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors for non-small cell lung cancer. A clinicopathologic study of 32 cases. JAMA Dermatol. 2017;153:906–910.
55. Reyes-Habito CM, Roh EK. Cutaneous reactions to chemotherapeutic drugs and targeted therapy for cancer: Part II. Targeted therapy. J Am Acad Dermatol. 2014;71:217.e1–217.e11; quiz 227–228.
56. Manousaridis I, Mavridou S, Goerdt S, et al. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol. 2013;27:11–18.
57. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516.
58. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–819.
59. Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013;14:e11–e18.
60. Anforth RM, Blumetti TCMP, Kefford RF, et al. Cutaneous manifestations of dabrafenib GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol. 2012;167:1153–1160.
61. Chu EY, Wanat KA, Miller CJ, et al. Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study. J Am Acad Dermatol. 2012;67:1265–1272.
62. Trefzer U, Minor D, Ribas A, et al. BREAK-2: a phase IIA trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF mutation-positive (V600E/K) metastatic melanoma. Pigment Cell Res. 2011;24:990–1075.
63. Zimmer L, Livingstone E, Hillen U, et al. Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management. Arch Dermatol. 2012;148:357–361.
64. Dummer R, Rinderknecht J, Goldinger SM. Ultraviolet A and photosensitivity during vemurafenib therapy. N Engl J Med. 2012;366:480–481.
65. DeYoung MB, MacConell L, Sarin V, et al. Encapsulation of exenatide in poly- (D, L-Lactide-Co-Glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther. 2011;13:1145–1154.
66. Boysen NC. Eosinophil-rich granulomatous panniculitis caused by exenatide injection. J Cutan Pathol. 2014;41:63–65.
67. Shan S-J, Guo Y. Exenatide-induced eosinophilic sclerosing lipogranuloma at the injection site. Am J Dermatopathol. 2014;36:510–512.
68. Andres-Ramos I, Blanco-Barrios S, Fernandez-Lopez E, et al. Exenatide-induced eosinophil-rich granulomatous panniculitis: a novel case showing injected microspheres. Am J Dermatopathol. 2015;37:801–802.
69. Vidal CI, Chaudhry S, Burkemper NM. Exenatide-induced panniculitis: utility of the acid-fast stain to identify injected microspheres. Am J Dermatopathol. 2017. [Epub ahead of print].
70. Sweet RD. Acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349–356.
71. Chan HL, Lee YS, Kuo TT. Sweet’s syndrome: clinicopathologic study in eleven cases. Int J Dermatol. 1994;33:425–432.
72. Eduardo Calonje J, Brenn T, Lazar A, et al. McKee’s Pathology of the Skin: with clinical correlations. Edinburgh: Elsevier/Saunders; 2012.
73. Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet syndrome: a dermal infiltrate of immature neutrophilic granulocytes. Arch Dermatol. 2005;141:834–842.
74. Jordaan HF. Acute febrile neutrophilic dermatosis: a histopathological study of 37 patients and a review of the literature. Am J Dermatopathol. 1989;11:99–111.
75. Deguchi M, Tsunoda T, Yuda F, et al. Sweet’s syndrome in acute myelogenous leukemia showing dermal infiltration of leukemic cells. Dermatology. 1997;194:182–184.
76. Wong KF, Chan JKC. Antimyeloperoxidase: antibody of choice for labeling myeloid cells including diagnosis of granulocytic sarcoma. Adv Anat Pathol. 1995;2:65–68.
77. Pinkus GS, Pinkus JL. Myeloperoxidase: a specific marker for myeloid cells in paraffin sections. Mod Pathol. 1991;4:733–741.
78. Cho-Vega JH, Medeiros LJ, Prieto VG, et al. Leukemia cutis. Am J Clin Pathol. 2008;129:130–142.
79. Su WP, Buechner SA, Li CY. Clinicopathologic correlations in leukemia cutis. J Am Acad Dermatol. 1984;11:121–128.
80. Kaddu S, Zenahlik P, Beham-Schmid C, et al. Specific cutaneous infiltrates in patients with myelogenous leukemia: a clinicopathologic study of 26 patients with assessment of diagnostic criteria. J Am Acad Dermatol. 1999;40:966–978.
81. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34.
82. Alegría-Landa V, Rodríguez-Pinilla SM, Santos-Briz A, et al. Clincopathologic, immunohistochemical, and molecular features of histiocytoid Sweet syndrome. JAMA Dermatol. 2017;153:651–659.
83. Vignon-Pennamen MD, Osio A, Battistella M. Histiocytoid Sweet Syndrome and Myelodysplastic Syndrome. JAMA Dermatol. 2017;153:835–836.
84. Osio A, Battistella M, Feugeas JP, et al. Myelodysplasia cutis vs leukaemia cutis. J Invest Dermatol. 2015;135:2321–2324.
85. Ghoufi L, Ortonne N, Ingen-Housz-Oro S, et al. Histiocytoid Sweet syndrome is more frequently associated with myelodysplastic syndromes than the classical neutrophilic variant: a comparative series of 62 patients. Medicine. 2016;95:1–10.
86. Bush JW, Wick MR. Cutaneous histiocytoid Sweet syndrome and its relationship to hematological diseases. J Cutan Pathol. 2016;43:394–399.
87. Baldus CD, Liyanarachchi S, Mrozek K, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA. 2004;101:3915–3920.
88. Goldberg L, Tijssen MR, Birger Y, et al. Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia. Blood. 2013;122:2694–2703.
89. Xu B, Naughton D, Busam K, et al. ERG is a useful immnohistochemical marker to distinguish leukemia cutis from nonneoplastic leukocytic infiltrates in the skin. Am J Dermatopathol. 2016;38:672–677.
90. Gleason BC, Zembowicz A, Granter SR. Non-bullous neutrophilic dermatosis: an uncommon dermatologic manifestation in patients with lupus erythematosus. J Cutan Pathol. 2006;33:721–725.
91. Brinster NK, Nunley J, Pariser R, et al. Nonbullous neutrophilic lupus erythematosus: a newly recognized variant of cutaneous lupus erythematosus. J Am Acad Dermatol. 2012;66:92–97.
92. Ramsey-Goldman R, Franz T, Solano FX, et al. Hydralazine induced lupus and Sweet’s syndrome. Report and review of the literature. J Rheumatol. 1990;17:682–684.
93. Sequeira W, Polisky RB, Alrenga DP. Neutrophilic dermatosis (Sweet’s syndrome). Association with a hydralazine-induced lupus syndrome. Am J Med. 1986;81:558.
94. Servitje O, Ribera M, Juanola X, et al. Acute neutrophilic dermatosis associated with hydralazine-induced lupus. Arch Dermatol. 1987;123:1435.
95. Saeb-Lima M, Charli-Joseph Y, Rodriguez-Acosta ED, et al. Autoimmunity-related neutrophilic dermatosis: a newly described entity that is not exclusive of systemic lupus erythematosus. Am J Dermatopathol. 2013:655–660.
96. Hau E, Vignon Pennamen MD, Battistella M, et al. Neutrophilic skin lesions in autoimmune connective tissue diseases: nine cases and a literature review. Medicine. 2014;93:1–13.
97. Broekaert SM, Böer-Auer A, Kerl K, et al. Neutrophilic epitheliotropism is a histopathologic clue to neutrophilic urticarial dermatosis. Am J Dermatopathol. 2016;38:39–49.
98. Kieffer C, Cribier B, Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature. Medicine (Baltimore). 2009;88:22–31.
99. Németh T, Mócsai A. The role of neutrophils in autoimmune diseases. Immunol Lett. 2012;143:9–19.
100. Eyles JL, Roberts AW, Metcalf D, et al. Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of inflammatory disease. Nat Clin Pract Rheumatol. 2006;2:500–510.
101. Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet’s syndrome. Clin Exp Immunol. 2014;178:48–56.
102. Caproni M, Torchia D, Cardinali C, et al. Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis. Br J Dermatol. 2004;151:784–791.
103. Essary LR, Wick MR. Cutaneous calciphylaxis. An underrecognized clinicopathologic entity. Am J Clin Pathol. 2000;113:280–287.
104. Fernandez KH, Liu V, Swick BL. Nonuremic calciphylaxis associated with histologic changes of pseudoxanthoma elasticum. Am J Dermatopathol. 2013;35:106–108.
105. Jeong HS, Dominguez AR. Calciphylaxis: controversies in pathogenesis, diagnosis and treatment. Am J Med Sci. 2016;351:217–227.
106. Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol. 2008;58:458–471.
107. Oliveira TM, Frazao JM. Calciphylaxis: from the disease to the diseased. J Nephrol. 2015;28:531–540.
108. Mochel MC, Arakaki RY, Wang G, et al. Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol. 2013;35:582–586.
109. Selye H, Grasso S, Dieudonne JM. On the role of adjuvants in calciphylaxis. Q Rev Allergy Appl Immunol. 1961;15:461–465.
110. Chen TY, Lehman JS, Gibson LE, et al. Histopathology of calciphylaxis: cohort study with clinical correlations. Am J Dermatopathol. 2017;39:795–802.
111. Halasz CL, Munger DP, Frimmer H, et al. Calciphylaxis: Comparison of radiologic imaging and histopathology. J Am Acad Dermatol. 2017;77:241–246.e3.
112. Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J. 2014;14:380–385.
113. Latus J, Kimmel M, Ott G, et al. Early stages of calciphylaxis: are skin biopsies the answer? Case Rep Dermatol. 2011;3:201–205.
114. Dookhan C, Ortega LM, Nayer A, et al. Perieccrine and pericapillary calcification in calciphylaxis. J Renal Inj Prev. 2015;4:9–10.
115. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4:113–122.
116. Cai MM, Smith ER, Brumby C, et al. Fetuin-A-containing calciprotein particle levels can be reduced by dialysis, sodium thiosulphate and plasma exchange. Potential therapeutic implications for calciphylaxis. Nephrology (Carlton). 2013;18:724–727.
117. Buka R, Wei H, Sapadin A, et al. Pseudoxanthoma elasticum and calcinosis cutis. J Am Acad Dermatol. 2000;43 (2 Pt 1):312–315.
118. Jean L, Bolognia JLJ, Julie V. Schaffer. Dermatology, 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:47.
119. Jurzyk RS, Ditre CM, Kantor GR, et al. Plaque-type intertriginous cutaneous calcification. Cutis. 1992;49:289–291.
120. Woo TY, Rasmussen JE. Disorders of transepidermal elimination. Part 2. Int J Dermatol. 1985;24:337–348.
121. Saxe N, Beighton P. Cutaneous manifestations of osteoectasia. Clin Exp Dermatol. 1982;7:605–609.
122. Cochran RJ, Wilkin JK. An unusual case of calcinosis cutis. J Am Acad Dermatol. 1983;8:103–106.
123. Nielsen AO, Christensen OB, Hentzer B, et al. Salpeter-induced dermal changes electron-microscopically indistinguishable from pseudoxanthoma elasticum. Acta Derm Venereol. 1978;58:323–327.
124. Mainetti C, Masouye I, Saurat JH. Pseudoxanthoma elasticum-like lesions in the L-tryptophan-induced eosinophilia-myalgia syndrome. J Am Acad Dermatol. 1991;24:657–658.
125. Aessopos A, Savvides P, Stamatelos G, et al. Pseudoxanthoma elasticum-like skin lesions and angioid streaks in beta-thalassemia. Am J Hematol. 1992;41:159–164.
126. Baccarani-Contri M, Bacchelli B, Boraldi F, et al. Characterization of pseudoxanthoma elasticum-like lesions in the skin of patients with beta-thalassemia. J Am Acad Dermatol. 2001;44:33–39.
127. Kasemsarn P, Boonchai W. Pseudoxanthoma elasticum-like lesions in beta-thalassemia/hemoglobin E patient: a case report. J Dermatol. 2013;40:409–410.
128. Yu S, Ming A, Wegman A. Pseudoxanthoma elasticum-like lesions in association with thalassaemia major. Australas J Dermatol. 2009;50:186–189.
129. Nathoo RK, Harb JN, Auerbach J, et al. Pseudoxanthoma elasticum-like changes in nonuremic calciphylaxis: case series and brief review of a helpful diagnostic clue. J Cutan Pathol. 2017;44:1064–1069.
130. Penn LA, Brinster N. Calciphylaxis with pseudoxanthoma elasticum-like changes: a case series. J Cutan Pathol. 2018;45:118–121.
131. Lewis KG, Lester BW, Pan TD, et al. Nephrogenic fibrosing dermopathy and calciphylaxis with pseudoxanthoma elasticum-like changes. J Cutan Pathol. 2006;33:695–700.
132. Nikko AP, Dunningan M, Cockerell CJ. Calciphylaxis with histologic changes of pseudoxanthoma elasticum. Am J Dermatopathol. 1996;18:396–399.
Keywords:

syphilis; immune checkpoint inhibitors; epidermal growth factor receptor inhibitors; exenatide microspheres; Sweet syndrome; histiocytoid Sweet syndrome; autoimmune neutrophilic dermatosis; neutrophilic urticarial dermatosis; calciphylaxis

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