Inflammatory Dermatoses
Inflammatory Dermatoses
Inflammatory Dermatoses
FIGURE 1. Various clinical manifestations of syphilis. A, Verrucous perianal plaque of condyloma lata in an infant with congenital syphilis.
Photo courtesy of Dr Elaine Siegfried. B, Pink to tan, minimally scaly, macules on trunk of adult woman with secondary syphilis. Photo
courtesy of Dr Mary Guo. C, Pink to tan nonscaly macules on the trunk of an infant with congenital syphilis. Photo courtesy of Dr Elaine
Siegfried.
Included in this were interstitial inflammation, endothelial lymphoma-like pattern was observed in both the upper and
swelling (Fig. 2A), irregular acanthosis, elongated rete lower aerodigestive tracts.5 Granulomas were also identified
ridges, vacuolar interface dermatitis (Fig. 2B), the presence in half of the cases studied.5 The epithelial surface was
of plasma cells (Fig. 2C), lymphocytes with ample cyto- eroded or ulcerated in the vast majority of cases, but may
plasm, neutrophils within the stratum corneum (Fig. 2D), a also appear hyperplastic.5 A distinct finding in the majority
lichenoid infiltrate, effacement, and psoriasiform acanthosis.4 of specimens was perineural plasma cells, and this can be a
In some instances, as few as 2 of these distinguishing features helpful clue to this at times challenging diagnosis.5 In
were present, which speaks to the challenge of an accurate addition, the use of special and immunohistochemical stains
diagnosis of this entity.4 In this study, the most common can further aid in the diagnostic work up.
findings overall were an interstitial inflammatory infiltrate, Historically silver impregnated stains have been used
endothelial swelling, irregular acanthosis, and elongated for treponema identification, including the Levaditi or
slender rete ridges.4 Plasma cells, often thought of as a Warthin-Starry stain. However, potential diagnostic pitfalls
characteristic histologic finding, were only noted in ∼70% of include a relatively low sensitivity and background artifac-
cases studied.4 In specimens where 5 or fewer features were tual staining, which may make interpretation difficult.6
present, interstitial inflammation and endothelial cell swelling Immunohistochemistry using antibodies to T. pallidum
were the most commonly represented, and found to be offers a more sensitive method of detection (Fig. 3). In
helpful diagnostic features in otherwise histologically subtle a study by Martin-Ezquerra and colleagues, the patterns
cases.4 Given the spectrum of pathologic findings of this of antitreponema immunohistochemical staining were
entity, a high level of suspicion must be applied. Another examined. In this study, immunohistochemistry identified
frequently encountered situation in which syphilis should spirochetes in 80% of specimens, in comparison to Warthin-
remain high in the differential is in biopsies of oral or genital Starry, which identified spirochetes in only 50% of speci-
mucosa. mens. In the majority of cases in which spirochetes were not
The primary chancre is the initial presenting symptom, identified by immunohistochemistry, the patients had
and while the genitalia is the most common location, other recently been treated, or had long-standing disease.6 This
sites of involvement are becoming more prevalent, including rate of detection is similar to previously reported sensitiv-
the oral mucosa. Clinically painless ulceration will be the ities, of 74% to 94% for immunohistochemistry and 31% to
most common presentation, although red or white patches, 71% for Warthin-Starry.6 In lesions of primary syphilis, the
as well as mass like lesions have also been reported.5 In this distribution of spirochetes often appeared perivascular in
location, the clinical differential diagnosis may include a nature, which they defined as a “vasculotropic pattern.”6 In
malignancy or an inflammatory dermatosis, including some cases, spirochetes were also present in an intercellular
immunobullous disorders, contact dermatitis, and lichen distribution in the lower epithelium, in particular in areas
planus. Syphilis may not be an initial diagnostic consid- adjacent to an ulceration.6 In lesions of secondary syphilis,
eration, and therefore a high index of suspicion must once spirochetes were seen more often within the epidermis in an
again be applied. In a recent report by Tse and colleagues, intercellular distribution, particularly in the lower levels
the histologic manifestations of syphilis of the aerodigestive of the epidermis.6 However, in some cases spirochetes
tract were characterized. They classified the histologic were located in the upper levels of the epidermis, within
findings into 3 patterns: plasma cell-rich, lymphohistiocytic the papillary dermis, and within follicular or sweat gland
with or without granulomas, and lymphoma-like with large epithelium.6 One word of caution regarding application of
atypical lymphoid cells.5 The most commonly observed immunohistochemistry for detection of T. pallidum, is that
pattern was the plasma cell rich, including those from the although sensitivity is superior to that of Warthin-Starry, it
oral mucosa.5 The lymphohistiocytic pattern was observed is not specific to T. pallidum species, and cross reactivity has
in cases from the lower gastrointestinal tract, and the been noted between other spirochetes, including Brachyspira
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 41
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
FIGURE 2. Various histologic findings of secondary syphilis. A, Endothelial cell swelling [hematoxylin and eosin (H&E), ×400]. B, Vacuolar
interface dermatitis with a superficial and deep lymphocytic perivascular and periadnexal infiltrate (H&E, ×100). C, Plasma cell infiltrate
(H&E, ×400). D, Collection of neutrophils within the superficial epidermis (H&E, ×200). Please see this image in color online.
FIGURE 3. A and B, Antitreponemal antibody immunohistochemistry (×600; ×400). Please see this image in color online.
42 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 43
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
and nivolumab, Belum and colleagues reported the incidence of inhibitors, and include cetuximab, panitumumab, gefitinib,
all grade rash to be 16.7% and 14.3% (relative risk 2.6 and 2.5), and erlotinib, among others. Cutaneous adverse effects of
respectively. Pruritus had an incidence of 20.2% and 13.2% this medication class are well-documented, frequently
(relative risk 49.9 and 34.5), respectively. Vitiligo had an inci- encountered, and can create a large impact on the quality
dence of 8.3% and 7.5% (relative risk 17.5 and 17.6), respectively. of life of patients. In addition, the presence of some of these
Similar to the rash seen with anti-CTLA-4 agents, the most cutaneous side effects has been shown to correlate with
common presentation of the rash associated with the anti-PD-1 treatment response and prognosis, ensuing an even greater
agents is a maculopapular eruption, which on histology shows a interest to clinicians. Among these are the well-known
lichenoid/interface pattern with a perivascular infiltrate that acneiform (papulopustular) eruptions, paronychia, xerosis,
includes eosinophils (Fig. 5).37,39,40 A mucosal lichenoid eruption hyperpigmentation, trichomegaly, telangiectasia, and a newer
has also been reported with anti-PD-L1 agents.41 Interestingly, recognized purpuric drug eruption.
vitiligo from anti-PD-1 agents tends to occur more commonly in The acneiform eruption secondary to EGFR inhibitors
patients treated for melanoma37 presumably secondary to acti- occurs in approximately half of the recipients of these drugs,
vation of the immune response against melanocytes. Early and in up to 75% to 100% of individuals taking cetuximab
studies suggest a more favorable outcome in melanoma patients specifically.52 This eruption typically begins within 1 week
that develop vitiligo following anti-PD-1 therapy.42,43 Inflam- of treatment, and is characterized by erythematous papules
matory lesions have been reported to precede depigmentation in and pustules without comedones on the head/neck, upper
some cases.44 Fascinating is the fact that treatment with anti-PD- trunk, and shoulders.52 The eruption may be pruritic, and
1 and anti-PD-L1 for lung carcinoma can lead to hair repig- there appears to be a dose-related response to the severity.
mentation in some cases, inferring the complexity of these agents Interestingly, the presence and severity of the eruption does
in different tumors.45 Unique adverse events with anti-PD-1 appear to correlate with treatment response and overall
therapy that do not appear to be seen with anti-CTLA-4 therapy survival, with improved rates within those individuals with
include a psoriasiform eruption,37,46,47 an immunobullous erup- this cutaneous eruption.52,53 Histopathology typically
tion that mimics bullous pemphigoid,30,48,49 and a vasculopathic reveals a neutrophilic infiltrate within the dermis and sur-
reaction.37 rounding the follicular infundibulum, with typical sparing of
sebaceous lobules.52 The pathogenesis of this eruption
Combination Therapy With the Checkpoint remains not well understood.52
Inhibitors Paronychia has been estimated to occur in ∼10% to
While therapy with CTLA-4 and PD-1 blockade has been 15% of individuals treated with cetuximab and gefitinib,
shown to be synergistic it is not surprising that the combination and typically occurs months after initiation of treatment.52
leads to a higher rate of skin toxicity than when each agent is This paronychia may involve multiple fingers and toes,
used alone (42% to 55% for single agent therapy compared with and can cause significant functional impairment.52 Histo-
59% to 71% for combination therapy).50,51 pathology demonstrates a marked dermal inflammatory
infiltrate, composed of plasma cells, lymphocytes, and
Cutaneous Reactions Associated With Epidermal neutrophils.52 Cultures have failed to identify causative
Growth Factor Receptor (EGFR) Inhibitors infectious organisms, except for reports of secondary
EGFR inhibitors are used frequently in the treatment of infection with Staphylococcus aureus.52 Subungual lobular
solid organ malignancy. These medications are broadly divided capillary hemangiomas (pyogenic granulomas) have also
into 2 categories, monoclonal antibodies and tyrosine kinase been reported.52
The other known cutaneous side effects reported in this
class of medications occur less frequently, but are well rec-
ognized. They include xerosis, hyperpigmentation, tricho-
megaly, and telangiectasia.52 More recently, a newly rec-
ognized purpuric drug eruption has been documented, with
unique clinical and histologic features.
Cho et al54 recently characterized this purpuric erup-
tion. 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 indi-
viduals, many of which were culture positive for S. aureus.54
Histopathology revealed epidermal dysmaturation, neu-
trophilic aggregation, erythrocyte extravasation, and endo-
thelial 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,
FIGURE 5. Vacuolar interface dermatitis with eosinophils in a
patient treated with nivolumab for metastatic melanoma (hem- Pseudomonas aeruginosa, and Serratia species.54 In their
atoxylin and eosin, ×100). High power magnification showing the review, the majority of patients improved with systemic
presence of eosinophils within the inflammatory infiltrate (inset) antibiotics.54 In addition to the reported cutaneous effects
(hematoxylin and eosin, ×400). Please see this image in color from targeted oncologic therapy, other distinct medication
online. reactions have recently been characterized with distinct
44 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
clinical and histologic presentations, including exenatide- BRAF inhibitors and is more common in patients taking
induced panniculitis. vemurafenib; thus, counseling on sun protection practices is
helpful in the management of these patients.64 Other cuta-
neous reactions in patients taking BRAF inhibitors include
Cutaneous Reactions to BRAF Inhibitors xerosis (dry skin), pruritus (itchy skin), and paronychia (nail
Over 80% of cutaneous melanoma demonstrates infection, where the nail and skin meet) all of which are
mutations in the MAPK pathway (RAS-RAF-MEK-ERK observed with administration > 3 months. Alopecia, plantar
mitogen-activated protein kinase pathway), which functions hyperkeratosis and panniculitis have also been reported with
in cell differentiation, proliferation, survival, stress response BRAF inhibitors.55
and apoptosis. BRAF V600E is one of the most common
mutations seen in melanoma involving this pathway.
Vemurafenib and dabrafenib are medications both Cutaneous Reactions Associated With Exenatide-
approved for the treatment of V600E BRAF positive induced Panniculitis
metastatic melanoma and work by inhibiting melanoma Exenatide is a glucagon-like peptide-1 receptor agonist,
tumorigenesis through inhibition of the MAPK pathway. used in the treatment of type II diabetes. This medication is
While these medications are generally well-tolerated, injected subcutaneously, typically in the abdomen, thigh, or
adverse reactions exist with cutaneous reactions affecting arm and can be dosed either twice a day or once per week in
74% of patients taking these inhibitors.55,56 Cutaneous an extended release formulation. The extended release for-
reactions include an exanthematous/maculopapular or mulation consists of poly (DL-lactic-co-glycolic acid)
papulopustular rash that affects the face, truck and arms, (PLGA) microspheres, which contain exenatide both on
and is dose dependent. Histology of the maculopapular rash their surface and within. During clinical trials of this med-
can appear as a perivascular dermatitis or a dermal hyper- ication, subcutaneous nodules were reported in patients
sensitivity eruption.19,57–59 A well-reported cutaneous effect using the extended release formulation, which sponta-
of these medication is the development of keratotic lesions. neously resolved within 3 to 6 weeks. Recent reports have
These lesions occur in 12% of patients taking vemurafenib further characterized this phenomenon as an eosinophil-rich
and 8% of patients taking dabrafenib and may appear granulomatous panniculitis.65–68 The pathologic findings
clinically and histologically as squamous cell carcinoma and reported are that of a mixed lobular and septal panniculitis,
keratoacanthoma. These lesions can be treated with simple with an associated granulomatous infiltrate composed of
excision and typically do not require dose modification. lymphocytes, histiocytes, eosinophils, and often multi-
Other keratotic lesions that can be seen include verrucous nucleated giant cells (Fig. 6A).65–69 In some reports, these
keratoses (seborrheic keratosis and verruca vulgaris) and microspheres have been visualized, and described as round
hypertrophic actinic keratoses.57,60,61 The use of a MEK structures that are birefringent and nonpolarizable.69 Inter-
inhibitor, trametinib, which also targets this pathway, and is estingly, these microspheres have been found to be high-
approved for metastatic or unrespectable melanoma with lighted by Acid fast (Fig. 6B) and Fite Stains. This positive
V600E or V600K mutations, has been shown to decrease the staining pattern has been postulated to be due to the lipid
incidence of these keratotic lesions when used in combina- quality and content of the PLGA used in these extended
tion with the BRAF inhibitors.56,62,63 Photosensitivity has release microspheres, but further studies are needed to elu-
additionally been reported in 7% to 12% of patients taking cidate this further.69 This characteristic reaction is one that
FIGURE 6. A, Exenatide panniculitis demonstrating a granulomatous infiltrate with intact microspheres (hematoxylin and eosin, ×400).
B, Microspheres highlighted by Acid Fast stain (×400). Please see this image in color online.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 45
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
FIGURE 8. Histopathology of classic Sweet syndrome. A, Perivascular and interstitial neutrophils with leukocytoclasia, marked papillary
dermal edema, and epidermal spongiosis (hematoxylin and eosin, ×100). B, Higher power of the dermal infiltrate highlighting the
neutrophils and nuclear debris in the absence of leukocytoclastic vasculitis (hematoxylin and eosin, ×400). Please see this image in color
online.
46 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
FIGURE 9. Histopathology of histiocytic Sweet syndrome. A, Interstitial mononuclear cells with a few neutrophils in a background of
dermal edema (hematoxylin and eosin, ×400). B, Myeloperoxidase immunohistochemical staining shows the mononuclear cells to be
positive (×200). Please see this image in color online.
histiocytoid mononuclear cells were strongly reactive for Over the 12 years between the foundational description
MPO, a reliable marker for myeloid cells, in particular of histiocytoid Sweet syndrome by Requena and colleagues
immature neutrophils.73,76,77 and the follow-up study by Alegría-Landa and colleagues,
The assertion by some, that the histiocytoid cells are in multiple case reports, small case series, and letters have
fact a manifestation of leukemia cutis, has sparked sig- debated the assertion that histiocytoid Sweet syndrome is
nificant debate since Requena and colleagues’ original simply a benign variant of Sweet syndrome. Detractors note
report. As leukemia cutis heralds death within 1 year for that FISH is only useful when there is a known underlying
88% of patients with AML and CML, the origin of these hematologic disorder with an identifiable chromosomal
cells is critical.78,79 The infiltrate in leukemia cutis can be abnormality, as a malignancy-specific probe is necessary to
histopathologically indistinguishable from the afore- characterize the infiltrate.83 In a study by Osio and col-
described infiltrate in histiocytoid Sweet syndrome, making leagues’s, FISH performed on the histiocytoid infiltrate on 6
this determination difficult.80 Requena and colleagues note patients with histiocytoid Sweet syndrome and underlying
that peripheral blood smears in 27 of their patients with MDS with a known associated bone marrow abnormality
histiocytoid Sweet syndrome did not demonstrate circulat- revealed the same genetic aberration in the infiltrate in 4 of 6
ing leukemic cells, and the bcr/abl fusion gene was not patients (a finding the authors termed “myelodysplasia
identified by fluorescent in situ hybridization (FISH) in the cutis”).84
dermal infiltrate. In addition, clinical follow-up over several Another contentious issue is whether histiocytoid Sweet
years did not eventuate in any acute or chronic myelogenous syndrome has a stronger association with hematologic
leukemia. Thus, Requena and colleagues assert in their malignancy as compared with classic Sweet syndrome, with
original publication that the histiocytoid cells are not leu- many authors disputing Requena and colleagues’ and Ale-
kemic and, furthermore, are not seen in association with gría-Landa and colleagues’ interpretation of the existing
underlying hematologic abnormalities in any higher data. A series of 62 patients with Sweet syndrome reported
frequency than classic Sweet Syndrome; 24% of their cases by Ghoufi et al85 demonstrated that histiocytoid Sweet
of histiocytoid Sweet syndrome were associated with an syndrome is indeed more frequently associated with hema-
underlying hematologic dyscrasia, whereas 21% of classic tologic malignancies, with MDS drawing the strongest
Sweet syndrome are associated with any type of underlying association. A total of 55.5% of patients with histiocytoid
malignancy.81 Sweet syndrome in their cohort had underlying hematologic
A report by Alegría-Landa et al82 in 2017 further dyscrasias (compared with 25% with classic Sweet syn-
examined this question by performing comprehensive drome). A significant proportion of these patients with his-
immunohistochemical profiling of the infiltrate in 33 tiocytoid Sweet syndrome had MDS. Bush and Wick86
patients with histiocytoid Sweet syndrome. The histiocytoid found a similar association rate of histiocytoid Sweet syn-
cells were again found to express MPO, as well as myeloid drome with hematologic malignancy (53%) in their meta-
nuclear differentiation antigen, further supportive of mye- analysis when they excluded the data from Requena and
lomonocytic lineage. In addition, they performed CD163/ colleagues’ initial report, which they felt to underrepresent
MPO dual staining and found minimal co-expression of the association.
CD163 and MPO, excluding the possibility that the cells While the association with underlying hematologic
represent histiocytes with aberrant MPO expression. The malignancy remains controversial, a novel immunohis-
authors also found a similar lack of the bcr/abl fusion gene, tochemical marker to distinguish the infiltrates in histiocy-
with the exception of one patient who was known to harbor toid Sweet syndrome and leukemia cutis may bring clarity to
the bcr/abl chromosomal abnormality in the bone marrow. the histopathologic diagnosis and its clinical implications.
They concluded that the patients studied were no more Previous attempts to identify leukemic cells in the skin with
likely to have or go on to develop hematologic dyscrasias blast markers CD34 and CD117 have been challenging, as
compared with patients with classic Sweet syndrome. these markers are often negative in leukemia cutis. Missense
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 47
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
48 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
TABLE 1. Key Distinguishing Features of Sweet Syndrome and Autoimmune Neutrophilic Dermatosis
Sweet Syndrome Autoimmune Neutrophilic Dermatosis
Clinical features Erythematous papules and nodules; may be bullous Erythematous papules and plaques; often urticarial,
no vesicles or bullae
Variable clinical associations: idiopathic, infection, Lesions may be transient (< 48 h)
hematologic dyscrasia, solid tumor
Presents with fever Associated with underlying AICTD
Dermal infiltrate Interstitial and perivascular neutrophilic infiltrate Interstitial and perivascular neutrophilic infiltrate
Papillary dermal edema Marked papillary dermal edema Lacks significant edema
Vacuolar interface change Absent Variably present
Leukocytoclastic vasculitis Absent Absent
Leukocytoclasia Present Present
Epitheliotropism Absent Present
Reticular dermal mucin Absent Variably present
Direct immunofluorescence Negative ∼50% show variable C3, IgG, IgM along the DEJ
reflective of underlying AICTD22
AICTD indicates autoimmune connective tissue diseases; DEJ, dermal-epidermal junction.
arthritis, Sjögren syndrome, and Still disease.95 It is now The role of neutrophils in autoimmune and auto-
widely accepted that neutrophil-rich dermatoses resembling inflammatory diseases has long been overlooked, with the
SS, with a neutrophil-rich infiltrate, leukocytoclasia and emphasis instead being on autoreactive T lymphocytes that
lack of primary vasculitis may occur in the setting of a develop after an “immunization” phase, and then activate a
variety of AICTDs, and “autoimmune neutrophilic derma- variety of cell types that damage host tissue (“effector”
tosis” is an appropriate description for the entity.96 Dis- phase). However, neutrophils are capable of contributing to
tinguishing the 2 patterns is essential to arrive at the correct autoimmunity, both in the “immunization” phase by
diagnosis (Table 1). exposing autoantigens when involved in a vasculitic process,
The more recently described entity, neutrophilic urti- during apoptosis, or as mediators of cell damage in the
carial dermatosis, also falls into the spectrum of auto- “effector” phase.99,100 In lesional skin of neutrophilic der-
immune neutrophilic dermatosis,97,98 neutrophilic urticarial matoses, cytokines that recruit neutrophils and amplify the
dermatosis is a transient eruption that commonly presents inflammatory response are known to be overexpressed.101 In
with urticarial lesions lasting <48 hours, leaving no purpura, addition, aberrant expression and/or activation of adhesion
and systemic symptoms in patients with AICTDs and and migration molecules that assist in neutrophil migration
autoinflammatory disorders. Histopathologically, there is a to local tissues (such as intercellular adhesion molecule-1)
perivascular and interstitial neutrophilic infiltrate with has been observed in the eruption of dermatomyositis.102
prominent leukocytoclasia, but lacking dermal edema or The specific mechanism of the neutrophilic dermatoses in
vasculitis. Distinguishing features are (1) neutrophilic epi- AICTD is poorly understood, but neutrophils appear to
theliotropism, whereby neutrophils are located within and play a role in pathogenesis.
around hair follicles, sebaceous glands and most commonly, It is essential for pathologists to recognize the role of
eccrine glands and ducts; and (2) basophilic degeneration of neutrophils in the spectrum of cutaneous manifestations of
collagen bundles, most prominent in biopsies with denser hematologic dyscrasias and connective tissue disorders and
neutrophilic infiltrates (Fig. 13). be familiar with the histologic features.
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 asso-
ciated 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,
FIGURE 13. Neutrophil epitheliotropism. There are neutrophils but it is now understood that medial calcification of arte-
extending into the basal layer of eccrine gland epithelia (hema- rioles followed by thrombotic occlusion are the key features
toxylin and eosin, ×400). Please see this image in color online. required for the development of calciphylaxis lesions.105–107
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 49
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
Calcification of the arteriole media is the result of lesions deteriorate to exquisitely painful, nonhealing, stellate
downstream effects of dysregulation of systemic minerali- ulcers with an overlying black eschar (Fig. 14).105
zation leading to an imbalance of procalcification and For both uremic and nonuremic patients, the diagnosis
anticalcification factors in both the circulation and local of calciphylaxis can be more elusive given its clinical sim-
tissue environment. Elevations in circulating calcium-phos- ilarities to many other entities, such as systemic infections,
phate product (CaXP) and upregulation of procalcifying hypercoagulable states, autoimmune diseases, vasculitis,
products in the extracellular matrix occur in the setting of and malignancies.105 In these cases, histologic confirmation
decreased levels of anticalcification products, namely is a vital diagnostic tool. Unfortunately, acquiring an ade-
Fetuin-A and matrix gla protein, found in the systemic quate tissue sample can prove challenging. In one retro-
circulation and extracellular matrix, respectively.94,96 As a spective review of 56 biopsies from confirmed calciphylaxis
result of this procalcification milieu and the presence patients, classic features of calcification in arterioles were
of various osteogenic factors, such as bone morphogenic noted in only 18% of samples.108
protein-4 and osteopontin, vascular smooth muscle cells It has been nearly 60 years since calciphylaxis was first
transform from a contractile phenotype to an osteoblast-like described in the medical literature,109 yet the literature
phenotype that results in calcification of the smooth muscle addressing its histologic features is largely comprised of case
of the arteriole media.105,107 Transformed vascular smooth reports and series. Only 3 retrospective studies examining
muscle cells not only promote calcification, but may also the histologic features of calciphylaxis have been published,
trigger intimal hyperplasia and vascular sloughing resulting all within the last 5 years.108,110,111
in nonthrombotic vascular occlusion.107 Skin biopsy remains the gold standard in the diagnosis
Thrombotic occlusion and hypercoagulability are also of calciphylaxis given the clinical similarities to many other
gaining appreciation for their role in the development in entities.105,112 Calcium deposition within the tunica media of
calciphylaxis lesions. Systemic hypercoagulability, including small to medium sized arteries and arterioles in the sub-
protein C and S deficiencies have been reported in cases of cutaneous fat is the most diagnostic histologic feature,46,61
calciphylaxis, and it is also believed that inflammatory but obtaining an adequate tissue sample is often compro-
cytokines and reactive oxygen species, triggered by vascular mised by various clinical factors, which can render a skin
injury, may induce a local hypercoagulable reaction with biopsy specimen nondiagnostic (Fig. 15). These challenges
subsequent areas of focal thrombosis and necrosis. It is this have lead many clinicians to rely on clinical features alone
appreciation of an underlying prothrombotic state that helps for the diagnosis.105,109,111,113 Fortunately, other histologic
to explain cases of calciphylaxis in nonuremic patients.105,106 features have been found to be significantly associated with
Early in the development of calciphylaxis, clinical find- calciphylaxis, including intimal hyperplasia, microthrombi,
ings are most notable for livedo racemose, persistent, net-like, and extravascular soft tissue calcification.108,110,111
reticulated, and erythematous to purpuric patches. There may Chen and colleagues recently demonstrated that a skin
be underlying erythematous to violaceous, tender, indurated biopsy can be especially useful in patients with end-stage
subcutaneous plaques and nodules. These lesions are most chronic kidney disease (CKD), as significant histologic dif-
commonly seen in adipose-rich areas of the trunk and ferences have been demonstrated in CKD patients with and
extremities, with the legs being the most common site of without calciphylaxis. The authors found that CKD patients
involvement. Less commonly, penile and digital involvement with calciphylaxis were significantly more likely to demon-
has been reported. As the disease progresses, these cutaneous strate thrombi and vessel wall calcification in the dermis and
superficial fat, thrombi within calcified vessels, and dermal
angioplasia compared with CKD patients without calci-
phylaxis. The authors also demonstrated that there were no
significant histopathologic changes in calciphylaxis patients
with and without renal disease.110
Perieccrine Calcification
Calcification of extravascular structures, such as der-
mal collagen and subcutaneous fat are helpful histologic
features, but its specificity is attenuated by conditions that
can demonstrate similar features, such as lupus and pan-
creatic 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 calcifica-
tion, detectable only with von Kossa and Alizarin red cal-
cium 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 cal-
cium 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 pub-
lished, perieccrine calcification in calciphylaxis has been
FIGURE 14. Stellate eschars on the leg of a woman with non- addressed in 2 publications. A case report by Dookhan
uremic calciphylaxis. Photo courtesy of Dr Zachary Schwager. et al114 confirmed the presence of this feature in a 44-year-
Please see this image in color online. old male with uremic calciphylaxis. Similar to the
50 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
FIGURE 15. Histology of calciphylaxis (A) tntravascular calcification and fibrin in a small caliber vessel in the subcutaneous fat (hema-
toxylin and eosin, ×200). B, von Kossa stain highlights calcium in the vessel wall (×200). Please see this image in color online.
aforementioned case-control study, perieccrine calcification manifests as yellowish, coalescing papules and redundant
was not identifiable with hematoxylin and eosin staining and folds in flexural skin, angioid streaks of the retina, and
was only visualized with von Kossa calcium staining. A cardiovascular claudication and infarctions (Fig. 17). His-
retrospective case-control study by Chen and colleagues did topathology of the skin reveals curled, frayed, and calcified
not identify perieccrine calcification in any of their 57 cal- elastic fibers in the mid reticular dermis.115–118
ciphylaxis subjects; however, calcium stains were not uti- Cutaneous PXE-like histopathologic features in the
lized in the analysis of these histologic specimens.11 absence of systemic involvement have been described in
association with various autoimmune and metabolic
Pseudoxanthoma Elasticum-like Changes disorders,119–128 in addition to 3 case reports and 2 case
Another histologic feature noted to be associated with series of uremic and nonuremic calciphylaxis.104,129–132
calciphylaxis in recent years in the presence of pseudox- These cases demonstrate histologic features of calciphylaxis
anthoma elasticum-like changes. Briefly, pseudoxanthoma in conjunction with the curled, frayed and calcified elastic
elasticum (PXE) is a rare, clinically distinct, genetic disorder fibers known to PXE, which can be localized to either the
that shares with calciphylaxis the common feature of cuta- reticular dermis or septae of the subcutaneous fat
neous calcification. It is, however, markedly distinct from (Fig. 18).104,129–132 This finding is identifiable with hema-
calciphylaxis in both its cutaneous and histologic pre- toxylin and eosin staining, but may be better visualized with
sentation. It is caused by an autosomal recessive mutation in special calcium stains (ie, von Kossa) and elastic fiber stains
the ABCC6 (ATP-binding cassette subfamily C member 6) (ie, Verhoeff-Van Gieson stain). The mechanism for the
gene, normally expressed in the liver and the kidney.115 development of PXE-like features in calciphylaxis is unclear,
While the exact function of this gene remains unknown, but given the frequent difficulty in demonstrating vascular
ABCC6-knockout mouse models demonstrate progressive
mineralization of connective tissue.115 Clinically, PXE
FIGURE 16. Subtle calcium deposits seen best on von Kossa stain FIGURE 17. Yellow papules coalescing into plaques in the axilla.
(×400). Please see this image in color online. Please see this image in color online.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 51
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
FIGURE 18. Pseudoxanthoma elasticum-like changes in calciphylaxis. A, Frayed and curled elastic fibers in the septae of the subcuta-
neous fat from same patient as in Figure 9 (hematoxylin and eosin, ×400). B, Verhoeff-van Gieson stain highlights the elastic fibers in the
fat sepate (×400). C, von Kossa stain confirms the presence of calcium in association with the altered elastic fibers in the fat (×200). Please
see this image in color online.
calcium deposition, it has been proposed as a feature that 5. Tse JY, Chan MP, Ferry JA, et al. Syphilis of the
may heighten suspicion for an underlying diagnosis of cal- aerodigestive tract. Am J Surg Pathol. 2017;42:472–478.
ciphylaxis in the appropriate clinical setting. 6. Martin-Ezquerra G, Fernandez-Casado A, Barco D, et al.
Treponema pallidum distribution patterns in mucocutaneous
lesions of primary and secondary syphilis: an immunohistochem-
CONCLUSIONS ical and ultrastructural study. Hum Pathol. 2009;40:624–630.
7. Ruiz SJ, Procop GW. Cross-reactivity of anti-Treponema immu-
In conclusion, inflammatory dermatopathology is an nohistochemistry with non-Treponema spirochetes: a simple call for
evolving field, with an ever-changing landscape. Changing caution. Arch Pathol Lab Med. 2016;140:1021–1022.
trends in infectious diseases, medication advances, and 8. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival
refined characterization of various dermatologic conditions with ipilimumab in patients with metastatic melanoma. N Engl
have accounted for recent updates within the field. This J Med. 2010;363:711–723.
complex subject demands a high index of suspicion, and 9. Robert C, Long GV, Brady B, et al. Nivolumab in previously
vigilance to maintaining up to date knowledge of derma- untreated melanoma without BRAF mutation. N Engl J Med.
tology to ensure an accurate diagnosis. 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.
REFERENCES 11. McDermott DF, Drake CG, Sznol M, et al. Survival, durable
1. Syphilis. 2017. Available at: cdc.gov. response, and long-term safety in patients with previously
2. Peeling RW, Mabey D, Kamb ML, et al. Syphilis. Nat Rev treated advanced renal cell carcinoma receiving nivolumab.
Dis Primers. 2017;3:17073. J Clin Oncol. 2015;33:2013–2020.
3. Weedon D. Skin Pathology, 2nd ed. London: Churchill- 12. Gettinger SN, Horn L, Gandhi L, et al. Overall survival and
Livingstone; 1998. long-term safety of nivolumab (anti-programmed death 1
4. Flamm A, Parikh K, Xie Q, et al. Histologic features of antibody, BMS-936558, ONO-4538) in patients with previ-
secondary syphilis: a multicenter retrospective review. J Am ously treated advanced non-small-cell lung cancer. J Clin
Acad Dermatol. 2015;73:1025–1030. Oncol. 2015;33:2004–2012.
52 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
13. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) 33. Sheik Ali S, Goddard AL, Luke JJ, et al. Drug-associated
treatment leads to clinical activity in metastatic bladder dermatomyositis following ipilimumab therapy: a novel
cancer. Nature. 2014;515:558–562. immune-mediated adverse event associated with cytotoxic
14. Ciccarese C, Alfieri S, Santoni M, et al. New toxicity profile T-lymphocyte antigen 4 blockade. JAMA Dermatol. 2015;151:
for novel immunotherapy agents: focus on immune-check- 195–199.
point inhibitors. Expert Opin Drug Metab Toxicol. 2016;12: 34. Yamaguchi Y, Abe R, Haga N, et al. A case of drug-
57–75. associated dermatomyositis following ipilimumab therapy.
15. Sibaud V, Meyer N, Lamant L, et al. Dermatologic Eur J Dermatol. 2016;26:320–321.
complications of anti-PD-1/PD-L1 immune checkpoint anti- 35. Ribas A, Chesney JA, Gordon MS, et al. Safety profile and
bodies. Curr Opin Oncol. 2016;28:254–263. pharmacokinetic analyses of the anti-CTLA4 antibody trem-
16. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into elimumab administered as a one hour infusion. J Transl Med.
its biological function and use in tumor immunotherapy. Nat 2012;10:236.
Immunol. 2002;3:611–618. 36. Ribas A, Kefford R, Marshall MA, et al. Phase III
17. Wolchok JD, Weber JS, Hamid O, et al. Ipilimumab efficacy randomized clinical trial comparing tremelimumab with
and safety in patients with advanced melanoma: a retro- standard-of-care chemotherapy in patients with advanced
spective analysis of HLA subtype from four trials. Cancer melanoma. J Clin Oncol. 2013;31:616–622.
Immun. 2010;10:9. 37. Belum VR, Benhuri B, Postow MA, et al. Characterisation
18. Lacouture ME, Wolchok JD, Yosipovitch G, et al. Ipilimu- and management of dermatologic adverse events to agents
mab in patients with cancer and the management of targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.
dermatologic adverse events. J Am Acad Dermatol. 2014;71: 38. Minkis K, Garden BC, Wu S, et al. The risk of rash associated
161–169. with ipilimumab in patients with cancer: a systematic review of
19. Curry JL, Torres-Cabala CA, Kim KB, et al. Dermatologic the literature and meta-analysis. J Am Acad Dermatol. 2013;69:
toxicities to targeted cancer therapy: shared clinical and e121–e128.
histologic adverse skin reactions. Int J Dermatol. 2014;53: 39. Joseph RW, Cappel M, Goedjen B, et al. Lichenoid dermatitis
376–384. in three patients with metastatic melanoma treated with anti-
20. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of PD-1 therapy. Cancer Immunol Res. 2015;3:18–22.
dermatologic toxicities from immune checkpoint blockade 40. Tetzlaff MT, Nagarajan P, Chon S, et al. Lichenoid
therapy. J Cutan Pathol. 2017;44:158–176. dermatologic toxicity from immune checkpoint blockade
21. Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a therapy: a detailed examination of the clinicopathologic
subset of patients with stage IV melanoma treated with anti- features. Am J Dermatopathol. 2017;39:121–129.
cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a 41. Sibaud V, Eid C, Belum VR, et al. Oral lichenoid reactions
single agent. Arch Dermatol. 2006;142:166–172. associated with anti-PD-1/PD-L1 therapies: clinicopatholog-
22. Voskens CJ, Goldinger SM, Loquai C, et al. The price of ical findings. J Eur Acad Dermatol Venereol. 2017;31:
tumor control: an analysis of rare side effects of anti-CTLA-4 e464–e469.
therapy in metastatic melanoma from the ipilimumab net- 42. Sanlorenzo M, Vujic I, Daud A, et al. Cutaneous adverse
work. PLoS One. 2013;8:e53745. events and their association with disease progression. JAMA
23. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of Dermatol. 2015;151:1206–1212.
cutaneous toxicities in patients with solid tumors treated with 43. Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in
immune checkpoint inhibitors: a meta-analysis. Future Oncol. resected and unresectable metastatic melanoma: character-
2015;11:2471–2484. istics of immune-related adverse events and association with
24. Hwang SJ, Carlos G, Wakade D, et al. Ipilimumab-induced outcomes. Clin Cancer Res. 2016;22:886–894.
acute generalized exanthematous pustulosis in a patient with 44. Hua C, Boussemart L, Mateus C, et al. Association of vitiligo
metastatic melanoma. Melanoma Res. 2016;26:417–420. with tumor response in patients with metastatic melanoma
25. Gormley R, Wanat K, Elenitsas R, et al. Ipilimumab-associated treated with pembrolizumab. JAMA Dermatol. 2016;152:45–51.
Sweet syndrome in a melanoma patient. J Am Acad Dermatol. 45. Rivera N, Boada A, Bielsa MI, et al. Hair repigmentation
2014;71:e211–e213. during immunotherapy treatment with an anti-programmed
26. Kyllo RL, Parker MK, Rosman I, et al. Ipilimumab-associated cell death 1 and anti-programmed cell death ligand 1 agent for
Sweet syndrome in a patient with high-risk melanoma. J Am lung cancer. JAMA Dermatol. 2017;153:1162–1165.
Acad Dermatol. 2014;70:e85–e86. 46. Totonchy MB, Ezaldein HH, Ko CJ, et al. Inverse psoriasi-
27. Pintova S, Sidhu H, Friedlander PA, et al. Sweet’s syndrome form eruption during pembrolizumab therapy for metastatic
in a patient with metastatic melanoma after ipilimumab melanoma. JAMA Dermatol. 2016;152:590–592.
therapy. Melanoma Res. 2013;23:498–501. 47. Ohtsuka M, Miura T, Mori T, et al. Occurrence of psoriasi-
28. Rudolph BM, Staib F, Von Stebut E, et al. Neutrophilic form eruption during nivolumab therapy for primary oral
disease of the skin and intestines after ipilimumab treatment mucosal melanoma. JAMA Dermatol. 2015;151:797–799.
for malignant melanoma-simultaneous occurrence of pyo- 48. Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic
derma gangrenosum and colitis. Eur J Dermatol. 2014;24: toxicities from immune checkpoint blockade with anti-PD-1
268–269. antibody therapy: a report on bullous skin eruptions. J Cutan
29. Reule RB, North JP. Cutaneous and pulmonary sarcoidosis- Pathol. 2016;43:688–696.
like reaction associated with ipilimumab. J Am Acad Dermatol. 49. Carlos G, Anforth R, Chou S, et al. A case of bullous
2013;69:e272–e273. pemphigoid in a patient with metastatic melanoma treated
30. Mochel MC, Ming ME, Imadojemu S, et al. Cutaneous with pembrolizumab. Melanoma Res. 2015;25:265–268.
autoimmune effects in the setting of therapeutic immune 50. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined
checkpoint inhibition for metastatic melanoma. J Cutan Pathol. nivolumab and ipilimumab or monotherapy in untreated
2016;43:787–791. melanoma. N Engl J Med. 2015;373:23–34.
31. Munoz J, Guillot B, Girard C, et al. First report of 51. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and
ipilimumab-induced Grover disease. Br J Dermatol. 2014;171: ipilimumab versus ipilimumab in untreated melanoma. N Engl
1236–1237. J Med. 2015;372:2006–2017.
32. Uemura M, Faisal F, Haymaker C, et al. A case report of 52. Hu JC, Sadeghi P, Pinter-Brown LC, et al. Cutaneous side
Grover’s disease from immunotherapy-a skin toxicity induced effects of epidermal growth factor receptor inhibitors: clinical
by inhibition of CTLA-4 but not PD-1. J Immunother Cancer. presentation, pathogenesis, and management. J Am Acad Dermatol.
2016;4:55. 2007;56:317–326.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 53
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Penn et al Adv Anat Pathol Volume 26, Number 1, January 2019
53. Abdel-Rahman O, Fouad M. Correlation of cetuximab- 75. Deguchi M, Tsunoda T, Yuda F, et al. Sweet’s syndrome in
induced skin rash and outcomes of solid tumor patients acute myelogenous leukemia showing dermal infiltration of
treated cetuximab: a systematic review and meta-analysis. Crit leukemic cells. Dermatology. 1997;194:182–184.
Rev Oncol Hematol. 2015;93:127–135. 76. Wong KF, Chan JKC. Antimyeloperoxidase: antibody of
54. Cho Y-T, Chen K-L, Sheen Y-S, et al. Purpuric drug eruptions choice for labeling myeloid cells including diagnosis of
caused by epidermal growth factor receptor inhibitors for non- granulocytic sarcoma. Adv Anat Pathol. 1995;2:65–68.
small cell lung cancer. A clinicopathologic study of 32 cases. 77. Pinkus GS, Pinkus JL. Myeloperoxidase: a specific marker for
JAMA Dermatol. 2017;153:906–910. myeloid cells in paraffin sections. Mod Pathol. 1991;4:
55. Reyes-Habito CM, Roh EK. Cutaneous reactions to chemo- 733–741.
therapeutic drugs and targeted therapy for cancer: Part II. 78. Cho-Vega JH, Medeiros LJ, Prieto VG, et al. Leukemia cutis.
Targeted therapy. J Am Acad Dermatol. 2014;71:217.e1–217. Am J Clin Pathol. 2008;129:130–142.
e11; quiz 227–228. 79. Su WP, Buechner SA, Li CY. Clinicopathologic correlations
56. Manousaridis I, Mavridou S, Goerdt S, et al. Cutaneous side in leukemia cutis. J Am Acad Dermatol. 1984;11:121–128.
effects of inhibitors of the RAS/RAF/MEK/ERK signalling 80. Kaddu S, Zenahlik P, Beham-Schmid C, et al. Specific
pathway and their management. J Eur Acad Dermatol Venereol. cutaneous infiltrates in patients with myelogenous leukemia:
2013;27:11–18. a clinicopathologic study of 26 patients with assessment of
57. Chapman PB, Hauschild A, Robert C, et al. Improved diagnostic criteria. J Am Acad Dermatol. 1999;40:966–978.
survival with vemurafenib in melanoma with BRAF V600E 81. Cohen PR. Sweet’s syndrome—a comprehensive review of an
mutation. N Engl J Med. 2011;364:2507–2516. acute febrile neutrophilic dermatosis. Orphanet J Rare Dis.
58. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of 2007;2:34.
mutated, activated BRAF in metastatic melanoma. N Engl J 82. Alegría-Landa V, Rodríguez-Pinilla SM, Santos-Briz A, et al.
Med. 2010;363:809–819. Clincopathologic, immunohistochemical, and molecular features
59. Anforth R, Fernandez-Penas P, Long GV. Cutaneous of histiocytoid Sweet syndrome. JAMA Dermatol. 2017;153:
toxicities of RAF inhibitors. Lancet Oncol. 2013;14:e11–e18. 651–659.
60. Anforth RM, Blumetti TCMP, Kefford RF, et al. Cutaneous 83. Vignon-Pennamen MD, Osio A, Battistella M. Histiocytoid
manifestations of dabrafenib GSK2118436): a selective Sweet Syndrome and Myelodysplastic Syndrome. JAMA
inhibitor of mutant BRAF in patients with metastatic Dermatol. 2017;153:835–836.
melanoma. Br J Dermatol. 2012;167:1153–1160. 84. Osio A, Battistella M, Feugeas JP, et al. Myelodysplasia cutis
61. Chu EY, Wanat KA, Miller CJ, et al. Diverse cutaneous side vs leukaemia cutis. J Invest Dermatol. 2015;135:2321–2324.
effects associated with BRAF inhibitor therapy: a clinicopa- 85. Ghoufi L, Ortonne N, Ingen-Housz-Oro S, et al. Histiocytoid
thologic study. J Am Acad Dermatol. 2012;67:1265–1272. Sweet syndrome is more frequently associated with myelodys-
62. Trefzer U, Minor D, Ribas A, et al. BREAK-2: a phase IIA plastic syndromes than the classical neutrophilic variant: a
trial of the selective BRAF kinase inhibitor GSK2118436 in comparative series of 62 patients. Medicine. 2016;95:1–10.
patients with BRAF mutation-positive (V600E/K) metastatic 86. Bush JW, Wick MR. Cutaneous histiocytoid Sweet syndrome
melanoma. Pigment Cell Res. 2011;24:990–1075. and its relationship to hematological diseases. J Cutan Pathol.
63. Zimmer L, Livingstone E, Hillen U, et al. Panniculitis with 2016;43:394–399.
arthralgia in patients with melanoma treated with selective 87. Baldus CD, Liyanarachchi S, Mrozek K, et al. Acute myeloid
BRAF inhibitors and its management. Arch Dermatol. 2012; leukemia with complex karyotypes and abnormal chromosome
148:357–361. 21: amplification discloses overexpression of APP, ETS2, and
64. Dummer R, Rinderknecht J, Goldinger SM. Ultraviolet A and ERG genes. Proc Natl Acad Sci USA. 2004;101:3915–3920.
photosensitivity during vemurafenib therapy. N Engl J Med. 88. Goldberg L, Tijssen MR, Birger Y, et al. Genome-scale
2012;366:480–481. expression and transcription factor binding profiles reveal
65. DeYoung MB, MacConell L, Sarin V, et al. Encapsulation of therapeutic targets in transgenic ERG myeloid leukemia.
exenatide in poly- (D, L-Lactide-Co-Glycolide) microspheres Blood. 2013;122:2694–2703.
produced an investigational long-acting once-weekly formu- 89. Xu B, Naughton D, Busam K, et al. ERG is a useful
lation for type 2 diabetes. Diabetes Technol Ther. 2011;13: immnohistochemical marker to distinguish leukemia cutis
1145–1154. from nonneoplastic leukocytic infiltrates in the skin. Am J
66. Boysen NC. Eosinophil-rich granulomatous panniculitis Dermatopathol. 2016;38:672–677.
caused by exenatide injection. J Cutan Pathol. 2014;41:63–65. 90. Gleason BC, Zembowicz A, Granter SR. Non-bullous
67. Shan S-J, Guo Y. Exenatide-induced eosinophilic sclerosing neutrophilic dermatosis: an uncommon dermatologic mani-
lipogranuloma at the injection site. Am J Dermatopathol. festation in patients with lupus erythematosus. J Cutan Pathol.
2014;36:510–512. 2006;33:721–725.
68. Andres-Ramos I, Blanco-Barrios S, Fernandez-Lopez E, et al. 91. Brinster NK, Nunley J, Pariser R, et al. Nonbullous
Exenatide-induced eosinophil-rich granulomatous panniculi- neutrophilic lupus erythematosus: a newly recognized variant
tis: a novel case showing injected microspheres. Am J of cutaneous lupus erythematosus. J Am Acad Dermatol. 2012;66:
Dermatopathol. 2015;37:801–802. 92–97.
69. Vidal CI, Chaudhry S, Burkemper NM. Exenatide-induced 92. Ramsey-Goldman R, Franz T, Solano FX, et al. Hydralazine
panniculitis: utility of the acid-fast stain to identify injected induced lupus and Sweet’s syndrome. Report and review of the
microspheres. Am J Dermatopathol. 2017. [Epub ahead of print]. literature. J Rheumatol. 1990;17:682–684.
70. Sweet RD. Acute febrile neutrophilic dermatosis. Br J 93. Sequeira W, Polisky RB, Alrenga DP. Neutrophilic derma-
Dermatol. 1964;76:349–356. tosis (Sweet’s syndrome). Association with a hydralazine-
71. Chan HL, Lee YS, Kuo TT. Sweet’s syndrome: clinicopatho- induced lupus syndrome. Am J Med. 1986;81:558.
logic study in eleven cases. Int J Dermatol. 1994;33:425–432. 94. Servitje O, Ribera M, Juanola X, et al. Acute neutrophilic
72. Eduardo Calonje J, Brenn T, Lazar A, et al. McKee’s dermatosis associated with hydralazine-induced lupus. Arch
Pathology of the Skin: with clinical correlations. Edinburgh: Dermatol. 1987;123:1435.
Elsevier/Saunders; 2012. 95. Saeb-Lima M, Charli-Joseph Y, Rodriguez-Acosta ED, et al.
73. Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet Autoimmunity-related neutrophilic dermatosis: a newly
syndrome: a dermal infiltrate of immature neutrophilic described entity that is not exclusive of systemic lupus
granulocytes. Arch Dermatol. 2005;141:834–842. erythematosus. Am J Dermatopathol. 2013:655–660.
74. Jordaan HF. Acute febrile neutrophilic dermatosis: a histo- 96. Hau E, Vignon Pennamen MD, Battistella M, et al. Neu-
pathological study of 37 patients and a review of the literature. trophilic skin lesions in autoimmune connective tissue diseases:
Am J Dermatopathol. 1989;11:99–111. nine cases and a literature review. Medicine. 2014;93:1–13.
54 | www.anatomicpathology.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol Volume 26, Number 1, January 2019 Inflammatory Dermatopathology
97. Broekaert SM, Böer-Auer A, Kerl K, et al. Neutrophilic 115. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma
epitheliotropism is a histopathologic clue to neutrophilic elasticum and skin: clinical manifestations, histopathology,
urticarial dermatosis. Am J Dermatopathol. 2016;38:39–49. pathomechanism, perspectives of treatment. Intractable Rare
98. Kieffer C, Cribier B, Lipsker D. Neutrophilic urticarial dermatosis: Dis Res. 2015;4:113–122.
a variant of neutrophilic urticaria strongly associated with systemic 116. Cai MM, Smith ER, Brumby C, et al. Fetuin-A-containing
disease. Report of 9 new cases and review of the literature. calciprotein particle levels can be reduced by dialysis, sodium
Medicine (Baltimore). 2009;88:22–31. thiosulphate and plasma exchange. Potential therapeutic
99. Németh T, Mócsai A. The role of neutrophils in autoimmune implications for calciphylaxis. Nephrology (Carlton). 2013;18:
diseases. Immunol Lett. 2012;143:9–19. 724–727.
100. Eyles JL, Roberts AW, Metcalf D, et al. Granulocyte colony- 117. Buka R, Wei H, Sapadin A, et al. Pseudoxanthoma elasticum and
stimulating factor and neutrophils—forgotten mediators of calcinosis cutis. J Am Acad Dermatol. 2000;43 (2 Pt 1):312–315.
inflammatory disease. Nat Clin Pract Rheumatol. 2006;2: 118. Jean L, Bolognia JLJ, Julie V. Schaffer. Dermatology, 3rd ed.
500–510. Philadelphia, PA: Elsevier Saunders; 2012:47.
101. Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines, 119. Jurzyk RS, Ditre CM, Kantor GR, et al. Plaque-type
chemokines and other effector molecules in two prototypic intertriginous cutaneous calcification. Cutis. 1992;49:289–291.
autoinflammatory skin diseases, pyoderma gangrenosum and 120. Woo TY, Rasmussen JE. Disorders of transepidermal
Sweet’s syndrome. Clin Exp Immunol. 2014;178:48–56. elimination. Part 2. Int J Dermatol. 1985;24:337–348.
102. Caproni M, Torchia D, Cardinali C, et al. Infiltrating cells, 121. Saxe N, Beighton P. Cutaneous manifestations of osteoectasia.
related cytokines and chemokine receptors in lesional skin Clin Exp Dermatol. 1982;7:605–609.
of patients with dermatomyositis. Br J Dermatol. 2004;151: 122. Cochran RJ, Wilkin JK. An unusual case of calcinosis cutis.
784–791. J Am Acad Dermatol. 1983;8:103–106.
103. Essary LR, Wick MR. Cutaneous calciphylaxis. An underrecog- 123. Nielsen AO, Christensen OB, Hentzer B, et al. Salpeter-
nized clinicopathologic entity. Am J Clin Pathol. 2000;113: induced dermal changes electron-microscopically indistin-
280–287. guishable from pseudoxanthoma elasticum. Acta Derm Venereol.
104. Fernandez KH, Liu V, Swick BL. Nonuremic calciphylaxis 1978;58:323–327.
associated with histologic changes of pseudoxanthoma elasti- 124. Mainetti C, Masouye I, Saurat JH. Pseudoxanthoma elasti-
cum. Am J Dermatopathol. 2013;35:106–108. cum-like lesions in the L-tryptophan-induced eosinophilia-
105. Jeong HS, Dominguez AR. Calciphylaxis: controversies in myalgia syndrome. J Am Acad Dermatol. 1991;24:657–658.
pathogenesis, diagnosis and treatment. Am J Med Sci. 2016; 125. Aessopos A, Savvides P, Stamatelos G, et al. Pseudoxanthoma
351:217–227. elasticum-like skin lesions and angioid streaks in beta-
106. Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to thalassemia. Am J Hematol. 1992;41:159–164.
nuclear factor kappa-B. J Am Acad Dermatol. 2008;58:458–471. 126. Baccarani-Contri M, Bacchelli B, Boraldi F, et al. Character-
107. Oliveira TM, Frazao JM. Calciphylaxis: from the disease to ization of pseudoxanthoma elasticum-like lesions in the skin of
the diseased. J Nephrol. 2015;28:531–540. patients with beta-thalassemia. J Am Acad Dermatol. 2001;44:
108. Mochel MC, Arakaki RY, Wang G, et al. Cutaneous 33–39.
calciphylaxis: a retrospective histopathologic evaluation. Am 127. Kasemsarn P, Boonchai W. Pseudoxanthoma elasticum-like
J Dermatopathol. 2013;35:582–586. lesions in beta-thalassemia/hemoglobin E patient: a case
109. Selye H, Grasso S, Dieudonne JM. On the role of adjuvants in report. J Dermatol. 2013;40:409–410.
calciphylaxis. Q Rev Allergy Appl Immunol. 1961;15:461–465. 128. Yu S, Ming A, Wegman A. Pseudoxanthoma elasticum-like
110. Chen TY, Lehman JS, Gibson LE, et al. Histopathology of lesions in association with thalassaemia major. Australas J
calciphylaxis: cohort study with clinical correlations. Am J Dermatol. 2009;50:186–189.
Dermatopathol. 2017;39:795–802. 129. Nathoo RK, Harb JN, Auerbach J, et al. Pseudoxanthoma
111. Halasz CL, Munger DP, Frimmer H, et al. Calciphylaxis: elasticum-like changes in nonuremic calciphylaxis: case series
Comparison of radiologic imaging and histopathology. J Am and brief review of a helpful diagnostic clue. J Cutan Pathol.
Acad Dermatol. 2017;77:241–246.e3. 2017;44:1064–1069.
112. Yerram P, Chaudhary K. Calcific uremic arteriolopathy in 130. Penn LA, Brinster N. Calciphylaxis with pseudoxanthoma
end stage renal disease: pathophysiology and management. elasticum-like changes: a case series. J Cutan Pathol. 2018;45:
Ochsner J. 2014;14:380–385. 118–121.
113. Latus J, Kimmel M, Ott G, et al. Early stages of calciphylaxis: 131. Lewis KG, Lester BW, Pan TD, et al. Nephrogenic fibrosing
are skin biopsies the answer? Case Rep Dermatol. 2011;3: dermopathy and calciphylaxis with pseudoxanthoma elasti-
201–205. cum-like changes. J Cutan Pathol. 2006;33:695–700.
114. Dookhan C, Ortega LM, Nayer A, et al. Perieccrine and 132. Nikko AP, Dunningan M, Cockerell CJ. Calciphylaxis with
pericapillary calcification in calciphylaxis. J Renal Inj Prev. histologic changes of pseudoxanthoma elasticum. Am J
2015;4:9–10. Dermatopathol. 1996;18:396–399.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.anatomicpathology.com | 55
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.