Accepted Manuscript: Seminars in Diagnostic Pathology

Accepted Manuscript
CUTANEOUS PARANEOPLASTIC SYNDROMES
Mark R. Wick M.D. , James W. Patterson M.D.
PII: S0740-2570(19)30008-5
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For inclusion in Seminars in Diagnostic Pathology:
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CUTANEOUS PARANEOPLASTIC SYNDROMES
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Mark R. Wick, M.D.
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James W. Patterson, M.D.
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From PRW Laboratories, Charlottesville, VA.
Contact information: Dr. Wick—PRW Laboratories, 2331 Seminole Lane, Suite 102, Charlottesville, VA
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22901 (Telephone 434-242-2410; E-mail-- [email protected])

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Wick & Patterson Page 2
Abstract
A variety of cutaneous abnormalities can be seen in patients with malignant diseases,

some of which are infectious, with others representing direct involvement of the skin by the
underlying disorder. Yet another group of lesions can be regarded as associated markers of the
malignant process, and, as such, are termed “paraneoplastic.” This review considers the latter
collection of conditions, grouping them by the generic type of malignancy that is usually linked
to the paraneoplasia. Some of the processes show a predominant association with alimentary
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tract malignancies (acanthosis nigricans, acrodermatitis paraneoplastica, florid cutaneous
papillomatosis, necrolytic migratory erythema, palmoplantar keratoderma, pancreatic fat
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necrosis, and pityriasis rotunda). Others are usually linked to a hematolymphoid malignancy
(acquired ichthyosis, exfoliative erythroderma, necrobiotic xanthogranuloma, pemphigus
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paraneoplastica, plane xanthoma, pyoderma gangrenosum, scleromyxedema, Sweet syndrome,
and leukocytoclastic vasculitis). Finally, yet another collection of paraneoplastic skin disorders
can associate themselves with anatomically-diverse malignancies (Leser-Trelat syndrome,
Trousseau syndrome, dermatomyositis, erythema gyratum repens, hypertrichosis lanuginosa
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acquisita, papuloerythroderma of Ofuji, tripe palms, and multicentric reticulohistiocytosis).
Recognition of these processes by the pathologist can be a valuable step in the characterization
of underlying malignant diseases.
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Key Words: Paraneoplastic conditions; skin diseases accompanying malignancies; non-
neoplastic disorders in cancer patients
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The word “paraneoplastic” is derived from the Greek roots para, meaning "to, at, or from
the side of," neo, meaning "new," and plasma, meaning "formation," and it is used to refer to
changes in tissues that are remote from a tumor or its metastases (1). As commonly used, the
term “paraneoplastic” usually refers to syndromes that are associated with malignant tumors,
although that is not universally true. The focus in this particular discussion is on conditions that
are, or can be, associated with malignancies.
Paraneoplastic conditions of the skin are particularly important. From an academic
standpoint, they can provide insights into basic tumor biology. In more practical terms, and in
contrast to most internal disorders, changes involving the skin are often readily identifiable at an
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early stage. Consequently, cutaneous lesions can serve as the harbingers of a malignant process,
allowing for earlier detection and treatment of the latter (Table 1). Although it is uncommon for
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the pathologist to make a definitive diagnosis of a paraneoplastic condition based upon biopsy
findings alone, it can occur, as in the case of necrolytic migratory erythema (linked to
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glucagonoma), acanthosis nigricans (gastrointestinal adenocarcinoma), or paraneoplastic
pemphigus (non- Hodgkin's lymphoma). Because the microscopic changes of paraneoplastic
lesions in the skin can also be seen in the absence of neoplasia, the more common role of the
pathologist is to suggest heightened surveillance for a malignant process when they are observed.
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Part I: Conditions that are Usually Linked to Malignant Alimentary Tract Neoplasms
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Necrolytic Migratory Erythema (NME; Glucagonoma Syndrome)
Clinical Findings
This syndrome features anemia, weight loss, glossitis, and adult-onset diabetes mellitus.
The characteristic cutaneous feature is a migrating annular erythema with erosions and crusting.
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It is concentrated in intertriginous areas of the trunk, groin, buttocks, and thighs, and perioral
lesions may occur (2-5). Necrolytic migratory erythema is most often associated with a
glucagon-secreting neuroendocrine tumor of the pancreas (3). In a typical case, elevated
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glucagon levels and reduced plasma amino acids are detected (2,4,6,7). Identical skin changes
have also been seen in association with neuroendocrine hepatic tumors, hepatic cirrhosis, jejunal
and rectal adenocarcinoma, myelodysplastic syndromes, inflammatory bowel disease,
pancreatitis, and malabsorption disorders (3,4,8). Skin lesions resolve with treatment of the
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underlying tumor and correction of nutritional deficiencies. There appears to be no clear

consensus regarding the pathogenesis of necrolytic migratory erythema, but amino acid, zinc,
and fatty acid deficiencies, caused by the catabolic effects of elevated glucagon levels, may all
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play a part (2,6,7).

Histopathology
The cutaneous lesions of NME show acanthosis, which may range from mild to marked.
Confluent parakeratosis overlies distinctly vacuolated keratinocytes in the upper portion of the
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epidermis (Figure 1). Necrosis may be superimposed, with the coalescence of vacuoles and
neutrophil accumulation, at times producing spongiform pustulation. Subcorneal pustules
occasionally may be the principal histopathologic finding (9,10). Within the superficial to mid
dermis, there is a perivascular infiltrate comprised mainly of lymphocytes but sometimes
including neutrophils.
Specificity of Findings and Differential Diagnosis
The presence of confluent parakeratosis overlying vacuolated superficial keratinocytes is
quite characteristic of NME and should raise suspicions of that diagnosis. However, several other
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nutritional deficiency disorders can have similar microscopic changes. The clinical presentations
of biotin deficiency, pellagra, and childhood acrodermatitis enteropathica should be sufficiently
distinctive, but adult onset zinc deficiency could be difficult to distinguish from necrolytic
migratory erythema in the
absence of laboratory data.
Psoriasiform varieties of necrolytic migratory erythema could be difficult to distinguish from
true psoriasis, but vacuolization of superficial keratinocytes is not typical of psoriasis.
Acrokeratosis Paraneoplastica (Bazex Syndrome)
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Clinical Findings
Individuals with this condition have psoriasiform or eczematous lesions that are
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concentrated on acral surfaces, including the hands, feet, knees, ears, nose, and cheeks. Brittle
nails with surrounding psoriasis- like changes can also occur. The skin lesions often have a
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distinctly violaceous color (11-19). Acrokeratosis paraneoplastica (AKP) is associated with
malignancies in virtually all cases, particularly associated with the aerodigestive tract. Examples
include carcinomas of the tongue, pharynx, soft palate, esophagus, and lung (13,17,19). The
development of AKP typically precedes initial symptoms of the underlying malignancy by an
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average of 11 months (13). In most cases, cutaneous lesions improve following treatment of the
associated malignancy. Possible causes of AKP include an immune response directed toward
particular tumor antigens, or tumor-induced inflammatory mediators such as transforming
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growth factor-alpha (15,16).
Histopathology
Microscopic findings in AKP include focal parakeratosis, hyperkeratosis, and acanthosis
(15,16,18) (Figure 2). Varying degrees of vacuolar keratinocyte alteration and apoptosis have
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been detected as well. Within the superficial dermis one sees a mild perivascular lymphocytic
infiltrate.
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In the absence of a clinical history, the microscopic findings in AKP are nonspecific. The
described constellation of histologic features would ordinarily raise the differential diagnosis of
psoriasis versus psoriasiform spongiotic dermatitis, a common issue in diagnostic
dermatopathology. However, neutrophil accumulations within the stratum corneum, as seen in
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psoriasis, have not been observed in AKP. The clinical presentation of AKP is quite
characteristic, and in that context, the microscopic findings can be strongly supportive of the
diagnosis.
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Acanthosis Nigricans
Clinical Findings
Acanthosis nigricans (AN) is perhaps best known as a sign of malignancy, but it also
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accompanies a group of endocrinologic disorders, particularly those associated with insulin

resistance and obesity (20,21). It may likewise be seen as an autosomal dominant familial
disorder or may be caused by certain medications, including corticosteroids, nicotinic acid, and
triazinate (22,23). "Malignant" acanthosis nigricans (so-called because of its association with
malignancy) is mainly a disorder of adults. It is most closely associated with gastrointestinal
carcinomas, but has been seen with carcinomas of the lung, kidney, and bladder, mycosis
fungoides, and carcinomas of the ovary and pancreas (24-28). AN may precede the detection of
malignancy in roughly 20% of cases, whereas it appears simultaneously with the cancer in 60%
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and follows the tumor diagnosis in another 20% of cases. The condition can regress, at least
temporarily, when the tumor has been resected. It appears that growth factors produced by the
tumors may be responsible causally for the development of AN (27). All forms of the disorder
feature pigmented, velvety plaques that are concentrated in flexures, such as the neck, axillae,
and groin (26,27). The palms may be hyperkeratotic and develop a "honeycomb" appearance.
Cases have been reported in which AN coexisted with tripe palms, mucosal papillomas, and the
sign of Leser-Trelat (eruptive seborrheic keratoses).
Histopathology
The findings in acanthosis nigricans are characteristic, if not pathognomonic, and include
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marked papillomatosis with "finger-like" projections of rete ridges, associated with
hyperkeratosis that tends to be basket-woven rather than compact (Figure 3). Acanthosis is mild,
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usually limited to the valleys between papillomatous formations (22). Basilar melanization is
often mild, except in dark-skinned individuals, and it is believed that in most instances, the
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pigmentation perceived clinically is primarily due to hyperkeratosis (27).
The changes of acanthosis nigricans are characteristic but not entirely specific. Similar
combinations of hyperkeratosis and papillomatosis can be seen in confluent and reticulated
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papillomatosis (a hyperkeratotic condition most commonly seen on the trunk of younger
individuals, unassociated with malignancy), some seborrheic keratoses, and epidermal nevi.
Seborrheic keratoses may also have horn cysts and a greater degree of acanthosis, while the
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changes in confluent and reticulated papillomatosis are generally less pronounced. Obviously,
the clinical history and physical examination have a great bearing on the diagnosis in many
cases. Once a diagnosis of acanthosis nigricans is established, there is still a need to determine
the underlying cause. In the absence of a family history, endocrinologic syndrome, obesity, or
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relevant medications, the development of this condition in an adult should prompt a search for
malignancy, particularly of the gastrointestinal tract.
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Florid Papillomatosis (FP; Schwartz-Burgess Syndrome)

Clinical Findings
FP begins with the abrupt appearance of many cutaneous papillomas that clinically
simulate the image of viral warts (29-33). The lesions are 1 to 3 mm in diameter, and usually are
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first seen in acral skin. With time, they become disseminated. Pruritus accompanies the lesions
in roughly 50% of cases. The suddenness of the eruption and the multiplicity of papillomas
facilitates distinction from verrucae and epidermodysplasia verruciformis. FP is associated with
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underlying cancer of the stomach (in the majority of cases) as well as carcinomas of the breast,
bladder, ovary, uterus, prostate, and lung (30-32). Uncommonly, squamous cell carcinoma or
lymphoma also may represent the underlying malignancy. Individuals with FP sometimes show
a clinical continuum of lesions that also have the appearance of acanthosis nigricans or eruptive
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seborrheic keratosis. FP tends to remit, at least in part, with successful treatment of the
associated neoplasm.
Histopathology
Histologically, the lesions of FP show hyperkeratosis, epidermal acanthosis, and
papillomatosis (Figure 4). There is no vacuolization of keratinocytes, and parakeratosis and
viral inclusions are absent (29,30).
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Specificity of Findings & Differential Diagnosis

For practical purposes, a diagnosis of FP always equates with the presence of an
underlying malignant neoplasm.
Pityriasis Rotunda
Clinical Findings
Pityriasis rotunda is characterized by ovoid, scaly, pigmented patches that principally
affect the trunk and extremities. Two types of the disorder have been described. Type I is seen in
adult Asian or black patients, and it is often associated with an underlying malignancy, usually
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gastric or hepatocellular carcinoma (34-40).
Type II pityriasis rotunda occurs before the age of 40 years, and is often familial. It has
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not been associated with internal diseases or malignant neoplasms (36). The clinical images of
type I and type II lesions are identical. They are represented by circular pink or light brown
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patches that are sharply defined with dry scaling, ranging between 0.5 and 20 cm in greatest
dimension. The lesions tend to be hyperpigmented in patients with dark skin and hypopigmented
in those with light skin (36,37).
Histopathology
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Type I pityriasis rotunda may be a biological variant of paraneoplastic ichthyosis vulgaris.
Accordingly, the histologic appearance of lesions features compact orthokeratosis, a lack of
spongiosis, and minimal dermal inflammation. The granular cell layer of the epidermis is often
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attenuated or absent, mimicking the microscopic image of hereditary ichthyosis vulgaris (35-37).
The appearance of pityriasis rotunda in an older adult, in the absence of a family history of that
condition, has a strong association with an underlying carcinoma. It usually arises in the
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stomach or liver.
Pancreatic Panniculitis (PP)

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Clinical Findings
The lesions of PP are predominantly distributed over the legs, trunk, and buttocks, as
violaceous or erythematous nodules and plaques in the subcutis. They may ulcerate
spontaneously and drain viscous, oily fluid. Patients with paraneoplastic PP are typically older
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adults with no prior history of pancreatic disease (41-44). The lesions may antedate discovery of
a malignant neoplasm by 1 to 7 months, or, conversely, they may develop months after the tumor
is identified.
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Laboratory studies usually reveal elevations in serum lipase, amylase, and trypsin levels,
although that finding is not universal. The blood level of carcinoembryonic antigen also may be
above normal (42,44). The most common pancreatic malignancy in this setting is acinar cell
adenocarcinoma, but conventional ductal adenocarcinoma and neuroendocrine pancreatic
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carcinoma sometimes cause PP as well. The clinical evolution is almost always adverse, owing
to the aggressive nature of the associated pancreatic tumors.
Histopathology
Skin and subcuticular biopsies in PP show lobular fat necrosis, associated with anuclear
adipocytes (ghost cells), microcalcifications, and a neutrophilic inflammatory infiltrate (44).
The microscopic features of PP, as just described, serve to distinguish it from other forms
of panniculitis such as erythema nodosum or erythema induratum. Patients with acute or chronic
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pancreatitis may also develop the syndrome, but differences in the clinical presentation of those
disorders and that of paraneoplastic PP facilitate the distinction between them.
Tylosis (Palmoplantar Keratoderma)

Clinical Findings
Tylosis, or keratosis palmaris et plantaris, can occur in a wide variety of genetic disorders. It can
also arise as an acquired disease in a number of ways, e.g., following arsenic exposure, as
keratoderma climactericum, or as an accompaniment of other dermatoses such as pityriasis rubra
pilaris. Clinically the hyperkeratosis can be diffuse, focal or nummular, or punctate (45-52).
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Acquired tylosis can also be associated with internal malignancies of varying types, ranging from
lymphoma to bronchogenic carcinoma (45,48,53). In fact, tripe palms may be regarded as a
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variant of palmar keratoderma. Tylosis has also been associated with gastrointestinal carcinoma
as part of a familial syndrome. The best known
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is the Howel-Evans syndrome, associating tylosis with the development of esophageal carcinoma
(46). The genetic locus for tylosis with esophageal cancer has been mapped to a 500 kb region on
chromosome 17q2S (47). In 1984, Bennion and Patterson reported on a family with punctate
keratoderma of palms and soles and carcinomas of the colon and pancreas (48).
Histopathology & Specificity of Findings
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Microscopically, all forms of keratoderma show orthokeratosis, variable parakeratosis,
hypergranulosis, and acanthosis (Figure 5). In punctate variants, a degree of keratin plugging
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can also be observed (49,51). Underlying malignancy should be included in the differential
diagnosis of conditions associated with acquired keratoderma of palms and soles, though it is not
the most common. Although Howel-Evans keratoderma begins in childhood, it tends to be later
in onset than is the case for benign hereditary keratoderma.
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Part II: Conditions that are Usually Linked to Hematolympoid Malignancies

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Paraneopiastic Pemphigus
Clinical Findings
In 1990, Anhalt et al. defined the disorder that is now known as paraneoplastic
pemphigus (54). Patients with that condition develop erosions of the lips and oropharynx,
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pseudomembranous conjunctivitis, and pruritic, polymorphous skin lesions with blisters and
erosions. Some lesions have a target-like configuration, and these, combined with the mucous
membrane changes can erroneously suggest the diagnosis of erythema multiforme.
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Paraneoplastic pemphigus has a strong association with lymphoproliferative disorders, including

non-Hodgkin lymphomas, thymoma, chronic lymphocytic leukemia, and Castleman's disease
(54-56). Other tumors are present in roughly 15% of all cases, including carcinomas, sarcomas,
and malignant melanoma. In typical cases that are associated with lymphoma, the neoplastic
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process is already established at the time of onset of paraneoplastic pemphigus. Unusual cases
have also been reported in which no tumor was detected (57). Patients with paraneoplastic
pemphigus have been shown to develop circulating antibodies to a variety of keratinocyte-
derived proteins, particularly desmoplakin I (250 kd), bullous pemphigoid antigen (230 kd),
envoplakin (210 kd), and periplakin (190 kd) (58,59). Presumably, autoantibodies which are
directed toward the underlying tumors cross-react with native epithelia that contain related
antigens (54,60).
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Histopathology
The microscopic image of paraneoplastic pemphigus combines features of erythema
multiforme with those of pemphigus vulgaris. There is vacuolar alteration of the basilar layer,
apoptotic keratinocytes can be found at all levels of the epidermis, and a superficial dermal
infiltrate is present comprising mainly lymphocytes, but with some eosinophils and neutrophils
(Figure 6). All of those changes can be seen in erythema multiforme. In addition, suprabasilar
acantholysis with cleft formation is often present (61,62). It is possible that the exposure of
antigens resulting from lichenoid dermatitis could promote the development of autoimmunity
and the subsequent acantholytic changes of pemphigus; this could be considered an example of a
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phenomenon termed "epitope spreading" (63).
Direct immunofluorescence shows a combination of intercellular epidermal deposits of
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IgG and C3 and linear-granular basement membrane zone staining for C3 and/or IgG, a
combination of findings that is also observed in pemphigus erythematosus (64). Positive
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intercellular IgG is also found by indirect immunofluorescence using monkey esophagus
substrate, as would also be the case for non-paraneoplastic forms of pemphigus. In addition, sera
from patients with paraneoplastic pemphigus show antibody binding to simple epithelia such as
that found in murine bladder, a finding not encountered in ordinary pemphigus.
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Microscopic findings in paraneoplastic pemphigus are potentially diagnostic in and of
themselves. The best opportunity for a specific diagnosis arises when interface (lichenoid)
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changes, sometimes resembling erythema multiforme, coexist with suprabasilar acantholysis.
Supportive evidence is provided by direct immunofluorescent studies, as described above. The
histologic differential diagnosis includes a variety of interface or lichenoid dermatoses,
particularly erythema multiforme but also graft versus host disease and fixed drug eruption. At
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times, biopsy findings may show only suprabasilar acantholysis without lichenoid tissue
changes, a circumstance that has been reported in 27% of cases (65-71).
Papuloerythroderma of Ofuji
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Clinical Findings
First described by Ofuji in 1984 (72), papuloerythroderma is another clinically distinctive
dermatosis, but one that lacks specific histopathologic features. This condition typically presents
in elderly men. Widespread erythema and solid, red-brown papules develop, with dramatic
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sparing of flexural folds-a finding often termed the "deck chair sign." Eosinophilia and
lymphopenia may accompany the skin eruption. Papuloerythroderma has a strong association
with malignancy, especially lymphoma. The most common lymphoproliferative disorder is T-
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cell lymphoma, particularly cutaneous T-cell lymphoma (73,74). Nonepidermotropic peripheral

T-cell lymphoma, Hodgkin's disease, and acute myeloid leukemia have also been reported. Solid
tumors have included gastric carcinoma (75), adenocarcinoma of the colon, and hepatocellular
carcinoma (76). Despite the apparently
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strong cancer association, some patients have not developed malignancy during a limited period
of follow-up, and sporadic cases have been related to HIV infection (77) and choledocholithiasis
with secondary sepsis (78).
Histopathology
Microscopic findings include parakeratosis, variable acanthosis, and spongiosis (Figure
7). A moderately intense perivascular and interstitial inflammatory infiltrate is seen in the upper
to mid dermis, comprised mainly of lymphocytes, with scattered eosinophils and plasma cells
(72-75).
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None of the microscopic changes just described are considered to be specific. In fact,
they can be observed in a variety of spongiotic dermatitides, including forms of eczematous
dermatitis and erythroderma. In the authors' experience, the diagnosis is largely a clinical one,
with histopathology playing mainly a supportive role. Clinically, the "deck chair sign" is far
more distinctive than any of the histopathologic features.
Exfoliative Dermatitis with Erythroderma

Clinical Features
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Exfoliative dermatitis, or erythroderma, has been reported in association with
lymphomas, leukemias, and Hodgkin's disease (79). However, the best-documented association
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with malignancy is with cutaneous T-cell lymphoma, in which erythroderma is an integral part of
the Sezary syndrome (80). In fact, it has been argued that cases of erythroderma linked to
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“chronic lymphocytic leukemia” were most likely examples of the Sezary syndrome (81).
Associations also exist with solid tumors (rarely), including carcinomas of the stomach, liver,
prostate, lung, thyroid, and gallbladder (82). Exfoliative dermatitis can precede, follow, or
present concomitantly with an underlying malignancy.
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Exfoliative dermatitis also develops in patients who do not have malignancies. In fact, it
is most often associated with drug reactions or a preexisting dermatosis, such as psoriasis,
contact dermatitis, or stasis dermatitis.
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Microscopically, one usually sees parakeratosis, acanthosis with mild spongiosis,
vasodilatation, and a chronic inflammatory infiltrate (Figure 8). Those findings are suggestive
of exfoliative dermatitis but are otherwise nonspecific. Occasionally, a lichenoid tissue reaction
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pattern can be identified. Atypical lymphocytes and Pautrier microabscesses would provide a
clue to the diagnosis of Sezary syndrome, or, alternatively, histologic changes may be
sufficiently specific to suggest an underlying dermatosis such as psoriasis.
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Dermatomyositis
Clinical Findings
Dermatomyositis is a well-known condition that combines the features of polymyositis
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with inflammatory skin lesions. Some patients present with identical skin lesions in the absence
of clinical and laboratory findings of myositis. When this situation lasts for over two years, it is
called "amyopathic dermatomyositis" (83). Internal malignancy has been reported in 15% to 25%
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of cases of dermatomyositis (84,85). On the other hand, polymyositis alone does not appear to
have an increased risk for malignancy (86). The neoplastic process may precede, develop
concurrently with, or follow the onset of dermatomyositis, with approximately equal frequencies
(87). Carcinomas of breast and lung are among the most common, but several other tumors have
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also been encountered, including lymphomas, melanoma, and sarcomas.

The literature suggests that a diagnosis of dermatomyositis should not, by itself, prompt a
detailed evaluation for malignancy. Instead, such an assessment should be guided by the history,
results of physical examination, and/or routine laboratory studies (88).
The most common clinical features include violaceous erythema and scale, particularly
on the head and neck or over the extensor surfaces of the extremities, often with poikiloderma
(variegated pigmentation and telangiectasia) and a degree of atrophy. "Heliotrope" eyelids are
classic signs but are not always found. Papules or plaques involving skin over the
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interphalangeal joints (Gottron's papules) are often seen, and there may be nailfold
telangiectasias or ragged-appearing cuticles (Samitz's sign). Photosensitivity, sometimes with a
burning sensation, and plaque-like cutaneous calcifications may also occur (89).
Histopathology
The most typical presentation is that of a lichenoid tissue reaction, with vacuolar
alteration of the basilar layer of the epidermis and formation of apoptotic keratinocytes. Often
the features are those of poikiloderma atrophicans vasculaire: basilar vacuolar change in an
atrophic epidermis, vasodilatation, and pigmentary incontinence (Figure 9). The superficial
dermal infiltrate seen in dermatomyositis tends to be mild, lymphocytic, and perivascular. A
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lyrnphoplasmacytic panniculitis can be seen, but in the authors' experience, it is uncommon.
Dermal mucin deposition is frequently identified with colloidal iron or alcian blue staining (90).
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Direct immunofluorescent studies tend to be negative, except for the presence of apoptotic
(Civatte) bodies in the basal epidermis that stain positively for IgM and C3.
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Lesions that manifest interface dermatitis raise a broad differential diagnosis, but the
presence of poikiloderma atrophicans vasculaire in an adult suggests three major possibilities--
dermatomyositis, lupus erythematosus, and the poikilodermatous phase of mycosis fungoides. A
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distinct separation between them is not always possible. However, in addition to epidermal
changes, lupus erythematosus often shows a prominent perivascular and perifollicular lymphoid
infiltrate accompanied by vacuolar alteration of the outer root sheath epithelium. Thinning of
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lateral follicular walls occurs in discoid lupus erythematosus. Direct immunofluorescence of skin
biopsies can be helpful because only lupus erythematosus is expected to show basement
membrane deposits of complement and immunoglobulin. Mycosis fungoides would be expected
to show atypical lymphocytes, exocytosis with formation of haloed intraepidermal cells or
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Pautrier microabscesses, possibly with an abnormal immunophenotype or positive T-cell

receptor gene rearrangement studies.
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Diffuse (Normolipemic) Plane Xanthoma

Clinical Findings
Plane xanthomas manifest with patchy or diffuse orange-yellow discoloration of the skin
on the face and trunk, and particularly in intertriginous areas such as the axillae (91,92). Most
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patients with these lesions are normolipemic, but plane xanthomas can certainly occur in
hyperlipoproteinemias of types 2 through 4. This condition has a strong association with multiple
myeloma (91). There have also been reports of plane xanthomatosis associated with chronic
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lymphocytic leukemia (93) and rectal adenocarcinoma (94). Clinical and histopathologic links
have been suggested between diffuse plane xanthoma and necrobiotic xanthogranuloma (see
below) (95,96)).
Histopathology
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Microscopic findings include clusters of foamy macrophages scattered throughout the

dermis, in the absence of fibrosis (Figure 10). Lymphocytic inflammation is typically sparse or
absent (97-100).
The distribution of foamy macrophages, minimal inflammation, and a lack of fibrosis are
suggestive of plane xanthoma. Clinical correlation is necessary to confirm the "diffuseness" of
the process. In addition to the hyperlipoproteinemias mentioned above, plane xanthomas can also
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accompany biliary cirrhosis. Cases showing foci of degenerate connective tissue or

multinucleated cells can resemble the histologic image of necrobiotic xanthogranuloma.
Acquired Ichthyosis
Clinical Findings
Acquired ichthyosis in adults is frequently associated with malignancy. The malignant
process is most often a lymphoma, Hodgkin's disease being more common than non-Hodgkin's
lymphomas (101). It has also been reported in association with lymphomatoid papulosis (102),
multiple myeloma (103), and, uncommonly, with solid tumors such as carcinomas of the breast
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or lung (104,105). Ichthyosis in this setting usually arises in patients with established malignant
disease, although it may occasionally be the initial manifestation. However, there are other
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potential causes of acquired ichthyosis, including malnutrition, hypothyroidism, sarcoidosis, and
drugs such as nicotinic acid and clofazimine.
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Histopathology
Microscopically, skin biopsies show compact orthokeratosis, a lack of spongiosis unless
secondary eczematization has occurred, and minimal dermal inflammation (Figure 11). The
granular cell layer is often attenuated or absent, mimicking the image of ichthyosis vulgaris
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(103,104). Some cases of ichthyosis associated with myeloma have also presented with follicular
keratotic spicules; biopsy of such lesions has demonstrated intercellular deposition of
cryoproteins (103). Certainly, ichthyosiform biopsy changes in adults, in the absence of a long-
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term or familial history, should raise the possibility of underlying malignancy, though as noted
above, there are other possible explanations for this finding.
Necrobiotic Xanthogranuloma
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Clinical Findings
Necrobiotic xanthogranuloma (NXG) is a rare granulomatous disease that is typified by
yellowish indurated cutaneous plaques and nodules that coalesce into indurated plaques (106-
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111). They are usually 0.5 to 2.0 cm in greatest dimension, often with superficial telangiectasias,
potential ulceration, and scarring. Incisional biopsy is recommended to establish the diagnosis.
Most NXG lesions (60%-70%) first affect the trunk or extremities and then involve the
periorbital skin (110). However, periocular lesions are neither pathognomonic nor required
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diagnostically. Blepharoptosis, restricted ocular motility, and proptosis are seen in 50% to 80%
of patients. NXG also may involve various extracutaneous sites, including the lung, myocardium,
larynx, pharynx, skeletal muscle, kidney, ovary, and intestine (107-109).
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The association between NXG and paraproteinemias is well documented. Most patients
(80-90%) with NXG have a serum monoclonal gammopathy, usually of the IgG κ type, but only
10% of patients develop plasmacytic myeloma (109,111). The skin lesions in NXG represent
reactive inflammatory infiltrates and are not associated with the presence of monoclonal plasma
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cells. Other lymphoproliferative and hematologic disorders may also be associated with NXG
(108).
Histopathology
Microscopically, the lesions of NXG show marked necrobiosis alternating with foci of
xanthogranulomatous infiltration in the reticular dermis and subcutis (106,107,110) (Figure 12).
In the latter location, a septal distribution may be present which imitates panniculitis. The
inflammatory infiltrate features the presence of epithelioid and xanthomatized histiocytes,
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multinucleated giant cells, lymphocytes, plasma cells, and cholesterol clefts. Focal vasculitis
may be observed as well. The lymphocytes and plasma cells in NXG are polytypic (107).
As mentioned earlier, the great majority of individuals with NXG have paraproteinemias,
but these may eventuate months or years after appearance of the skin lesions. Histologic
differential diagnosis principally centers on infectious granulomas, but no microorganisms are
demonstrable by culture or histochemical staining in NXG.
Paraneoplastic Scleromyxedema
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Clinical Findings
The characteristic cutaneous manifestation of scleromyxedema is the widespread eruption
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of 2 to 3 mm, firm, waxy, closely-spaced, dome-shaped or flat-topped papules involving the
hands, forearms, head, neck, upper trunk, and thighs (112,113). Papules are often arranged in
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linear arrays and the surrounding skin is shiny and indurated. The glabella is typically involved
with formation of deep furrows that produce the characteristic leonine faces. Cutaneous
furrowing also is seen on the trunk or limbs, producing the "Shar-Pei sign" (113). Erythema,
edema, and a brownish discoloration may be seen in the involved skin, and pruritus is relatively
The mucous membranes are spared. US

common. Eyebrow, axillary, and pubic hair may be sparse in patients with scleromyxedema.
As the condition progresses, erythematous and infiltrated plaques may appear with skin
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stiffening, sclerodactyly, and decreased motility of the mouth and joints (112,113). On the
proximal interphalangeal joints, a central depression surrounded by an elevated rim (caused by
skin thickening) can be seen and is called the "doughnut sign" (112,113). Patients with
scleromyxedema can also have internal lesions that involve the neurologic, rheumatologic,
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cardiovascular, and gastrointestinal systems, as well as the lungs and kidneys (114).
Scleromyxedema is associated with paraproteinemias. The monoclonal gammopathy is
usually represented by IgG with a predominance of lambda light chains, but IgG kappa
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dominance also may be seen (111-113). Patients with scleromyxedema in the absence of a
paraproteinemia are considered to have an atypical form of the disease. The disease progresses to
outright multiple myeloma in < 10% of cases. Anecdotal associations with other hematologic
malignancies such as Hodgkin and non-Hodgkin lymphomas (115), Waldenström
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macroglobulinemia, and myelomonocytic leukemia, or visceral carcinomas have been reported

as well.
Histopathology
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Scleromyxedema features the presence of a triad of microscopic features that includes

diffuse deposition of dermal mucin, dermal fibrosis, and a proliferation of randomly arranged
fibroblasts in the corium (Figure 13). The epidermis may be normal or thinned, hair follicles
may be atrophic, and a slight perivascular dermal lymphoplasmacytic infiltrate is often present.
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Elastic fibers are often fragmented and decreased quantitatively. An interstitial, granuloma
annulare-like pattern has been described in some cases of scleromyxedema, typified by a diffuse
proliferation of histiocytes, giant cells, and lymphocytes in the upper dermis (116). Those
elements form loose granulomas that disrupt dermal collagen fibers.
The histological appearance of scleromyxedema is similar to that of cutaneous
myxedema in thyroid disease, scleroderma (systemic sclerosis), scleredema of Buschke, and
nephrogenic fibrosing dermopathy (112). Therefore, attention to laboratory data pertaining to
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thyroid function, serum glucose levels, and renal function is crucial to differential diagnosis in
this setting. The presence of a paraproteinemia would be selective for scleromyxedema.
Sweet's Syndrome (Acute Febrile Neutrophilic Dermatosis)

Clinical Findings
Although it is often described as an uncommon entity, Sweet's syndrome (SS) is not rare,
particularly in academic and referral centers. In this condition, erythematous and potentially
painful plaques and nodules develop over the face, trunk, or extremities. Characteristically, the
lesions arise suddenly, are accompanied by fever and leukocytosis, and are particularly
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responsive to treatment with systemic corticosteroids. Several disease associations have been
reported, represented by autoimmune-inflammatory, infectious, iatrogenic, and pregnancy-
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related conditions (117-120). Idiopathic cases also occur.
The other significant disease linkage is with malignancy, seen in roughly 10% of SS
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cases (121-128). Leukemia has been the most frequent condition in that category, particularly
acute myeloid or myelomonocytic leukemia (121). SS has also accompanied chronic myeloid
leukemia (122). Other hematologic dyscrasias seen with SS have included hairy cell leukemia
and myelodysplastic syndrome (123). There have also been reports of SS occurring with non-
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Hodgkin lymphoma (124), myeloma (125), and solid tumors (126,127). Most examples in the
latter category are carcinomas of the bladder, prostate, and uterine cervix.
Histopathology
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Microscopic findings in SS include pronounced papillary dermal edema and a dense
neutrophilic infiltrate in the upper to mid-corium. Leukocytoclasis is usually apparent, but
leukocytoclastic vasculitis typically cannot be demonstrated (128) (Figure 14). A neutrophil-
poor variant has been described (129), but it is sufficiently unusual that reconsideration of the
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diagnosis would be warranted. A “histiocytoid” variant of SS is, in fact, caused by dermal

infiltrates of immature myeloid cells (130).
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The microscopic findings in SS are characteristic, and often diagnostic. Its histologic
image does overlap to some extent with that of early pyoderma gangrenosum, and those
disorders may, in fact, be part of a single continuum (131,132). However, early lesions of
“classic” pyoderma gangrenosum often show the presence of acute folliculitis (128), whereas SS
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does not. Moreover, it is not typical for SS lesions to be ulcerated, as seen in pyoderma
gangrenosum. The lesions of erythema elevatum diutinum can have overlapping microscopic
features. Another condition termed "rheumatoid neutrophilic dermatosis" also bears a close
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resemblance to SS microscopically, but in the authors' experience, it shows deep as well as

superficial dermal inflammation with a lesser degree of karyorrhexis, and may be associated with
the changes of interstitial granulomatous dermatitis (133). The majority of SS cases are not
associated with malignancy, but the detection of primitive myeloid forms in the infiltrate should
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always prompt an investigation for possible underlying leukemia.
Paraneoplastic Pyoderma Gangrenosum (PPG)

Clinical Findings
Pyoderma gangrenosum starts as a painful papule or pustule that develops into a nodule;
this then ulcerates and forms violaceous borders with purulent exudates and a necrotic base.
Classical PG is more frequently located on the lower limbs, and the bullous variant occurs is
seen chiefly on the arms (134-136). The pathergy phenomenon has been frequently described in
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PPG, in regard to the development of new lesions or worsening of pre-existing lesions after
different types of trauma, such as debridement, intradermal injections, vaccinations, or surgical
scars (134). This phenomenon is found in up to 50% of patients. Bullous or atypical pyoderma
gangrenosum is associated with an underlying hematological malignancy (acute myelogenous
leukemia, myelodysplasia, myeloproliferative disorders, non-Hodgkin lymphomas, and multiple
myeloma) in 7% of cases (136-141).
Histopathology
Histopathological findings of pyoderma gangrenosum in general are not specific,
encompassing areas with abscess, zones of neutrophilic and lymphocytic infiltrate, and moderate
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vasculitis with fibrinoid necrosis. In bullous PPG, which is more often associated with an
underlying malignancy, one sees diffuse neutrophilic dermal inflammation without vasculitis.
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Direct immunofluorescence studies may demonstrate positive perivascular labeling for C3, IgM,
IgA, or IgG (134).
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The principal differential diagnostic considerations in cases of PPG include infectious
cellulitis, leukocytoclastic vasculitis, and Sweet syndrome. Cultures and histochemical stains for
microorganisms are negative in PPG, and vasculitis is not expected in Sweet syndrome. The
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clinical presentation of pyoderma, especially the bullous variant, is quite dissimilar to that of
leukocytoclastic vasculitis.
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Paraneoplastic Cutaneous Vasculitis
Clinical Findings
In 1986, Longley et al. (142) suggested that malignant neoplasms might produce tumor-
related antigens that consequently cause paraneoplastic vasculitis. Concurrently, two criteria
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were advanced to establish the presence of a paraneoplastic vasculitis: first, the simultaneous
appearance of vasculitis and a neoplasm; and second, their parallel course. The pathogenetic
mechanisms for the development of paraneoplastic vasculitis remain unknown, but it appears to
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represent approximately 4% of all cases of cutaneous vasculitis in adults (143-152). Moreover, it

is not understood why there is a stronger association between vasculitis and hematologic
malignancies (e.g., myelodysplasia, leukemia, non-Hodgkin lymphoma) as compared with solid
tumors (such as carcinomas of the head and neck, breast, lung, and urinary bladder) (149,150).
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The most frequently-seen skin lesions are represented by palpable purpura, leg ulcers,
urticaria, and macular erythema. The cutaneous lesions are usually located on the legs. Fever,
general malaise, and arthralgias also may be present (142,145,149). Paraneoplastic vasculitis can
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remit after successful treatment of the underlying malignant tumor, but it otherwise persists
despite appropriate treatment of the skin lesions.
Histopathology
Skin biopsies show small-vessel neutrophilic vasculitis, with the variable presence of
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fibrinoid change in vessel walls (Figure 15). Extravasated erythrocytes are seen surrounding the
inflamed vessels, which may extend into the deep corium and subcutis. In florid cases,
epidermal microinfarction and necrosis may be apparent (153).
Microscopically, paraneoplastic cutaneous vasculitis shows no definable differences from
vasculitis that is unassociated with an underlying malignancy. However, the presence of
recalcitrant vasculitis in an elderly patient should prompt consideration of the possibility that it is
tumor-related.
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Part III: Conditions that are Linked to Anatomically-Diverse Malignancies
Superficial Thrombophlebitis
The association between superficial migratory thrombophlebitis and malignancy was first
described by Trousseau in 1865, and therefore it is sometimes referred to as Trousseau's
syndrome (154). Nodules or cords appear on the lower legs or elsewhere, conveying the
impression of "migration." Although an association with Behcet's or Buerger's diseases is
known, there is also often an association with an underlying cancer, particularly involving the
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pancreas, stomach, lung, prostate, or hematopoietic system (155). The hypercoagulable state
associated with these malignancies likely predisposes patients to the syndrome (156,157).
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Microscopically, a vein at the dermal-subcutaneous interface shows thrombosis, with an
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inflammatory infiltrate consisting mainly of neutrophils at first, followed by lymphocytes and
granulomatous elements. The infiltrates are concentrated in the immediate vicinity of the
involved vessel (156,157) (Figure 16). Although veins are traditionally distinguished from
arteries by the finding of an internal elastic lamina in the latter, veins can also possess an elastic
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lamina. A paper by Dalton et al. indicates that the smooth muscle pattern of the vessel wall may
be diagnostic: arteries have a circumferential smooth muscle pattern, while that in veins is more
haphazard and "cobblestoned" in appearance (158). In the absence of another explanation, biopsy
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changes of superficial thrombophlebitis should at least prompt the consideration of internal
malignancy, particularly carcinoma of the body or tail of the pancreas.
Hypertrichosis Lanuginosa (Malignant Down)

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Clinical Findings
This acquired condition consists of extensive growth of lanugo hairs that cover the face
and can progress to the neck, trunk, and extremities (159,160). Most reported patients have had a
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malignancy, usually carcinoma. These have included carcinomas of the lung, colon, gallbladder,
rectum, uterus, breast, endometrium, and prostate; lymphoma has also been reported (160-163).
In the majority of reported patients, the malignancy was known to be present when the lanugo
hair growth occurred, but
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in a few cases, hair growth preceded identification of the cancer. Resolution of the condition has
occasionally been reported to follow treatment of the underlying malignancy (161). The
pathogenesis of hypertrichosis lanuginosa is unclear, and an endocrinologic mechanism has not
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been discovered.
Histopathology
A histopathologic study by Hegedus and Schorr described the presence of mantle hair
follicles in hypertrichosis lanuginosa. The follicular mantle is a poorly recognized structure
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championed by Pinkus (163). It consists of cords of basaloid cells that extend downward around
the follicular infundibulum with a resemblance in tissue sections to a set of parentheses (Figure
17). They sometimes contain sebaceous cells and are believed to give rise to sebaceous glands.
Most reported cases of hypertrichosis lanuginosa have not included histopathologic descriptions,
so it remains to be seen if this is truly a characteristic finding of the disorder.
Mantle hair follicles can occasionally be seen as an incidental finding in biopsies done for
other reasons, so their identification does not "make" a diagnosis of hypertrichosis lanuginosa.
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The condition is so striking clinically that the diagnosis is often made without resorting to
histopathology. However, the pathologist might be called upon to support the diagnosis, which
could be accomplished by finding increased numbers of lanugo hairs per unit area (best
accomplished with horizontal sectioning of a biopsy specimen), together with the detection of
mantle hair follicles (best identified in vertically oriented sections).
Tripe Palms
Clinical Findings
"Tripe palms" represents a form of acquired palmar keratoderma in which the palms take
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on what is most commonly described as a rugose (wrinkled) appearance, resembling the luminal
surface of the small bowel. It is sometimes observed together with acanthosis nigricans or the
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sign of Leser-Trelat (164-167), but it can also appear as an isolated finding. Despite some earlier
literature contaminated with cases of acanthosis nigricans and keratoderma not necessarily
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featuring the typical "tripe palm" appearance, the evidence suggests that tripe palms constitute an
independent sign of internal malignancy. Carcinomas of the lung and stomach appear to be the
most common (166).
Histopathology
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Little has been written about the histopathology of tripe palms. In some instances, only
"hyperkeratosis" has been emphasized (168). However, a study by Requena et al. demonstrated
an undulant (wavy) epidermis featuring hyperkeratosis, papillomatosis, and acanthosis (169).
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Additional histopathologic studies will be necessary to determine if the changes that have
been described are specific for the diagnosis of tripe palms. It certainly seems likely that there
would be considerable overlap with other forms of palmar keratoderma, most of which are not
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associated with malignancy. However, an appreciation of undulation of the epidermis could be

diagnostically useful.
Proper evaluation of this feature would require sufficient sampling to enable inspection of a
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reasonable stretch of epidermis, and it might also be dependent upon the orientation of the
specimen (i.e., whether parallel or perpendicular to the surface undulation). Again, clinical
correlation would be decisive in most cases.
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The Sign of Leser-Trelat

Clinical Findings
The sign of Leser-Trelat consists of the rapid increase in the number and/or size of
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seborrheic keratoses, particularly on the trunk, in association with an internal malignancy.

Inflammation of seborrheic keratoses may be a part of this process (170), and it is conceivable
that a host inflammatory response directed toward existing but subtle seborrheic keratoses could
account for the "rapid increase" of lesions seen in some cases. Since multiple seborrheic
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keratoses are prevalent, among older adults,

and rapidity of onset may be questionable in any given case, a determination that the sign is
present may be problematic. In addition, purists do not accept the development of multiple
keratoses in the setting of erythroderma, even if that erythroderma is a manifestation of
cutaneous T-cell lymphoma, i.e., Sezary syndrome. As mentioned previously, coexistence of this
sign with acanthosis nigricans has been reported.
The malignancies associated 'with the sign of Leser-Trelat include gastrointestinal or
pancreatic carcinomas and lymphomas (171-174). The eruption of seborrheic keratoses can
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precede recognition of the cancer, or it can follow or develop concurrently (174). The seborrheic
keratoses may resolve following treatment of the primary tumor. A role for growth factors in the
production of these lesions has been suggested, including epidermal growth factor and TGF-a
(175).
Histopathology
The microscopic findings have differed somewhat from case to case, ranging from typical
seborrheic keratoses to foci of hyperkeratosis with variable degrees of papillomatosis (174,176)
(Figure 18). Inflammation may be an integral part of the development of Leser-Trelat seborrheic
keratoses, at least in some cases.
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Unfortunately, seborrheic keratoses, including inflamed seborrheic keratoses, are quite
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common, and this histopathologic finding by itself is not diagnostic of the sign. However, in the
context of rapidly eruptive seborrheic keratoses (particularly if other changes, such as acanthosis.
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nigricans or tripe palms, are also present), the microscopic features can be supportive of the
diagnosis of the sign of Leser-Trelat.
Erythema Gyratum Repens

Clinical Findings
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Erythema gyratum repens is surely one of the most dramatic clinical presentations in all
of dermatology. In this condition, arcuate erythematous bands, sometimes with a trailing edge of
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scale, migrate over the skin surface. In some cases, this produces intricate patterns resembling
the grain of wood (177-183). Involvement is concentrated over the trunk and proximal
extremities. This condition has a strong association with cancers, including those in the lung,
breast, and other anatomic sites (179,181,183). However, though they are most strongly
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associated with malignancy, the same changes have accompanied nonneoplastic conditions such
as cystic hypertrophy of the breast and pulmonary tuberculosis, and they have rarely arisen in
apparently normal individuals. When linked with malignancy, the cutaneous eruption may arise
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either before or after the detection of the tumor.

Histopathology
The microscopic findings include foci of parakeratosis and spongiosis and a moderately
intense, perivascular infiltrate concentrated around vessels of the superficial to mid-dermis,
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comprised of lymphocytes and macrophages (180,181) (Figure 19). The infiltrates may rarely be
more diffuse or contain eosinophils (180). On direct immunofluorescence, granular IgG and C3
deposition can be seen along the dermal-epidermal junction (184), the significance of which is
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not entirely clear.

The histopathologic image of this entity is non-specific. Basically, a diagnosis of
erythema gyratum repens depends upon the clinical presentation, which, as mentioned, is usually
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quite striking. However, the microscopic findings can be supportive of the diagnosis. The
combination of focal parakeratosis, spongiosis, and a superficial perivascular lymphocytic and
macrophagic infiltrate can also be seen in the superficial variant of erythema annulare
centrifugum (EAC), another less complex annular eruption that is not usually associated with
internal cancer. It is interesting to note that in some case reports, erythema gyratum repens has
begun as a more localized annular erythema with the clinical features of EAC.
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Multicentric Reticulohistiocytosis
Clinical Findings
This uncommon histiocytic proliferative disorder is associated with a widespread
papulonodular eruption and a severe arthritis, involving particularly the interphalangeal joints of
the hands. Malignancies have been reported in up to 25% to 30% of cases (185-189). There have
been a variety of types, including mesotheliomas and carcinomas of various organs (186).
Histopathology
Microscopically, the cutaneous lesions show a dermal infiltrate of mononuclear and
multinucleated cells with eosinophilic "ground glass" cytoplasm and nuclei with distinct
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chromatin rims and prominent nucleoli (Figure 20). These cells express macrophage markers
such as CD68 and CD163, and are sometimes factor XIIIa positive (190). Spontaneous
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regression may occur after a period of years, though residual damage to joints may persist.
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Other Skin Lesions Related to Visceral Malignancies—The Genodermatoses
The genodermatoses are inherited syndromes that feature the presence of various
cutaneous marker lesions. They include Gardner’s syndrome, in which unique epidermal
inclusion cysts and soft tissue fibromas are associated with gastrointestinal carcinomas
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(191,192); Cowden syndrome, featuring the presence of trichilemmomas and sclerotic cutaneous
fibromas together with malignant tumors of various organs (193,194); Muir-Torre syndrome, in
which multiple sebaceous skin tumors or “keratoacanthomas” are linked to malignancies of the
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alimentary or genitourinary tracts (195,196); and Birt-Hogg-Dube’ syndrome, a disorder that
shows an association between cutaneous fibrofolliculomas and various visceral malignant
neoplasms (197,198). Because these conditions are not truly paraneoplastic, but are rather
genetically-driven multisystem diseases, they have not been considered in this discussion.
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186. El-Haddad B, Hammoud D, Shaver T, Shahouri S. Malignancy-associated

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Table 1: Cutaneous Paraneoplastic Syndromes—Associations with Visceral Malignancies
Conditions that are Usually Linked to Malignant Neoplasms of the Alimentary Tract
-Acanthosis nigricans
-Acrodermatitis paraneoplastica (Bazex syndrome)
-Florid cutaneous papillomatosis
-Necrolytic migratory erythema (glucagonoma syndrome)
-Palmoplantar keratoderma
-Pancreatic fat necrosis
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-Pityriasis rotunda
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Conditions that are Usually Linked to Hematolymphoid Malignancies
-Acquired ichthyosis
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-Exfoliative erythroderma
-Necrobiotic xanthogranuloma
-Paraneoplastic pemphigus
-Plane xanthoma
-Pyoderma gangrenosum
-Scleromyxedema US
-Sweet syndrome (aseptic neutrophilic dermatosis)
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-Vasculitis
Conditions that are Linked to Anatomically Diverse Malignancies

-Birt-Hogg-Dube syndrome (Renal cell carcinomas]
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-Cowden syndrome (Thyroid, genitourinary, gastrointestinal, & breast carcinomas]

-Dermatomyositis [Ovarian, lung, breast, & gastrointestinal carcinomas]
-Erythema gyratum repens [Lung, esophageal, & breast carcinomas]
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-Gardner syndrome [Thyroid & gastrointestinal carcinomas]

-Hypertrichosis lanuginosa acquisita [Gastrointestinal, lung, & breast carcinomas]
-Leser-Trelat syndrome (eruptive seborrheic keratoses) [Gastrointestinal tumors & -
hematolymphoid malignancies]
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-Multicentric reticulohistiocytosis [Hematolymphoid malignancies; breast &

genitourinary carcinomas]
-Muir Torre syndrome [Gastrointestinal & genitourinary carcinomas]
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-Papuloerythroderma of Ofuji [Hematolymphoid malignancies; hepatic & gastrointestinal

carcinomas]
-Superficial thrombophlebitis (Trousseau syndrome) [Pancreatic, gastric, & lung
carcinomas]
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-Tripe palms [Lung & gastric carcinomas]

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Figure Legends
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Figure 1. Necrolytic migratory erythema. This patient with a pancreatic glucagonoma has erythematous,
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crusted erosions on the extremities (left panel). Microscopically, they are typified by confluent
parakeratosis over an attenuated epidermis with superficial cytoplasmic pallor (right panels).
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Figure 2. Bazex syndrome. Well-demarcated, violaceous, eczematoid lesions are seen on the distal
extremities (left panel). Microscopically, they have the appearance of subacute or chronic spongiotic
dermatitis (right panel).
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Figure 3. Acanthosis nigricans. Pigmented, velvety plaques are seen on the posterior neck (left panel).
Histologically, epidermal papillomatosis is present with hyperkeratosis and slight basilar
hyperpigmentation (right panel).
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Figure 4. Florid papillomatosis. Numerous and confluent squamous papillomas are present in the skin of
the upper legs (left panel). Microscopically, epidermal papilomatosis is accompanied by orthokeratosis,
scant dermal chronic inflammation, and an attenuated granular layer (right panel).
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Figure 5. Tylosis (palmoplantar keratoderma). Dense hyperkeratosis is present on the weight-bearing
portions of the soles (left panel). Microscopically, the lesions show marked orthokeratosis,
hypergranulosis, and acanthosis (right panel).
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Figure 6. Paraneoplastic pemphigus. Erosive lesions of the oral mucosa and perioral skin are similar to
those of erythema multiforme (left panel). Microscopically, basal epidermal vacuolization is apparent
with keratinocyte apoptosis, as well as suprabasilar acantholysis (top right panel). Direct
immunofluorescence studies show circumferential labeling of keratinocytes and linear labeling of the
epidermal basement membrane for IgG (bottom right panel).
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Figure 7. Ofuij’s papuloerythroderma. Generalized erythema is present with sparing of the flexural folds
(the “deck-chair” sign) (left panel). Histologically, the lesions have a resemblance to those of
eczematoid dermatitis (right panel).
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Figure 8. Exfoliative erythrodermatitis. Diffuse erythrodema is present, with numerous crusted plaques
(left panel). The microscopic image is again that of spongiotic dermatitis (right panel).
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Figure 9. Dermatomyositis. Confluent erythematous papules and plaques are present over the doral
hands (top left panel) and in the periocular skin (bottom left panel). A skin biopsy shows epidermal
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atrophy, basal vacuolization, interface dermatitis, and pigment incontinence (top right panel). A striated
muscle biopsy demonstrates numerous infiltrates of lymphocytes (bottom right panel).
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Figure 10. Normolipemic (plane) xanthoma. Diffuse yellow-orange discoloration of the facial skin is
present (left panel), represented by diffuse infiltration of the dermis by markedly xanthomatized
histiocytes (right panel).
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Figure 11. Acquired ichthyosis. Plate-like scales are present over the forearm, resembling the
appearance of a fish (left panel). Compact orthokeratosis with attenuation of the epidermal granular
layer is seen histologically (right panel).
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Figure 12. Necrobiotic xanthogranuloma. Indurated, coalescent brown-red plaques are present in the
facial skin (left panel). Histologically, marked necrobiosis is seen in the corium, with infiltrates of
epithelioid, multinucleated, and xanthomatized histiocytes with polarized nuclei (right panels).
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Figure 13. Scleromyxedema paraneoplastica. Confluent papules and nodules are present in the upper
facial skin, with prominent involvement of the nose (left upper panel). Dermal hypercellularity (top right
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panel) with a random proliferation of fibroblasts (bottom left panel) and mucin deposition (bottom right
panel—colloidal iron stain) are seen.
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Figure 14. Sweet syndrome. Red-brown plaques and nodules are present in the pretibial skin (left
panel). Diffuse dermal neutrophilia is apparent (top right panel) with karryorrhexis (bottom right panel).
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Figure 15. Leukocytoclastic small-vessel vasculitis. Palpable purpuric lesions are present in the skin of
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the lower legs (left panel). Destructive intravascular infiltrates of neutrophils are present in the dermis,
with erythrocyte extravasation and karryorrhexis (right panel).
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Figure 16. Trousseau syndrome. Erythematous, firm cords are present in the skin of the forearm,
representing superficial thrombophlebitis (left panel). Transmural and perivascular infiltration of
superficial veins by neutrophils is present histologically (right panel).
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Figure 17. Hypertrichosis lanuginosa acquisita. A profuse growth of lanugo hair is seen in the periocular
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facial skin (left panel). A skin biopsy of this condition shows numerous small hair follicles with the
appearance of “mantle” hairs (right panel)
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Figure 18. Leser-Trelat syndrome. Numerous, eruptive seborrheic keratoses are present in the skin of
the trunk (left panel). The lesions comprise interlocking cords and nests of cytologically-bland
keratinocytes, with pigmentation and formation of squamous “horn cysts” (right panel).
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Figure 19. Erythema gyratum repens. Arcuate erythematous bands are seen on the trunk, resembling
wood grain (left panel). Dense superficial and deep perivascular lymphoid infiltrates are present
microscopically (right panel).
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Figure 20. Multicentric reticulohistiocytosis. Several nodules are present in the juxtaarticular skin of the
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hands (left), with deformative arthritis. The dermis contains a confluent infiltrate of large polygonal
histiocytes with “glassy” cytoplasm (right panels).

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CUTANEOUS PARANEOPLASTIC SYNDROMES

Mark R. Wick M.D. , James W. Patterson M.D.

To appear in: Seminars in Diagnostic Pathology

For inclusion in Seminars in Diagnostic Pathology:

From PRW Laboratories, Charlottesville, VA.

22901 (Telephone 434-242-2410; E-mail-- [email protected])

Wick & Patterson Page 2

A variety of cutaneous abnormalities can be seen in patients with malignant diseases,

Wick & Patterson Page 3

underlying tumor and correction of nutritional deficiencies. There appears to be no clear

play a part (2,6,7).

Wick & Patterson Page 4

Acrokeratosis Paraneoplastica (Bazex Syndrome)

accompanies a group of endocrinologic disorders, particularly those associated with insulin

Wick & Patterson Page 5

Florid Papillomatosis (FP; Schwartz-Burgess Syndrome)

Wick & Patterson Page 6

Specificity of Findings & Differential Diagnosis

Pancreatic Panniculitis (PP)

Wick & Patterson Page 7

Tylosis (Palmoplantar Keratoderma)

Part II: Conditions that are Usually Linked to Hematolympoid Malignancies

Paraneoplastic pemphigus has a strong association with lymphoproliferative disorders, including

Wick & Patterson Page 8

cell lymphoma, particularly cutaneous T-cell lymphoma (73,74). Nonepidermotropic peripheral

Wick & Patterson Page 9

Specificity of Findings and Differential Diagnosis

Exfoliative Dermatitis with Erythroderma

also been encountered, including lymphomas, melanoma, and sarcomas.

Wick & Patterson Page 10

Pautrier microabscesses, possibly with an abnormal immunophenotype or positive T-cell

Diffuse (Normolipemic) Plane Xanthoma

Microscopic findings include clusters of foamy macrophages scattered throughout the

Wick & Patterson Page 11

accompany biliary cirrhosis. Cases showing foci of degenerate connective tissue or

Wick & Patterson Page 12

The mucous membranes are spared. US

macroglobulinemia, and myelomonocytic leukemia, or visceral carcinomas have been reported

Scleromyxedema features the presence of a triad of microscopic features that includes

Wick & Patterson Page 13

Sweet's Syndrome (Acute Febrile Neutrophilic Dermatosis)

diagnosis would be warranted. A “histiocytoid” variant of SS is, in fact, caused by dermal

resemblance to SS microscopically, but in the authors' experience, it shows deep as well as

always prompt an investigation for possible underlying leukemia.

Paraneoplastic Pyoderma Gangrenosum (PPG)

Wick & Patterson Page 14

represent approximately 4% of all cases of cutaneous vasculitis in adults (143-152). Moreover, it

Wick & Patterson Page 15

Part III: Conditions that are Linked to Anatomically-Diverse Malignancies

Hypertrichosis Lanuginosa (Malignant Down)

Wick & Patterson Page 16

associated with malignancy. However, an appreciation of undulation of the epidermis could be

The Sign of Leser-Trelat

seborrheic keratoses, particularly on the trunk, in association with an internal malignancy.

keratoses are prevalent, among older adults,

Wick & Patterson Page 17

Erythema Gyratum Repens

either before or after the detection of the tumor.