Diagnosis and treatment or paraneoplastic disorders

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Dermatologic Therapy, Vol. 23, 2010, 662–675
Printed in the United States · All rights reserved
© 2010 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY
ISSN 1396-0296
Diagnosis and treatment
of cutaneous
paraneoplastic disorders
dth_1371
662..675
Ana Maria Abreu Velez & Michael S. Howard
Georgia Dermatopathology Associates, Atlanta, Georgia
ABSTRACT: The skin plays a critical role in the detection of internal malignances. Cutaneous signs of
these disorders afford clinicians opportunities for early diagnosis and treatment. We aim to succinctly
review the recognition, diagnosis, and treatment of selected cutaneous paraneoplastic diseases. Skin
disorders that may be associated with paraneoplastic syndromes include: cutaneous metastases, tripe
palms, Sweet’s syndrome, glucagonoma, Paget’s disease and extramammary Paget’s disease, acanthosis nigricans, Birt-Hogg-Dube syndrome, basal cell nevus syndrome, Bazex syndrome (acrokeratosis
paraneoplastica), carcinoid syndrome, Cowden’s disease(multiple hamartoma syndrome), dermatomyositis, erythema gyratum repens, ichthyosis aquisita, von Recklinghausen’s disease, pityriasis
rotunda, pyoderma gangrenosum, Quincke’s edema (angioedema and paraneoplastic uricaria), paraneoplastic pemphigus, Degos’ disease, superior vena cava syndrome, Werner’s syndrome, diffuse normolipemic plane xanthomas, and yellow nail syndrome. Treatment for these disorders depends on the
nature and anatomic distribution of the primary neoplastic process.
KEYWORDS: paraneoplastic disorders, skin manifestations
Introduction
A broad range of cutaneous signs may be related to
internal malignancy. Cancer may manifest in the
skin as direct metastases (e.g., leukemia cutis, cutaneous T cell lymphoma, mammary Paget’s disease)
or as diverse dermatologic entities called paraneoplastic syndromes, which signal that a remote
malignancy is present (1–7). Cutaneous manifestations may develop before a diagnosis of malignancy is determined; thus, these findings may aid
the dermatology and dermatopathology community in attaining an early identification of malignancy. In general, it has been accepted that a
paraneoplastic syndrome may be defined when (i)
the malignancy and syndrome appear simultaAddress correspondence and reprint requests to: Ana Maria
Abreu-Velez, MD, PhD, Georgia Dermatopathology Associates,
1534 North Decatur Road, NE; Suite 206, Atlanta, GA
30307-1000, or email: [email protected]
Conflict of interest: None.
662
neously; and (ii), their clinical courses do not significantly differ (1–7). Furthermore, it has been
proposed that, ideally, (iii) remote cutaneous
manifestations should be specific to the tumor
causing them. It also has been suggested that (iv)
paraneoplastic syndromes should be uncommon
relative to the prevalence of the neoplastic process
(1–7). Finally, (v) the skin manifestations and the
malignant neoplasm should be demonstrably and
directly associated (1–7). Of note, internal malignancies are often difficult to detect, and they may
exert subtle physiologic influences without their
diagnosis being established. Finally, the study of
these syndromes has contributed greatly to our
understanding of the effects of internal malignancy
biology upon the skin.
Cutaneous metastases
Cutaneous metastases are rare, and the reported
prevalence varies from 0.7% to 10% of all patients
Paraneoplastic skin disorders
with malignant neoplastic diseases (1,2). Any
malignant neoplasm can metastasize to the skin.
Cutaneous metastases from cancers of the lung,
large intestine, and kidney are most prevalent in
men; cancers of the breast and large intestine are
most prevalent in women (1,2). Metastases to the
skin are typically flesh-colored to violaceous
nodules that often present anatomically close to the
primary neoplasm; the most common sites for their
presentation are the scalp, neck, and trunk (1,2).
Differential diagnoses for a cutaneous metastasis
include pilar (trichilemmal) or epidermal inclusion
cysts, adnexal tumors, neurofibromas, and lipomas.
Cutaneous metastases from the lung are frequently
moderately or poorly differentiated. In fact, undifferentiated cutaneous metastases most often originate from the lung in men, from the breast in
women, and from noncutaneous primary malignant melanoma (1–7). They typically invade the
lymphovascular system and are typically histologically limited to the dermis and subcutaneous
tissues. The most common tumor histologic
subtype is adenocarcinoma (ACC), followed by
squamous cell carcinoma (SCC), small cell carcinoma, and large cell carcinoma (LCC) (1–7). Some
studies indicate ACC to have the highest incidence
and LCC to have the lowest incidence. However, two
Japanese studies found LCC to have the highest
incidence, displaying about 10% of LCCs of the lung
metastasizing to the skin (1–7). Other types of lung
cancer that rarely metastasize to the skin include
mesothelioma, bronchial carcinoids, bronchiolar
carcinoma, mucoepidermoid carcinoma, pulmonary sarcoma, intravascular bronchioalveolar
tumor, well-differentiated fetal ACC, pleural epithelioid hemangioendothelioma, and adenoid cystic
carcinoma (1–7). Metastatic ACCs from the lung are
usually moderately differentiated. They sometimes
show well-differentiated glandular structures or
intracytoplasmic mucin. In these cases, gastrointestinal, ovarian, kidney, and breast primaries
should be ruled out. Metastatic squamous cell carcinomas from the lung are often moderately or
poorly differentiated. In these cases, upper GI
primaries should be ruled out (1–7). Small-cell carcinomas are generally anaplastic and have hyperchromatic nuclei with minimal cytoplasm. Clinical
information, immunohistochemistry (IHC), and
electron microscopy for dense core granules can
help distinguish small cell pulmonary carcinoma
from other histologically similar cancers. Mesotheliomas most often metastasize to the skin by direct
invasion or by traumatic seeding; however, they
may rarely metastasize to distant sites (1–7). These
tumors may resemble angioendotheliomatous
malignancies. In some cases, mesothelioma may
require electron microscopy to differentiate its
diagnosis vis-a-vis ACC. Cutaneous bronchial carcinoid metastases classically display a histologic
trabecular pattern. An additional clue in diagnosing
these patients may be the presence of a clinical
carcinoid syndrome (1–7). Treatment for these disorders depends upon successful identification and
therapy for the primary neoplastic process. Paget’s
disease and extramammary Paget’s disease can also
produce skin metastases (8,9).
Glucagonoma syndrome
Glucagonoma syndrome is elicited by a glucagonsecreting tumor, and may be clinically associated
with hyperglucagonemia, necrolytic migratory
erythema (NME), recent onset of diabetes mellitus,
anemia, weight loss, and diarrhea. The NME is
widespread, with predilection for the perineum,
abdomen, groin, buttocks, and lower extremities
(10–18). Frequently, these areas may be dry or fissured as a result (10–18). The eruption begins with
uneven patches of intense erythema, superficial
flaccid vesicles, and bullae that later rupture and
create extensive erosions or exudative, crusted
plaques. Other mucocutaneous findings are cheilosis, atrophic glossitis, oral mucosal inflammation,
and alopecia (10–18). All stages of lesion development may be observed simultaneously. The initial
eruption may be exacerbated by pressure or trauma
to the affected areas. Almost all patients with NME
have a pancreatic alpha cell tumor, and elevated
glucagon levels. In approximately one-half of
patients, there are alpha cell tumor liver metastases
at the time of diagnosis (10–18). The histopathologic features of NME are nonspecific and include:
epidermal necrosis, subcorneal pustules, confluent
parakeratosis, epidermal hyperplasia, marked papillary dermal hyperplasia in a psoriasiform pattern,
angioplasia of the papillary dermis, and suppurative folliculitis. Histologically, vacuolated, pale,
swollen epidermal cells with necrosis of the superficial epidermis are most characteristic (10–18).
Immunofluorescence studies are classically negative. The pathogenesis of NME is unknown,
although various mechanisms have been suggested. These include hyperglucagonemia, zinc
deficiency, fatty acid deficiency, hypoaminoacidemia, and liver disease (10–18). Associated conditions were first outlined in 1942; since then, NME
has been described in as many as 70% of individuals
with a glucagonoma. NME is further considered an
integral part of the “glucagonoma syndrome,”
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Abreu Velez & Howard
which includes hyperglucagonemia, diabetes mellitus, and hypoaminoacidemia (10–18). When NME
is identified in the absence of a glucagonoma, it
may be considered part of a “pseudoglucagonoma
syndrome”(10–18). Pseudoglucagonoma syndrome
is less common than glucagonoma syndrome and
may occur in a number of systemic disorders such
Celiac disease, ulcerative colitis, Crohn’s disease,
hepatic cirrhosis, hepatocellular carcinoma, lung
cancer(including small cell lung cancer), tumors
that secrete insulin or insulin-like growth factor 2,
and duodenal carcinoma. With complete resection
of the underlying tumor, the NME cutaneous manifestations classically resolve rapidly (10–18).
Birt-Hogg-Dube syndrome
Birt-Hogg-Dube (BHD) syndrome, initially
described in 1977, is a genodermatosis characterized by the development of small, dome-shaped
papules on the face, neck, and upper trunk (19–22).
It has been associated with renal neoplasms, renal
and pulmonary cysts, and benign tumors of the hair
follicles. The disorder has been reported in more
than 100 families worldwide, and it is inherited in an
autosomal dominant pattern. The pattern of mutations and spectrum of symptoms are heterogeneous between individuals. BHD syndrome affects
the skin, and increases the risk of certain types of
tumors. The BHD tumors classically first appear in a
person’s 20s or 30s (19–22). People with BHD syndrome also have an increased risk of developing
benign or malignant renal neoplasms (oncocytoma
and chromophobe renal cell carcinoma, respectively) and possible tumors in other organs and
tissues. Additionally, affected individuals frequently
develop cysts in the lungs, which may in turn
rupture and cause pneumothoraces and pulmonary collapse. Mutations in the FLCN gene, located
on the short arm of chromosome 17 (17p11.2),
cause BHD syndrome (19–22). These mutations are
often passed in an autosomal dominant fashion,
but can occur as new mutations in an individual
with no prior family history of the disorder. The
FLCN gene produces a protein called folliculin. The
normal function of this protein is still being investigated, but it appears to act as a tumor suppressor.
Tumor suppressors normally prevent cells from
growing and dividing in an uncontrolled manner.
Thus, mutations in the FLCN gene may interfere
with the ability of folliculin to restrain cell growth
and division, leading to the formation of benign and
malignant tumors. Recent studies suggest that folliculin accomplishes its function through interac-
664
tion with the mTOR pathway (19–22). People with
BHD are born with one mutated copy of the FLCN
gene in each cell. During their lifetime, random
mutations might inactivate the normal copy of the
gene in a subset of cells. When this occurs, the result
is that these cells have no functional copies of the
FLCN gene, allowing the cells to divide uncontrollably and form tumors (19–22). Such a loss of heterozygosity is a common mechanism in cancer
tumorigenesis and is frequently detected in the
renal malignancies associated with BHD. The BHD
syndrome may be diagnosed by clinical findings
and/or molecular genetic testing to detect mutations in the FLCN gene. The classical clinical triad
includes: (i) benign growths of the hair follicles, (ii)
pulmonary cysts and/or spontaneous pneumothorax, and (iii) bilateral, multifocal renal tumors (19–
22). First, the cutaneous manifestations of BHD
were originally described as fibrofolliculomas
(abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at
the periphery, often found on the face), and acrochordons (skin tags). The dermatologic diagnosis of
BHD can be made in an individual five or more skin
lesions, at least one of which must be confirmed as
a fibrofolliculoma by histology. Second, most individuals (89%) with BHD are found to have multiple
cysts in both lungs, and 24% have had one or more
episodes of spontaneous pneumothorax. The cysts
can be detected by chest computed tomography
(CT) scan. Finally, BHD renal tumors may represent
multiple histologic types, but certain subtypes
(including chromophobe tumors, oncocytoma, and
oncocytic hybrid tumors) are more commonly
encountered (19–22). Although the original syndrome was discovered and defined beginning with
cutaneous findings, it is now recognized that individuals with BHD may only manifest the pulmonary
and/or renal findings, without any skin lesions.
Some genetic studies testing for FLCN mutations
have detected mutations in 88% of probands with
BHD (19–22). Thus, either some people with a clinical diagnosis of BHD have mutations that are not
detectable by current technology or mutations
in another (currently undefined) gene could be
responsible for a minority of BHD cases. Genetic
testing can be useful in confirming the clinical diagnosis of BHD, and in providing a means of detecting
other individuals at risk in a family (19–22).
Basal cell nevus syndrome
Basal cell nevus syndrome (BCNS) is a rare autosomal dominant disorder characterized by multiple
Paraneoplastic skin disorders
basal cell carcinomas of the skin, odontogenic keratocysts of the jaws, and a variety of skeletal anomalies. The syndrome represents the consequence of
abnormalities in the PTCH gene. The syndrome has
been documented for 50 years, but more recent
developments in molecular genetics have dramatically increased understanding of its pathophysiology. Other manifestations are palmoplantar pits,
atypical facies (broad nasal root, frontal bossing,
and hypertelorism), epidermal inclusion cysts,
intracranial calcifications, developmental malformations, and a predisposition to other benign and
malignant tumors (23–29). Patients with BCNS have
an elevated risk of developing medulloblastoma at
young ages, with approximately 5% developing this
tumor in the first years of life. BCNS has also been
associated with meningiomas, and in anecdotic
case reports with ovarian cancer, salivary gland
carcinoma, non-Hodgkin’s lymphoma, and nasopharyngeal rhabdomyosarcoma (23–29). Abnormalities of the skin, the skeletal system, the
genitourinary system, and the central nervous
system (CNS) are most common. A variety of less
common neoplasms are also associated with BCNS.
The prevalence is reported to be approximately one
case per 56,000–164,000 population. The prevalence is likely to be considerably higher in individuals younger than 20 years of age. Disease morbidity
and premature mortality are primarily related to
the development of skin cancers, as well as other
tumors associated with the syndrome. Actual mortality rates are unavailable; morbidity from multiple
skin cancers and their treatment may be severe (23–
29). The syndrome is found in all races. However, a
finite but smaller percentage of African Americans
present with skin cancer (and have fewer skin
cancers) relative to whites who are affected. The
decreased number of skin cancers, a diagnostic
hallmark, may account for the comparatively fewer
African Americans documented in reviews of the
syndrome (23–29). However, full expression of the
non-skin cancer features of the syndrome is found
in African Americans. Men and women are affected
similarly by BCNS. The male-to-female ratio is estimated to be 1 : 1.3. The disease is present (inherited) at birth, and most commonly manifests itself
with either basal cell carcinomas (BCC)s (usually
multiple) occurring at a young age (i.e., third decade
or earlier) or odontogenic keratocysts presenting in
the second or third decade (23–29). Other incidental
findings, such as cleft lip, or asymptomatic findings
such as hypertelorism, may be noticed earlier, but
these features may not lead to the diagnosis until
the development of more specific findings. Selected
findings seen in the syndrome, such as jaw cysts,
BCCs, calcification of the falx cerebri, and ovarian
fibromas, manifest with increasing age in the
affected individual. As previously noted, some
findings may present early in childhood. Medulloblastoma, although a relatively uncommon manifestation of BCNS, is a tumor of early childhood.
Radiologic abnormalities, such as bifid ribs, or
asymptomatic findings, such as palmar pits, may be
present at a higher frequency in BCNS in childhood;
these findings may be helpful in making an early
diagnosis (23–29). Many of the features of this syndrome present as signs rather than symptoms.
Symptoms are often related to the following major
findings. Cutaneous symptoms may be reported
due to local invasion of an aggressive BCC, leading
to pain. Metastases are extremely rare. Neurologic
symptoms may be reported due to medulloblastoma. Genitourinary symptoms may be reported
due to ovarian fibromas; these lesions are classically
asymptomatic, but may cause pain secondary to
torsion. Dental symptoms may be reported due to
odontogenic keratocysts (also called keratocystic
odontogenic tumors), manifesting as jaw pain due
to abnormal dentition. Despite the recent understanding of the underlying genetic basis of BCNS,
the diagnosis remains largely clinical. Kimonis et al.
have suggested the following diagnostic criteria to
help the clinician. Although not absolute, these criteria help guide the clinician in choosing laboratory
evaluations for both diagnostic purposes and
ongoing surveillance (23–29). Clinicians must
remember that some of the findings listed may
present at different ages; therefore, ongoing surveillance with respect to diagnosis may be needed.
Diagnosis of this syndrome is made in the presence
of two major criteria, or one major and two minor
criteria. The major criteria consist of the following:
(i) more than two BCCs or one BCC in patients
younger than 20 years, (ii) odontogenic keratocysts
of the jaw (proven by histologic analysis), (iii) three
or more palmar or plantar pits, (iv) bilamellar calcification of the falx cerebri, (v) bifid, fused, or markedly splayed ribs, and (vi) any first-degree relative
with this syndrome. The minor criteria include the
following: (i) macrocephaly, (ii) congenital facial
malformations, such as cleft lip or palate, frontal
bossing, coarse facies, and moderate or severe
hypertelorism, (iii) other skeletal abnormalities,
such as a sprengel deformity, marked pectus deformity, or marked syndactyly of the digits, (iv) radiologic abnormalities, such as bridging of the sella
turcica, vertebral anomalies, modeling defects of
the hands and feet, or flame-shaped lucencies of the
hands and the feet, and (v) ovarian fibroma or
medulloblastoma (23–29).
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Bazex syndrome (acrokeratosis
paraneoplastica) or acrokeratosis
neoplastica
Bazex syndrome is a rare, acral psoriasiform dermatosis associated with internal malignancies, most
frequently SCC of the upper aerodigestive tract (30–
34). The syndrome typically precedes the diagnosis
of malignancy. The term Bazex syndrome describes
two concurrent entities, both described by Bazex
and colleagues: (i) acrokeratosis neoplastica (AN)
and (ii) the genetic syndrome of basal cell carcinomas, follicular atrophoderma, hypotrichosis, and
disorders of sweating (30–34). Bazex syndrome is
characterized by violaceous erythema and scaling
of the hands, feet, nose, auricular helices, and scalp.
In advanced stages, the elbows, knees, and cheeks
may be involved, and nail dystrophy may also be
present. Bazex syndrome is always associated with
an underlying neoplasm. As noted, the most commonly associated malignancies are SCCs of the
head and neck (30–34). Bazex syndrome has also
been associated with GI tract and pulmonary carcinomas. In 63% of cases, skin lesions precede the
diagnosis of the tumor by approximately 1 year.
Paraneoplastic acrokeratosis generally responds
to successful treatment of the underlying tumor,
and fails to improve when the neoplasm persists
(30–34). The pathophysiology of AN is not well
understood. Proposed mechanisms include crossreactivity between skin and tumor antigens, the
actions of tumor-produced growth factors, and
even zinc deficiency. Approximately 140 cases have
been reported in the literature. In one review, only
12 of 140 cases were in women. Patients present
with asymptomatic, acrally located psoriasiform, or
hyperpigmented lesions (30–34). The lesions are
treatment resistant. As the tumor progresses, the
lesions of AN may spread and may involve the
cheeks, elbows, knees, and trunk. In one review,
when skin findings preceded the diagnosis of malignancy, they were present for an average of 1 year.
The physician should inquire regarding risk factors
for malignancy, including smoking habits, alcohol
consumption, and family history. Upon further
questioning, patients may admit to mild constitutional symptoms, weight loss, and other nonspecific findings of internal malignancy (30–34). In
summary, cutaneous manifestations of AN often
present as follows: symmetrical, acral, scaly, red-toviolaceous plaques or patches, with possible
involvement of the fingers, distal hands, feet, nose,
and helices of the ears: Isolated involvement of the
helices is particularly suggestive of AN. Involve-
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ment of the cheeks, trunk, elbows, knees, palms,
and soles in advanced disease are common. Nail
dystrophy and swelling of the digits with a blue-toviolet discoloration are common. Acrally distributed, hyperpigmented patches are possible in
persons with darker skin types, as well as bullae
of the hands and feet. Other physical examination
findings suggesting paraneoplasia include ichthyosis, pruritus, a sign of Leser-Trélat, clubbing, and
dermatomyositis (DM). A complete physical examination should thus be performed in all pertinent
patients. The physical examination should include
a thorough head and neck examination, including
endoscopic examination and pelvic examination in
women (30–34). Most AN cases are associated with
SCCs of the upper one-third of the respiratory or GI
tracts (i.e., oropharynx/larynx, lungs, or esophagus). Case reports also describe SCCs of the thymus,
vulva, and skin. Additional reported associated
tumors include poorly differentiated carcinoma,
ACCs of multiple primary sites, small cell carcinomas of the lung, malignant lymphomas, ductal
carcinomas of the breast, carcinoids, multiple
myeloma, transitional cell carcinomas of the
bladder, well-differentiated thymic carcinomas,
and cholangiocarcinomas (30–34).
Carcinoid syndrome
Carcinoid syndrome refers to an array of symptoms
that occur secondary to carcinoid tumors (35–38).
Carcinoid tumors are discrete, yellow, wellcircumscribed tumors that can occur anywhere
along the gastrointestinal tract, as well as in the
lung. They most commonly affect the appendix,
ileum, or rectum. Carcinoids are neuroendocrine
tumors that are characterized by production of
serotonin (5-hydroxytryptamine; 5-HT). Although
clinically rare (15 cases/1,000,000 population), carcinoid tumors account for 75% of gastrointestinal
endocrine tumors. Carcinoid syndrome often (75%
of patients) includes periodic flushing of the face
and trunk, with episodes lasting from 10 to 30
minutes. Associated with the flushing are dyspnea,
wheezing, abdominal pain with explosive diarrhea,
right-sided heart valvular changes, and hypotension (35,38). Carcinoid tumors represent 90% of
appendiceal tumors. Other documented sites of
carcinoid tumor include bronchi, ovary, pancreas,
and gallbladder. Classically, tumors from the GI
tract do not cause symptoms until they metastasize
to the liver, because an uninvolved, healthy liver
can detoxify the amines responsible for the symptoms. In contrast, carcinoid tumors originating in
Paraneoplastic skin disorders
locations other than the GI tract (such as ovary and
bronchi) can produce symptoms before they
metastasize. The carcinoid syndrome occurs in
approximately 10% of carcinoid tumor patients,
and manifests when vasoactive substances from
the tumor(s) enter the systemic circulation while
escaping hepatic degradation (35,38). The most
important clinical finding is the previously noted
flushing of the skin, usually of the head and upper
thorax. Secretory diarrhea and abdominal cramps
are also characteristic features of the syndrome.
When the diarrhea is intensive, it may lead to electrolyte disturbances and dehydration. Other associated symptoms are nausea and vomiting.
Bronchoconstriction affects a smaller number of
patients, and often accompanies flushing. About
50% of patients have cardiac abnormalities, caused
by serotonin-induced fibrosis of the tricuspid and
pulmonary valves. Elevated levels of circulating
serotonin have been associated with cardiac
failure, due to fibrous deposits on the endocardium. Clinically, “TIPS” is a pertinent acronym for
tricuspid insufficiency, and pulmonary stenosis
(due to fibrosis of tricuspid and pulmonary valves).
Abdominal pain is often due to desmoplastic reactions within the mesentery, and/or hepatic
metastases (35–38). Interestingly, it is commonly
but incorrectly thought that serotonin is the cause
of clinical flushing. The flushing results from
tumoral secretion of kallikrein, the enzyme that
catalyzes the conversion of kininogen to lysylbradykinin. The latter is further converted to
bradykinin, one of the most powerful vasodilators
known (35–38). Other components of the carcinoid
syndrome are a pellagra-like syndrome (probably
caused by diversion of large amounts of tryptophan from synthesis of vitamin B3 (niacin), to
the synthesis of pertinent 5-hydroxyindoles such as
serotonin), and uncommonly, bronchoconstriction. The pathogenesis of the cardiac lesions and
the bronchoconstriction are unknown, but the
former probably involves activation of serotonin
5-HT2B receptors by serotonin. In most patients,
there is also increased urinary excretion of 5-HIAA,
a degradation product of serotonin (35–38). The
diagnosis is often based on (i) the clinical history,
(ii) measurement of plasma levels of tumorally
secreted chromogranin A, and (iii) by measuring
24-hour urine levels of 5-HIAA. Patients with carcinoid syndrome usually excrete greater than 25 mg
of 5-HIAA per day. For localization of both primary
lesions and metastases, the initial imaging method
of choice is octreoscan, where 111Indium-labeled
somatostatin analogues are utilized in scintilography for detecting tumor-expressing somatostatin
receptors. Median detection rates with octreoscan
are about 89%, in contrast to other imaging techniques such as CT scans and magnetic resonance
imaging scans, both with detection rates of
approximately 80%. Usually on CT scan, one will
note a spider-like or crab-like change in the mesentery due to the fibrosis from the release of serotonin. Positron electron tomography scans (which
can evaluate for increased metabolism of glucose)
may also aid in localizing carcinoid tumor primary
lesions and/or for confirming metastases (35–38).
Cowden’s disease (multiple
hamartoma syndrome)
Cowden’s disease is an autosomal dominantly
inherited condition that results in hamartomatous
neoplasms of the skin, mucosa, GI tract, bones,
central nervous system, and genitourinary tract.
The hamartomas are small, benign growths that
are most commonly found on the skin and mucous
membranes. People with Cowden’s syndrome have
an increased risk of developing several types of
cancer, including malignancies of the breast,
thyroid, and uterus. Women with Cowden’s syndrome have as much as a 25–50% lifetime risk of
developing breast cancer, and up to 75% have
benign breast conditions such as ductal hyperplasia, intraductal papillomatosis, adenosis, lobular
atrophy, fibroadenomas, and fibrocystic changes
(39–41). In addition, over one-half of those affected
have follicular adenomas or multinodular goiter
of the thyroid. Other malignancies that appear to
be associated with Cowden’s syndrome include
endometrial and renal cancers. Other signs and
symptoms of Cowden’s syndrome can include an
enlarged head, a rare benign brain tumor called
Lhermitte-Duclos disease, and glycogenic acanthosis of the esophagus. The majority of affected
individuals develop the characteristic skin lesions
by age 20 (39–41). Specific mucocutaneous that are
consistently present include multiple facial trichilemmomas located on the central face and perioral
area, multiple papules on the buccal mucosa that
coalesce having a cobblestone appearance, acral
keratoses, and palmoplantar keratoses. Consistent
systemic manifestations include gastrointestinal
polyps, thyroid tumors, fibrocystic disease of the
breast, and ovarian cysts. Malignancy has been
reported to be present in 40–50% of patients with
Cowden’s disease; the most common malignancy
is ACC of the breast, which occurs in 20–30% of
women with Cowden’s disease. To a lesser degree,
thyroid, colon, prostate, uterus, cervix, and bladder
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Abreu Velez & Howard
carcinomas are associated with Cowden’s disease.
Family members of patients with this syndrome
should thus also be evaluated for the presence of
disease lesions. Mutations in the PTEN (phosphatase and tensin homolog) gene cause Cowden’s
syndrome (39–41). PTEN is a tumor suppressor
gene, which means it helps control the growth and
division of cells. Inherited mutations in the PTEN
gene have been found in about 80% of people with
Cowden’s syndrome. These mutations prevent the
PTEN protein from effectively regulating cell survival and division, which can lead to the formation
of tumors. Cowden’s syndrome is one of several
inherited diseases caused by mutations in the
PTEN gene (39–41). In the other 20% of Cowden’s
syndrome cases, the cause of the disorder is
unknown. Some of these cases may be caused by
mutations in a region of DNA that regulates the
activity of the PTEN gene. Others may have mutations in certain subunits of succinate dehydrogenase, a mitochondrial enzyme. The succinate
dehydrogenase mutations are also inherited in an
autosomal dominant pattern; thus, one copy of the
altered gene in each cell is sufficient to cause the
disorder. In some cases, an affected person inherits
the mutation from one affected parent. Other cases
may result from new “de novo” mutations in the
gene. The “de novo” cases occur in people with no
history of the disorder in their family. The “de novo”
cases are characterized by numerous hamartomas,
among other symptoms (39–41).
DM
DM is an inflammatory condition resulting in (i)
proximal myopathy, (ii) violaceous (heliotrope)
inflammatory changes of the periorbital areas and
eyelids, (iii) erythematous urticarial patches that
spread from the face to the neck, and later to the
shoulders and arms, and (iv) flat-topped violaceous papules over the knuckles (Gottron’s
papules) (42–44). Periungual telangiectasis, cuticular overgrowth, poikiloderma, and scaly alopecia
are also found. Calcinosis cutis may be present,
most often in juvenile DM. Systemic symptoms
may include symmetrical proximal muscle fatigue,
fever, anorexia, weight loss, and Raynaud’s syndrome. Patients with DM who are older than 50
years have an increased risk for developing cancer;
25–30% have an associated malignancy (42–44). In
a study of 57 patients with DM and malignancy, the
authors found that the diagnosis of cancer
occurred before diagnosis of DM in 39% of cases,
after the diagnosis of DM in 34% of cases, and con-
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current with diagnosis of DM in 27% of cases.
Ovarian cancer is more frequently observed in
patients with DM than in the general population;
however, the frequency of other types of cancers
seen in DM patients are similar to those found in
the general population, so patients should have a
malignancy workup appropriate for their age. Most
cancers occur within 2 years of DM diagnosis, so
patients should be screened for at least 3 years following the initial diagnosis of DM (42–44).
Erythema gyratum repens
Erythema gyratum repens (EGR) is a skin rash
characterized by concentric, erythematous, scaly
bands with a “wood grain” appearance. The lesions
are frequently pruritic, and affect the trunk and
proximal extremities, sparing the face, hands, and
feet (45–48). Occasionally, palmoplantar keratoderma and ichthyosis may also be present. In one
report, 84% of patients with EGR had an associated
malignant neoplasia, most commonly lung carcinoma. Other sites developing malignancy related
to EGR are breast, urinary bladder, uterus, GI tract,
and prostate (45–48). The skin rash usually precedes the detection of the malignancy, and it also
commonly improves or resolves after successful
treatment of the malignancy. EGR is a migrating,
figurate, or cyclic erythema that is believed to be
a paraneoplastic process (45–48). In addition to
other clinical features, the characteristic concentric erythematous bands forming a “wood grain”
appearance help distinguish EGR from other figurate erythemas, such as erythema annulare centrifugum, erythema chronicum migrans, and
erythema marginatum. The pathogenesis of EGR
remains unknown. The following hypotheses have
been proposed: that first, tumor antigens may form
and cross-react with endogenous skin antigens
(45–48). Second, tumor products may alter endogenous skin antigens, making them susceptible to
autoimmune recognition. Third, tumor antigens
may form immune complexes with antibodies,
which are then deposited into cutaneous tissues.
A mechanism explaining the clinical migrating
erythema has also been proposed (45–48). The
model involves a localized ground substance phenomenon. Granulocytes release factors that stimulate proliferating fibroblasts, producing ground
substance with increased viscosity. This viscous
ground substance serves to impede or “wall off” the
tissue spread of inflammatory mediators. In EGR,
the advancing erythema may represent the
advancement of inflammatory mediators through
Paraneoplastic skin disorders
stroma that is unable to keep them “walled off”;
thus, the migrating erythema phenomenon is
appreciated. EGR is clinically rare. A clinical review
in 1992 by Boyd cited 49 patients reported in the
medical literature. A current literature search
yielded a handful of additional case reports (45–
48). No specific complications are associated with
the skin manifestations of EGR, and the condition
alone does not lead to death. Rash symptoms
include intense pruritus; morbidity and mortality
may occur related to the underlying malignancy.
EGR occurs predominantly in white persons; the
male-to-female ratio is 2 : 1. EGR usually occurs in
patients older than 40 years, with a mean age of 63
years; however, it has been reported from age 16–75
years (45–48). The appearance of EGR often precedes the detection of malignancy. The skin eruption is present an average of 9 months prior to the
diagnosis of malignancy, with a range of 1–72
months. In a minority of patients, EGR occurred
simultaneously with, or up to 9 months after, the
detection of the neoplasm. EGR has distinctive dermatologic manifestations characterized by the following: (i) the “wood grain” appearance created by
concentric, mildly scaling bands of flat-to-raised
erythema, (ii) fairly rapid migration (up to 1 cm/d),
(iii) intense pruritus, and (iv) a clinical rash course
that closely mirrors the course of the underlying
malignancy, with clearance of rash and relief of
pruritus within 6 weeks subsequent to resolution of
underlying disorder (45–48).
epidermal barrier function, and topical applications should be utilized with caution due to possible increased absorption and resultant toxicity.
An emollient, preferably plain petrolatum, mineral
oil, or lotions containing urea or a-hydroxy acids
(e.g., lactic, glycolic, and pyruvic acids), should be
applied twice a day, especially after bathing and
while the skin is still wet. Blotting with a towel
removes excess applied material. Ichthyosis typically responds well to the keratolytic propylene
glycol. Occlusion should be maintained overnight.
After scaling has decreased, less frequent application is required. Other useful keratolytics include
ceramide-based creams, 6% salicylic acid gel,
hydrophilic petrolatum combined with water (in
equal parts), and the alpha hydroxy acids in various
bases. Topical calcipotriol cream has also been
used with success; however, this vitamin D derivative can result in hypercalcemia when used over
extensive areas, especially in children. Importantly,
ichthyosis should be distinguished from xerosis,
which frequently responds to lubricating creams
(49–53). As noted previously, although the use of
selected medications and benign conditions may
be related to acquired ichthyosis (including
hypothyroidism, sarcoidosis, and malnutrition),
new onset of ichthyosis in adult life is often related
to an underlying malignancy (49–53). Hodgkin’s
disease was found in approximately 70% of
patients with acquired ichthyosis and internal neoplasia (49–53). Acquired ichthyosis has also been
related to T cell lymphomas, multiple myeloma,
and lung, breast, and cervical carcinomas.
Ichthyosis acquisita
Ichthyosis aquisita is characterized by rhomboidal
scales that rise above the skin surface. Ichthyosis
may be an early manifestation of selected systemic
diseases (e.g., leprosy, hypothyroidism, lymphoma,
and AIDS) (49–53). Some drugs cause ichthyosis
(e.g., nicotinic acid, triparanol, and butyrophenones). The dry scales may be delicate and localized to the trunk and legs, or thickened and
widespread. Biopsy of ichthyotic skin is usually not
diagnostic of a systemic disease; however, there are
exceptions, most notably sarcoidosis, in which a
thick scale may appear on the legs, and a biopsy
typically shows the characteristic granulomas.
Treatment of ichthyosis includes removal of exacerbating factors, as well as applying moisturizers
and keratolytics; infection prophylaxis may also be
indicated in select cases. When ichthyosis is caused
by a systemic disorder, therapeutic results are
greatest if the primary disease process can be corrected (49–53). In any ichthyosis, there is impaired
Neurofibromatosis (von
Recklinghausen’s disease)
Neurofibromatosis is an autosomal dominant disorder characterized by developmental changes in
the nervous system, bones, and skin. NF causes
benign, clinical tumors (54–58). NF 2 (NF2) is often
associated with scoliosis (curvature of the spine),
cafe au lait spots, learning difficulties, eye problems, and epilepsy. The skin lesions of NF are neurofibromas, multiple café-au-lait macules, axillary
freckles, bronzing, and giant pigmented hairy nevi.
In NF type 1, optic gliomas are the most common
nervous system tumors. They occur in approximately 15% of patients, and may result in blindness
if left untreated. Other associated nervous system
neoplasms in NF are astrocytomas, vestibular
schwannomas (acoustic neuromas), and, less
often, ependymomas and meningiomas (54–58). In
NF type 2, there is a close association with acoustic
669
Abreu Velez & Howard
neuromas. Patients with NF are at risk for developing other tumors of neural crest origin, such as
neurofibrosarcomas, pheochromocytomas, and
rhabdomyosarcomas. NF-1 is caused by a mutation of a gene on the long arm of chromosome 17
which encodes a protein known as neurofibromin,
which plays a role in intracellular signaling. The
neurofibromin is a negative regulator of the Ras
oncogene. The mutant gene is transmitted with an
autosomal dominant pattern of inheritance, but up
to 50% of NF-1 cases arise due to spontaneous
mutation. The incidence of NF-1 is about 1 in 3500
live births (54–58). The neurofibromin gene has
been sequenced and found to be 350,000 base pairs
in length. However, the protein is 2818 amino acids
long, leading to the concept of splice variants. For
example, exons 9a, 23a, and 48a are expressed in
the neurons of the forebrain, muscle tissues, and
adult neurons, respectively. Homology studies
have shown that neurofibromin is 30% similar to
proteins in the GTPase activating protein (GAP)
family (54–58). The homologous sequence is in the
central portion of neurofibromin and, being
similar to the GAP family, is recognized as a negative regulator of the Ras kinase. Additionally, since
neurofibromin is such a large protein, other active
domains of the protein have been identified. One
such domain interacts with the protein adenyl
cyclase, and a second with the collapsin response
mediator protein. Together with domains yet to be
discovered, neurofibromin regulates many of the
pathways responsible for cell proliferation, learning impairments, and skeletal defects, and also
plays a role in neuronal development. A neurofibroma is a mass lesion of the peripheral nervous
system. Its cellular lineage is uncertain; it may
derive from Schwann cells, other perineural cell
lines, or fibroblasts (54–58). Neurofibromas may
arise sporadically or in association with NF. A neurofibroma may arise at any point along a peripheral
nerve. A cutaneous neurofibroma presents as a
firm, rubbery nodule of varying size under the skin.
A solitary neurofibroma may also occur in a deeper
nerve trunk, and only be seen on cross-sectional
imaging (e.g., CT or magnetic resonance) as a fusiform enlargement of a nerve (54–58). The hallmark
lesion of NF-1 is the plexiform neurofibroma. These
lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major
nerves, blood vessels, and other vital structures.
These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue
(54–58). When a plexiform neurofibroma manifests
on a leg or arm, it will elicit extra blood circulation,
670
and thus may accelerate the growth of the limb.
The resultant growth may cause considerable differences in length between left and right limbs.
To equalize the differences during childhood, epiphysiodesis orthopedic surgery may be utilized, to
halt growth at the epiphyseal (growth) plate (54–
58). Epiphysiodesis may be performed on one side
of the bone to help correct an angular deformity, or
on both sides to stop growth of the bone completely. The surgery must also be carefully planned,
as it is nonreversible. The clinical goal is to make
the limbs at nearly equal lengths at the end of
growth (54–58). Schwannomas are peripheral
nerve sheath tumors, seen with increased frequency in NF-1. In practice, the major distinction
between a schwannoma and a solitary neurofibroma is that a schwannoma can be resected while
sparing the underlying nerve, whereas resection of
a neurofibroma requires the sacrifice of the underlying nerve. Malignant peripheral nerve-sheath
tumors, once called neurofibrosarcomas, can arise
from degeneration of a plexiform neurofibroma;
such is, however, a rare complication (54–58). A
plexiform neurofibromas has a lifetime risk of
8–12% of such malignant transformation. The
central nervous system, cognitive, and the skeletal
manifestations of NF are beyond the scope of this
review.
Paraneoplastic pemphigus
Paraneoplastic pemphigus (PNP) is an acantholytic
mucocutaneous syndrome characterized by
painful mucosal erosions, ulcerations, and polymorphous skin lesions that progress to blistering
eruptions on the trunk and extremities (59–63).
Histologic findings are vacuolar interface changes,
keratinocyte necrosis, and intraepidermal acantholysis. Malignancies associated with PNP are
lymphoproliferative disorders such as nonHodgkin’s B-cell lymphoma, chronic lymphocytic
leukemia, Waldenström’s macroglobulinemia,
Hodgkin’s disease, T cell lymphoma, Castleman’s
tumor, and thymoma. PNP is associated with a
high mortality rate (75–80%). Other neoplasms
associated with PNP include Kaposi’s sarcoma and
carcinomas of the breast, skin, mucous membranes, lung, uterus and cervix, ovary, stomach,
liver, and gastrointestinal tract. Other authors had
identified 16 cases of pemphigus associated with
myasthenia gravis and thymoma, 11 associated
with myasthenia gravis alone, and eight associated
with thymitis or thymoma alone (59–63). Almost
half (43%) of the patients had pemphigus erythe-
Paraneoplastic skin disorders
matosus, and another third had pemphigus vulgaris. The effect of thymic ablation on the course of
the skin disease was variable. Pemphigus vulgaris
and erythematosus were equally common in the
setting of thymoma, each occurring in 44% of
cases, and pemphigus foliaceus was seen in 11% of
cases (59–63). Sixty-seven percent of patients had
benign thymoma, and only two had malignant
thymoma. The sequential relationship between
the skin manifestations and thymoma was variable (59–63). In more than half of the cases, the
thymoma preceded pemphigus (mean 89 months);
in 22%, the thymoma was detected after the diagnosis of pemphigus (mean 25 months); and in only
one case were the disorders diagnosed simultaneously. The association of pemphigus, thymoma,
and autoimmune disease was also described (59–
63). Myasthenia gravis is by far the most common
associated autoimmune disease. Other associated
autoimmune diseases include bone marrow erythroid aplasia, systemic lupus erythematosus, and
bullous pemphigoid. Pemphigus vulgaris, pemphigus erythematosus, and pemphigus foliaceus
occur at nearly equal frequencies. Although these
skin diseases in this setting are described under the
rubric of PNP, perhaps a more precise moniker
would be cutaneous paraneoplastic autoimmune
vesiculobullous disease. The autoantibodies in the
serum of patients with PNP immunoprecipitate a
complex of high-molecular weight proteins from
keratinocytes with relative molecular weights of
250, 230, 210, 190, and 170 kd. The 250-kd antigen
is now known to represent desmoplakin I, and the
210-kd antigen represents desmoplakin II (desmosomal plaque proteins). The 230-kd antigen is
bullous pemphigoid antigen. Antibodies to a
130-kd antigen (similar to that seen in pemphigus
vulgaris) have also been detected. The desmoplakins play a pivotal role in anchoring the
network of intermediate filaments to desmosomes
(59–63).
Pityriasis rotunda
Pityriasis rotunda is an unusual skin condition
characterized by round, scaly, hyperpigmented
lesions on the trunk and proximal extremities (49).
The hands, feet, and face are usually spared. It is
more commonly seen in deeply pigmented South
African and West Indian patients. Histologically, it
is similar to ichthyosis vulgaris. Pityriasis rotunda
is associated with internal malignancies in 6% of
cases, with gastric carcinoma and hepatic carcinomas being the most frequent neoplasms (49).
Pyoderma gangrenosum
Pyoderma gangrenosum (PG) is characterized by
lesions that begin with painful pustules and/or
erythematous nodules, which then form an ulcer
that contains raised, violaceous, undermined
borders and a hemorrhagic exudate partially
covered by necrotic tissue (64–66). Up to 50%
of patients have an associated condition such as
inflammatory bowel disease, diverticulosis, arthritis, chronic hepatitis, Behçet’s syndrome, or hematologic neoplasia (64–66). The frequency of
concomitant malignant disease in patients with PG
is uncertain, but it has been estimated at 4.5–7%
(64–66). Atypical or bullous PG has been related to
hematologic malignancies, acute myelogenous leukemia being the most frequently associated malignancy. It has also been reported in chronic myeloid
leukemia, multiple myeloma (usually IgA type),
Waldenström’s macroglobulinemia, Hodgkin’s and
non-Hodgkin’s lymphomas, and in solid tumor
malignancies such as carcinoid, colon, breast, and
bladder carcinoma (64–66).
Quincke’s edema (angioedema and
paraneoplastic uricaria)
Angioedema is characterized by acute onset of nonpruritic, nonpitting, and circumscribed areas of
edema secondary to increased vascular permeability (67,68). Angioedema is most apparent in distensible tissues, such as lips, eyes, earlobes, and
tongue, and also may involve the larynx, extremities, and genitalia. Angioedema can be classified
as (i) hereditary angioedema, (ii) angioedema due
to acquired deficiency of the inhibitor of the first
component of human complement (C1-INH), (iii)
angioedema associated with allergic reactions,
(iv) angioedema secondary to drugs, and (v) idiopathic angioedema. Angioedema due to acquired
deficiency of C1-INH is a rare condition. It is characterized by increased consumption of C1-INH that
leads to an enhanced complement system cascade
reaction, and results in increased vascular permeability and edema. C1-INH deficiency angioedema
is suspected in patients (i) with a history of recurrent angioedema without urticaria, (ii) in or after
their fourth decade of life, (iii) with a negative family
history of angioedema, and (iv) with C1-INH
functional levels below 50% of normal (67,68).
The C1-INH type of angioedema has been associated with chronic lymphocytic leukemia, nonHodgkin’s lymphoma, multiple myeloma, and
Waldenström’s macroglobulinemia. The associated
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Abreu Velez & Howard
risk for hematolymphoid malignancy is 35% and for
other malignancies 8%, based on a study of 128
patients (67,68).
Sweet’s syndrome (acute febrile
neutrophilic dermatosis)
Sweet’s syndrome is characterized by fever, neutrophilia, and an abrupt onset of erythematous,
painful papules and nodules that coalesce to form
irregular, sharply bordered plaques, primarily on
the face, neck, and extremities (69,70). Pseudovesiculation, a vesiculated appearance due to
intense edema, is commonly present within the
lesions. Extracutaneous manifestations of Sweet’s
syndrome are arthritis, conjunctivitis, and episcleritis. Histologically, it is characterized by an
inflammatory infiltrate, predominantly containing
neutrophils, that is diffusely distributed in the
upper dermis (69,70). Sweet’s syndrome may be (i)
idiopathic, (ii) associated with an upper respiratory
tract infection, (iii) drug induced, or (iv) associated
with malignancy (paraneoplastic), in which the
onset or recurrence of the skin lesions are temporally associated with the presence of cancer. Some
retrospective studies have been performed to
assess the incidence of malignancy associated with
Sweet’s syndrome. Selected studies have shown
that of 448 persons studied, 96 (21%) presented
with a simultaneous hematologic malignancy or
solid tumor (69,70). The most common hematologic malignancy was acute myelogenous leukemia, and of the solid tumors, carcinomas of
genitourinary organs, breast, and GI tract were frequent. Findings that may suggest underlying
malignancy include absence of antecedent respiratory infections, anemia, platelet abnormalities,
and bullous PG with pronounced ulceration
(69,70).
Degos’ disease (also called malignant atrophic
papulosis) is a rare vasculopathy that affects the
endothelial lining of small arteries and veins,
resulting in occlusion (blockage of the vessel) and
tissue infarction (71–73). The blood vessels affected
include those supplying the skin, gastrointestinal
tract, and central nervous system (71–73). Thus,
the disease may result in bowel ischemia (mesenteric ischemia or ischemic colitis), chronic skin
lesions, ocular lesions, strokes, spinal lesions,
mononeuritis multiplex, epilepsy, headaches, or
cognitive disorders. Pleural or pericardial effusions
have also been also reported. The outcome of the
disease can be fatal, with a median survival of 2 to
3 years, although some appear to have a benign
672
form (Degos’ acanthoma) which affects only the
skin (71–73). There are fewer than 50 living patients
at present known worldwide, and fewer than 200
reported in the medical literature. Treatment
options are limited, consisting mainly of antiplatelet drugs, anticoagulants, and immunosuppressants; the effect of treatment is limited to case
reports. It has been suggested that Degos’ disease is
not a discrete nosologic disorder, rather a final
clinical and histologic end point of several diverse
vascular systemic disorders (71–73).
Tripe palms
Tripe palms is a condition characterized by pronounced dermatoglyphics and a thickened, velvety
appearance of the palms (and sometimes the
soles), resembling the surface appearance of small
bowel villi (74). Histologically, hyperkeratosis, papillomatosis, and acanthosis are commonly seen. In
a review of 77 patients with tripe palms, more than
90% of published cases of tripe palms occurred in
patients with cancer, and in 77% of cases, this condition was associated with acanthosis nigricans
(74). The most common associated neoplasms
were pulmonary and gastric carcinomas. In more
than 40% of the reported patients, tripe palms
represented the presenting sign of an underlying
neoplasm; conversely, in 30%, the tripe palm presentation followed the diagnosis of cancer (74).
Superior vena cava syndrome
The superior vena cava represents the major
venous drainage from the head, neck, upper
thorax, and upper extremities. Superior vena cava
syndrome (SVCS) is caused by a gradual compression of the superior vena cava, resulting in obstruction of its blood flow (75). Dyspnea and facial
swelling are the most frequent symptoms. Facial
and upper extremity edema and jugular venous
distention (with or without cyanosis) are classically present on physical examination. The most
common etiology for SVCS is a mediastinal malignancy. Bronchogenic carcinoma is associated in
80% of cases, with small cell carcinoma representing the majority of these lung cancers; mediastinal
lymphomas are associated with 18% of cases. Less
commonly, SVCS may be caused by metastases of
other malignancies (75). Nonmalignant causes of
SVCS consist of mediastinal fibrosis, aortic aneurysms, vasculitis, infections, benign mediastinal
Paraneoplastic skin disorders
tumors, and thromboses secondary to the presence of central vein catheters (75).
Werner’s syndrome associated with
malignant neoplasms
Werner’s syndrome is a rare, autosomal recessive
disease resulting in premature aging (75–79). It is
characterized by cataracts, short stature, premature graying of the hair and baldness, laryngeal
atrophy, high-pitched voice, distal muscle atrophy,
endocrine disorders such as diabetes mellitus,
osteoporosis, and hypogonadism. The skin manifestations of Werner’s syndrome include dryness,
atrophy, a scleroderma-like appearance, beak
nose, hyperkeratosis over bony prominences, and
chronic leg ulcers. Some authors have described
Werner’s syndrome associated with fibrosarcoma
of the mediastinum and multiple basal cell carcinomas. In two of these basal cell carcinomas, since
the sclerotic skin made it difficult to assess the
extent of the tumor, a microscopically controlled
excision (Mohs’ chemosurgery) was utilized
(75–79).
Xanthomas
Diffuse normolipemic plane xanthomas are characterized by large, yellow-brown, plaque lesions,
classically involving the eyelids, sides of the neck,
upper trunk, buttocks, and the flexural folds in normolipemic persons. Histologically, the lesions
contain dermal clusters of perivascular giant cells
with foamy cytoplasms. Diffuse normolipemic
plane xanthoma has been associated with monoclonal gammopathy, multiple myeloma, mycosis
fungoides, and with other lymphoproliferative and
myeloproliferative disorders such as leukemia,
lymphoma, and Castleman’s disease. An association with angiokeratoma of Fordyce is also documented (80).
Yellow nail syndrome
Yellow nail syndrome (YNS) is a rare disorder characterized by nail changes, lymphedema, pleural
effusions, and chronic respiratory tract infections
such as bronchitis and sinusitis (81–83). Affected
nails have yellow discoloration, are thickened and
grow slowly. Sometimes, nails present with loss of
cuticula, and erythema and edema of the proximal
nail folds. The nail changes may be the initial manifestation, preceding other symptoms by years. YNS
has been associated with autoimmune diseases
such as thyroiditis, rheumatoid arthritis, and
acquired immunodeficiency syndrome, as well as
with certain medications (81–83). YNS has been
related to malignancies, including mycosis
fungoides, laryngeal carcinoma, gallbladder carcinoma, bronchial carcinoma, breast cancer, nonHodgkin lymphoma, and endometrial cancer. In
several reported cases, the nail deformity resolved
after successful treatment of the associated neoplasm (81–83).
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