Download Bazex syndrome - Abdel Hamid Derm Atlas

Paraneoplastic cutaneous
manifestations
Is there any way to diagnose or deny Neurology Paraneoplastic Syndrome?
Paraneoplastic diseases
•
•
Paraneoplastic diseases may be defined as hormonal, neurological or hematological disturbances
and as clinical and biochemical imbalances associated with the presence of malignancies without
direct association with primary tumor invasion or metastasis. The skin often signals systemic
changes. Some neoplastic diseases that affect internal organs may trigger several cutaneous
manifestations. Although these dermatoses are relatively unusual, the recognition of some typical
paraneoplastic dermatoses may lead to the early diagnosis of a neoplasm and determine a better
prognosis The skin may provide the doctor with signs that are suggestive of systemic diseases,
thus contributing to the diagnosis of many diseases, including malignancies. More than 50
dermatological conditions have been reported as potential markers of malignancy. The skin may
be directly or indirectly involved in malignancies. Direct involvement implies the presence of tumor
cells in the skin caused by direct tumor extension or metastasis. Indirect involvement, in turn, is
caused by a variety of factors (inflammatory, proliferative or metabolic factors) related to the
neoplasia, such as polypeptides, hormones, cytokines, antibodies or growth factors that act as
mediators, interfering with cell communication and, consequently, with its activity. In this case,
there is no presence of neoplastic cells in the skin, and this involvement is considered a
dermatological paraneoplastic syndrome.
Paraneoplastic dermatoses are a heterogeneous group of clinical manifestations that may have a
benign appearance. They are the second most common paraneoplastic syndrome, only behind
endocrine syndromes. It is not always easy to determine the correlation between a dermatologic
finding and an internal neoplasm or even to define the frequency of this association in the general
population. Curth, in his studies of acanthosis nigricans maligna, proposed some criteria to assess
the causal relationship between dermatological change and potential underlying malignancy
Curth’s criteria for the diagnosis of cutaneous paraneoplastic
syndromes
Association of dermatoses with systemic neoplasias
Paraneoplastic
Dermatologic
Syndromes
Paraneoplastic Dermatologic Syndromes
Cutaneous manifestations of internal malignancies
An. Bras. Dermatol. vol.85 no.5 Rio de Janeiro 2010
ACANTHOSIS NIGRICANS MALIGNA
•
•
•
•
•
•
•
•
•
•
Acanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such
as the posterior and lateral folds of the neck, the armpits, groin , navel, forehead, and other areas.
Classification
Acanthosis nigricans is conventionally divided into benign and malignant forms, although may be divided into syndromes according to
cause.
Benign This may include obesity-related, hereditary, and endocrine forms of acanthosis nigricans.
Malignant. This may include forms that are associated with tumour products and insulin-like activity, or tumor necrosis factor.
An alternate classification system still used to describe acanthosis nigricans was proposed in 1994. It delineates acanthosis nigricans
syndromes according to their associated syndromes, including benign and malignant forms, forms associated with obesity and drugs,
acral acanthosis nigricans, unilateral acanthosis nigricans, and mixed and syndromic forms. .
Acanthosis nigricans maligna occurs equally in both sexes without racial predilection or familial association. The
disease has a sudden onset with extensive and severe lesions that develop quickly. It affects adults with an
average age of 40 years. In contrast, the benign form usually manifests earlier in life and develops slowly.
Clinical manifestations. It begins with symmetrical hyperpigmentation in intertriginous areas such as the axilla,
cubital fossa, submammary, inguinal and posterior cervical regions, although any part of the body can be
affected Lesions then become slightly infiltrated, with velvety hyperkeratotic plaques, commonly surrounded by
acrochordons. There may be an association with generalized pruritus and involvement of mucosal surfaces, which
present a verrucous aspect in severe cases . Approximately 25% of patients present concomitant involvement of
the palmoplantar region in a pattern known as tripe palms (acquired pachydermatoglyphia). It may also be
associated with the sudden onset of multiple lesions of seborrheic keratosis (Leser-Trélat sign). .
Associated malignancies ANM can precede, occur simultaneously or occur after the diagnosis of cancer. ANM
is associated with 90% of all abdominal cancers; 55-61% are of gastric origin, and adenocarcinoma is found in 7090% of cases . Other less associated malignant conditions include uterine, liver, intestine, pancreas, thyroid,
ovary, kidney, breast, lung, bladder and gallbladder cancers, mostly consisting of adenocarcinomas. An
association with lymphomas and mycosis fungoides has also been reported.
ANM tends to evolve simultaneously with the underlying neoplasia and it aggravates as the condition worsens. It
improves with treatment or relapses in the occurrence of metastasis, often serving as a standard measure of
progression or recurrence of malignancy Despite the presence of acanthosis nigricans in benign and nonneoplastic conditions, such as drug use and insulin resistance, a detailed medical history should be taken from
patients diagnosed with this dermatosis. The diagnosis of ANM should be strongly considered in adults over 40
years of age, without endocrinological changes or genetically determined diseases with fast-growing skin lesions.
In these individuals, an extensive gastrointestinal evaluation is mandatory. Prognosis, however, is poor.
Underlying tumors present in patients with ANM tend to have an aggressive behavior, which leads to a mean
survival of 2 years after the diagnosis of ANM.
Acanthosis Nigricans Maligna
Acanthosis Nigricans Maligna
Acanthosis
Nigricans Maligna
Acanthosis Nigricans Maligna
Causes of acanthosis nigricans
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Causes
It typically occurs in individuals younger than age 40, may be genetically inherited, and is associated with obesity or endocrinopathies, such
as hypothyroidism, acromegaly, polycystic ovary disease, insulin-resistant diabetes, or Cushing's disease.
Type I - familial
Familial acanthosis may arise as a result of an autosomal dominant trait, presenting at birth or developing during childhood.
Type II - endocrine
Endocrine syndromes associated with acanthosis nigricans can develop in many conditions, particularly:
@ starts with insulin resistance, such as diabetes mellitus and metabolic syndrome
@ excess circulating androgens, particularly Cushing's disease, acromegaly, polycystic ovarian disease
@ Addison's disease and hypothyroidism
@ Rare diseases, including pinealoma, leprechaunism, lipotrophic diabetes, pineal hyperplasia syndrome, pituitary basophilism, ovarian hyperthecosis,
stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, and Alstrom syndrome.
Acanthosis nigricans associated with endocrine dysfunction is more insidious in its onset, is less widespread, and the patients are often concurrently
obese.
Type III - obesity and pseudoacanthosis nigricans
In young persons, AN is a visible marker which strongly suggests insulin resistance. Higher than normal insulin levels in the blood stream cause the
growth of darkened skin over certain areas of the body. No skin treatment will get rid of AN. Acanthosis nigricans may lighten up and possibly go away
by treating the root cause, insulin resistance, but it can take months or years to do so. Insulin resistance syndromes may be divided into type A (HAIRAN) and type B syndromes. The majority of cases of acanthosis nigricans are associated with obesity and otherwise idiopathic. This is likely because of
insulin resistance, and more likely to occur in darker-skinned persons. This can also be referred to as pseudoacanthosis nigricans.
Type IV - drug-related
Acanthosis nigricans has been linked to the use of nicotinic acid, glucocorticoid use, combined oral contraceptive pills, and growth hormone therapy.
Type V - malignancy
Malignant acanthosis nigricans refers to acanthosis nigricans occurring as a paraneoplastic syndrome associated with a cancer. Malignant acanthosis
nigricans is most commonly associated with gastrointestinal adenocarcinomas, as well as genitourinary cancers such as those of the prostate, breast,
and ovary. Other cancers, such as those of the lung, stomach, and lymphoma, are occasionally associated with acanthosis nigricans.
This form of acanthosis nigricans is more likely to involve mucous membranes (25-50% of cases) Malignant acanthosis nigricans that may either
precede (18%), accompany (60%), or follow (22%) the onset of an internal cancer. Malignancy-associated acanthosis nigricans is usually rapid in onset
and may be accompanied by skin tags, multiple seborrheic keratoses, or tripe palms
Acral acanthotic anomaly
Acral acanthotic anomaly refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet, in the
absence of any other findings, in otherwise healthy individuals. While the etiology remains unknown, its presence does not suggest a likelihood of
malignancy
Pathogenesis of acanthosis nigricans
•
•
•
•
•
•
The pathogenesis of acanthosis nigricans is poorly understood, and likely to
relate to an interplay of factors, including insulin-mediated activation
of ILGF receptors on keratinocytes, and increased growth factor levels.
Factors involved in the development of acanthosis nigricans include:
Increased circulating insulin. This activates keratinocyte ILGF receptors,
particularly IGF-1. At high concentrations, insulin may also displace IGF-1
from IGFBP. Increased circulating IGF may lead to keratinocyte and dermal
fibroblast proliferation.
Fibroblast growth factor. Hereditary variants are associated
with FGFR defects.
Increased TGF, which appears to be the mechanism for malignancyassociated acanthosis nigricans. TGF acts on epidermal tissue via
the EGFR.
In conjunction with increased end levels of ILGF, it is likely that perspiration
and friction may be necessary predetermin
Histopathology of acanthosis nigricans
•
•
Histopathology.
Histologically, ANM
shows hyperkeratosis,
papillomatosis and
some degree of
acanthosis with
thickening of the
spinous layer of the
epidermis. The dark
color is more related to
hyperkeratosis than to
the presence of
melanin; therefore, the
term "acanthosis
nigricans" is merely
descriptive, as there is
no proliferation of
melanocytes
ACQUIRED PACHYDERMATOGLYPHIA
ACQUIRED PACHYDERMATOGLYPHIA
•
•
•
•
Also referred to as tripe palms or acanthosis palmaris, acquired
pachydermatoglyphia (AP) is a term that was introduced in the medical
literature in 1970 by Clark. It is a skin condition that is usually associated
with Leser-Trélat sign and ( Acanthosis nigricans maligna) ANM, being
considered by some authors much more a variant of ANM than actually a
new disease. It predominantly affects adults, with a predilection for males
Clinical manifestations. It presents with yellowish, velvety, diffuse palmar
hyperkeratosis, with accentuated dermatoglyphic patterns, leading to a
rough appearance that resembles the intestinal villosities, which explains
the term tripe palms
Associated malignancies. Neoplastic processes have been reported in
90% of cases of ( Acquired pachydermatoglypha) AP Gastric and lung
cancer account for 50% of tumors. In the absence of an association with
ANM, lung cancer becomes more prevalent, being found in more than 50%
of cases. Other neoplasms have been correlated with AP, such as breast
and genitourinary tract cancers.
Histopathology. Histological examination reveals acanthosis and
hyperkeratosis, and perivascular deposition of mucin in the dermis may be
observed.
Tripe palms
Tripe palms
•
•
•
•
•
•
•
Tripe palms are characterized by thickened velvety palms
that have the appearance of tripe, the stomach lining of beef,
pork, or sheep. Approximately 90% of cases of tripe palms
are associated with internal malignancy. This skin disease is
very rare. It usually occurs before the diagnosis of the
cancer, but may arise during any point in the course of the
malignancy.
What is the cause of tripe palms?
The cause of tripe palms is not clearly understood but is
thought that it is due to substances from the associated
cancer that stimulate the palmar skin cells to proliferate.
Tripe palms are frequently seen in conjunction
with acanthosis nigricans. In these cases, the underlying
malignancy is most commonly stomach (35%) or lung (11%)
cancer. In cases where tripe palms occur without acanthosis
nigricans, lung cancers are usually responsible. Less
commonly associated cancers include head and neck
tumors, and tumors of the genitourinary tract.
Tripe palms are less frequently associated with bullous
pemphigoid, psoriasis, and exfoliative dermatitis
The diagnosis is made from the characteristic appearance of
tripe palms. Scaling and skin thickening may be noted on
skin biopsy but these are are non-specific histological
findings.
In over 40% of patients, tripe palms are the first sign of an
undiagnosed cancer, hence all patients should undergo a full
diagnostic workup for an associated malignancy, particularly
lung or gastrointestinal carcinoma..
Tripe palms
ERYTHEMA GYRATUM REPENS
ERYTHEMA GYRATUM REPENS
•
•
•
•
•
•
Erythema gyratum repens (EGR) is a rare dermatosis. It was first described in 1952 by Gammel in a patient nine
months before the appearance of a breast adenocarcinoma. Lesions usually recede some weeks after removal of
the tumor, and the clinical manifestations are considered typical of a paraneoplastic dermatosis. The average age
of onset is 63 years, and the disease affects twice as many men than women.
Clinical manifestations. It presents as a widespread, serpiginous, polycyclic and pruriginous erythema which is
desquamative around the edges and fast-growing, about 1 cm/day, producing concentric figures that resemble a
wood surface Hands and feet are often spared. Other manifestations include palmoplantar keratosis, ichthyosis
and onychodystrophy in the sacral region.
Patients with this dermatosis should be considered as having malignancy and should be mandatorily evaluated.
The evolution of EGR often accompanies an underlying neoplastic disease. Successful treatment of the neoplasia
often leads to complete resolution of the lesions.
Associated malignancies. Malignant neoplasms are found in 82% of the patients with EGR. Lung cancer is the
most common (32%), followed by cancer of the esophagus (8%) and breast (6%). Other malignancies have been
associated with EGR, such as colon, stomach, bladder, prostate, uterine, rectal and pancreatic cancer and
multiple myeloma. The diagnosis of EGR precedes the diagnosis of the neoplasia in approximately 80% of
patients, on average from four to nine months. Non-neoplastic conditions may be rarely associated with EGR,
such as tuberculosis, pregnancy, calcinosis, esophageal dysmotility, sclerodactyly, Sjogren's syndrome and
CREST syndrome.
Histopathology. Histopathology is nonspecific, showing mild hyperkeratosis, parakeratosis, acanthosis and
spongiosis with a perivascular mononuclear inflammatory infiltrate in the dermis.
Pathophysiology. Its pathophysiology is unknown. Immune mechanisms are probably involved since
immunosuppression accompanies the resolution of EGR. The immunological explanation is supported by the
presence of immune deposits (C3) in the sublamina densa seen by direct immunofluorescence (DIF). In some
cases, anti-basement membrane antibodies were detected by DIF. The theory states that antibodies to tumor
antigens may react against skin antigens, which justifies the deposition of immune complexes in this tissue
ERYTHEMA GYRATUM REPENS
Erythema gyratum repens pathology
•
•
Erythema gyratum
repens is a clinically
distinctive figurate
or annular erythema that
is usually associated with
underlying malignancy.
The eruption is rapidly
migrating and composed
of concentric rings
forming a wood-grain
pattern.
Histological features of
erythema gyratum
repens are not diagnostic
and include
hyperkeratosis,
parakeratosis,
acanthosis and
spongiosis. There may
be perivascular
lymphohistiocytic
infiltrate in the papillary
dermis ( arrow shows
parakeratosis).
Erythema gyratum
repens pathology
ACROKERATOSIS PARANEOPLASTICA
(Bazex syndrome)
ACROKERATOSIS PARANEOPLASTICA
(Bazex syndrome)
•
•
•
•
•
Clinical manifestations. Erythematous lesions with a psoriasiform aspect that manifest as symmetrical
erythematous-violaceous scaly patches on the bridge of the nose, helix, and distal ends of the extremities are
initially found. As the disease progresses, desquamation affects the dorsal and palmoplantar regions producing a
violaceous keratorderma. The nails may also be affected from the onset, with subungual hyperkeratosis,
onycholysis and dystrophy Eventually, additional areas may be affected such as the knees, legs, arms and scalp,
with centripetal distribution of the lesions. Bullous lesions, mainly in the hands and feet, have been
described. Although lesions show a psoriasiform aspect, their distribution is not typical of psoriasis, helping with
differential diagnosis.
Lesions are resistant to targeted therapy (steroids or keratolytic drugs). In about 90% of cases, the dermatosis
follows the neoplastic course with improvement after effective treatment of the neoplasia and recurrence when the
tumor returns. Nail changes, however, slowly improve and may be persistent.
Associated malignancies. All the cases cited in the literature were associated with malignancy. Skin
manifestations often precede the diagnosis of cancer in approximately 2-6 months in 65-70% of patients; less
often, they occur simultaneously (10-15%) or after tumor diagnosis (15-25% ( About 80% of cases are associated
with tumors of the upper aerodigestive tract (oral cavity, larynx, pharynx, trachea, esophagus and lung), commonly
squamous cell carcinoma. 6 Metastasis to cervical lymph nodes appears to be common in patients with Bazex
syndrome. In a retrospective study, 48.6% of cancers involved the oropharynx and larynx, followed by the lung
(17%) and esophagus (10.6%). Isolated cases associated with ductal breast cancer, cholangiocarcinoma, colon
adenocarcinoma and Hodgkin's disease have been reported.
Histopathology. Its histopathology is nonspecific, with findings of hyperkeratosis, acanthosis, parakeratosis,
vacuolar degeneration, pigmentary incontinence and perivascular lymphocytic infiltrate. DIF shows local deposits
of immunoglobulins, complement (C3) or fibrin in the basement membrane.
Pathophysiology. Its pathophysiology remains unknown. Immunological factors with antibodies directed against
the tumor in a cross-reaction with the epidermis or basement membrane have been considered. Another possibility
is the secretion of growth factors by the tumor leading to the growth and differentiation of epidermal cells. In many
cases, the presence of the same type of human leukocyte antigen (A3 and B8) suggests a genetic susceptibility to
this dermatosis
ACROKERATOSIS PARANEOPLASTICA
(Bazex syndrome)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Acrokeratosis neoplastica is also known as ‘paraneoplastic acrokeratosis’ and ‘Bazex syndrome’ – but is quite
different from the genetic syndrome also called ‘Bazex syndrome’, in which there are many basal cell carcinomas.
What is acrokeratosis neoplastica?
Acrokeratosis neoplastica is a rare skin condition with features rather like psoriasis. It is more often than not
associated with squamous cell carcinoma of the upper respiratory or gastrointestinal tract. It is far more common
in males than females.
The condition usually begins with scaling dermatosis of the fingers and toes that may quickly spread to the nails.
Onset is sometimes quite gradual. Cutaneous features include:
@ Severely abnormal nails with painful paronychia (swollen red nail folds) with no evidence of bacterial or fungal
infection.
@ Scaly eruptions on the external ears that may progress to involve the cheeks and nose
@ Diffuse thickening and scaling of the palms and soles (keratoderma), with a peculiar honeycomb appearance
@ Eventually the skin disease may spread to involve trunk, limbs and scalp
@ Some patients are itchy (paraneoplastic pruritus)
Patients may have weight loss, fatigue, general malaise, and other non-specific symptoms that point towards
internal malignancy.
The cause of acrokeratosis neoplastica
Most cases of acrokeratosis neoplastica are due to an internal cancer. The cancer is usually a squamous cell
carcinoma of the upper respiratory tract or the upper gastrointestinal tract (oral cavity, pharynx, larynx,
oesophagus). At diagnosis the lymph nodes are usually already involved.
Other cancers that have been found with acrokeratosis neoplastica include squamous cell carcinoma of the
thymus and vulva, anaplastic small cell carcinoma of the lung and adenocarcinoma of the uterus.
The signs and symptoms of acrokeratosis neoplastica suggest the presence of circulating antibodies to tumour
antigens. The chemical messengers, cytokines, that are released by skin and immune cells, may also play a role.
Topical corticosteroids and emollient creams containing urea, lactic acid or salicylic acid, may reduce the thickness
and irritation of the scaly skin lesions. Therapy with a type of vitamin D, cholecalciferol, or calcipotriol cream, has
also been reported to be of benefit. Oral retinoids such as acitretin may help the cutaneous features .
ACROKERATOSIS PARANEOPLASTICA
(Bazex syndrome)
Acrokeratosis paraneoplastica (Bazex syndrome)
Dermatology Online Journal 10 (1): 21
ACROKERATOSIS PARANEOPLASTICA
(Bazex syndrome)
•
Bazex syndrome. Dystrophic nails in a patient with laryngeal squamous cell
carcinoma
Acrokeratosis paraneoplastica (Bazex syndrome).
•
Histologic examination demonstrates (A) hyperkeratosis, a thickened granular layer,
and scattered parakeratotic columns in the stratum corneum (H&E, x40) and (B)
acanthosis, and eosinophilic and vacuolar degeneration with exocytosis in the
spinous layer (H&E, x100).
Acrokeratosis paraneoplastica in serous ovarian carcinoma
BMC Cancer 2015: 15: 507
•
Biopsy was taken from the sole of the left foot: Histology of plantar skin showing
compact hyperkeratosis and irregular epidermal hyperplasia without any elements of
mycosis; enlarged 10 (a) and 40 (b) times
ACQUIRED HYPERTRICHOSIS LANUGINOSA
ACQUIRED HYPERTRICHOSIS LANUGINOSA
•
•
•
•
•
•
•
Hypertrichosis lanuginosa acquisita is a very rare condition characterised by the rapid growth of long, fine, lanugotype (i.e.: fetal) hair particularly around the eyebrows, forehead, ears and nose. It is similar to congenital
hypertrichosis lanuginosa (see hypertrichosis) except that it appears later on in adulthood and in most cases
associated with an underlying cancer.
Although the face is the most commonly affected area, some patients have extensive involvement that includes
the trunk, axillae and extremities. Palms, soles, scalp and pubic regions tend to be spared. The hair referred to as
‘malignant down’ is fine, thin and unpigmented. Lanugo hairs are normally present from the third month of foetal
life through to the end of gestation and are shed almost completely before birth.
Other associated symptoms include glossitis, a bumpy enlarged tongue, disturbances of taste and smell, and, less
frequently, diarrhoea, weight loss, and enlarged lymph glands. Other paraneoplastic skin conditions that may also
occur include acquired ichthyosis, acanthosis nigricans, and tripe palms.
The cause of hypertrichosis lanuginosa acquisita
The cause of hypertrichosis lanuginosa acquisita is unknown but it is thought to be in response to hormones or
substances released by the tumour. Most cases of hypertrichosis lanuginosa acquisita are associated with an
internal malignancy. The most frequently associated cancers include lung, breast and uterine cancers, colorectal
cancer, lymphoma, and bladder cancer. The ‘malignant down’ most often occurs late in the course of the cancer,
however in some cases it may be the presenting sign of a tumour and can appear up to 2 years prior to diagnosis
of cancer.
Less commonly, hypertrichosis lanuginosa acquisita is associated with non-malignant disease such as anorexia
nervosa, hyperthyroidism, and acquired immune deficiency syndrome (AIDS) associated with human
immunodeficiency virus infection (HIV). It may also be a side effect of drugs such as ciclosporin, phenytoin,
interferon, spironolactone, and corticosteroids.
Malignant forms of hypertrichosis lanuginosa acquisita look exactly the same as those cases associated with
harmless diseases or drugs. Hence it is important that when non-malignant causes have been ruled out, patients
undergo comprehensive screening and careful monitoring to detect any associated malignancy
ACQUIRED HYPERTRICHOSIS LANUGINOSA
•
•
•
•
•
•
t is a rare paraneoplastic dermatosis is characterized by the sudden onset of thin and soft hair, lanugo-like, initially
on the face... Women are three times more affected than men, with an average age of 40-70 years.
Clinical manifestations. It presents with long, thin, soft, non-pigmented hair that affects the face and ears . It may
involve the thorax and extremities, spreading in a craniocaudal manner. Manifestations such as painful glossitis,
angular cheilitis, hypertrophic fungiform papillae and altered taste and smell can be present. Complaints of weight
loss, lymphadenopathy and diarrhea are also common. This dermatosis may be associated with ANM.
The report of lanugo-like hair growth in areas that were previously hair free should be seen as an important
indicator of the possibility of internal malignancy. In the evaluation of patients with AHL, an extensive clinical
history and physical examination are necessary, in conjunction with laboratory screening, chest radiography,
colonoscopy and, in women, mammography. Successful treatment of the tumor usually leads to regression of
pathological hair growth.
Associated malignancies. AHL often precedes tumor diagnosis in about two and a half years. In the presence of
this dermatosis, however, metastasis is common, which is why prognosis is poor, with mean survival of less than
three years after diagnosis. Among women, colorectal cancer is the most frequent association, followed by lung
and breast cancer. Men show greater association with lung cancer, followed by colorectal cancer. Associations
with lymphomas, leukemias, and kidney, pancreatic, uterine and ovarian cancer have been reported.
Histopathology. Histologically, hairs are described as being horizontal or parallel to the epidermis, which
contrasts with the vertical position of normal hair.
Pathophysiology. So far no biochemical abnormality has been identified in the pathophysiology of the disease ,
neither has the involvement of virilizing hormones. It is believed that growth factors secreted by tumor cells are
involved; various fibroblast growth factors (FGF) are known to regulate hair growth. Secretion of FGF has been
reported in lung cancer, as well as production of other factors that participate in hair follicle growth, such as
Wingless proteins and β-Catenin; the latter is able to start new hair growth in vitro. The recent observation that
treatment of AHL with EGF-α receptor antagonist may result in hypertrichosis is also intriguing.
ACQUIRED HYPERTRICHOSIS LANUGINOSA
ACQUIRED HYPERTRICHOSIS LANUGINOSA
Lichenoid skin lesions &
mucosal erosions as a
paraneoplastic syndrome
Violaceous, mildly scaly, discrete
to confluent papules and plaque
over the back.
Lichenoid skin lesions & mucosal erosions as a paraneoplastic syndrome
•
•
(a). Direct immunofluorescence of perilesional skin section showing IgG
deposits on cell surface (star) and basement membrane zone (arrow). The
arrow (→) points to a obliquely cut dermal papillae.
(b). Indirect immunofluorescence of rat bladder section, showing positive IgG
reactivity with the transitional epithelium over 1:10
NECROLYTIC MIGRATORY ERYTHEMA
NECROLYTIC MIGRATORY ERYTHEMA
•
•
•
•
•
•
Necrolytic migratory erythema (NME) is often associated with glucagonoma syndrome and consists of the triad
NME, glucose intolerance and hyperglucagonemia, whose levels greater than 1000 pg/mL are highly suggestive of
glucagonoma. NME is more common in women after 45 years of age..
Clinical manifestations. NME features a characteristic skin eruption of red patches with irregular borders, intact
and ruptured vesicles, and crust formation. It commonly affects the limbs and skin surrounding the lips, although
less commonly the abdomen, perineum, thighs, buttocks, and groin may be affected. Frequently these areas may
be left dry or fissured as a result. All stages of lesion development may be observed synchronously. The initial
eruption may be exacerbated by pressure or trauma to the affected areas.
Lesions may be pruritic and painful and are associated with glossitis, angular cheilitis, normocytic anemia, weight
loss, diabetes, abdominal pain, dyspepsia, diarrhea, venous thrombosis, alopecia, steatorrhea and
neuropsychiatric symptoms. There is a high risk of thromboembolism,
Associated malignancies. Glucagonoma is a rare endocrine tumor of pancreatic alpha cells.. A CT scan may be
useful in the diagnosis. In addition, 95% of glucagonomas are positive in somatostatin receptor
scintigraphic. Somatostatin positivity may be useful in the treatment of the symptoms and signs of glucagonoma,
since that hormone inhibits glucagon secretion and improves the clinical symptoms without, however, inhibiting
tumor growth.
Glucagonoma is often slow-growing, which is why there is a delay of three years on average in the diagnosis,
when about 50% of patients already have metastasis to liver, vertebrae, ovary and peritoneum, often resistant to
chemotherapy. Resolution of the dermatosis is obtained by tumor resection in the absence of metastasis, and
residual hyperpigmentation at the sites previously affected is common..
Pathophysiology. It has been suggested that, in the presence of cancer, zinc and amino acids needed for the
formation of albumin (the main carrier of zinc) may be reduced due to the catabolic state consequent to glucagon.
Reduced levels of serum amino acids would lead to increased production of arachidonic acid, thus leading to
inflammation of the skin. This theory would explain the dermatological findings of ENM in diseases without any
evidence of glucagonoma, such as malabsorption syndromes, liver failure, inflammatory bowel disease and celiac
disease, in which there is also loss of amino acids and minerals. Another theory points to decreased niacin, a
biomolecule that is necessary for epidermal growth and renewal, as the primary responsible for NME. Disorders
involving niacin, such as pellagra, result in dermatitis, diarrhea and neurological alterations. Diarrhea and
neurological alterations are also reported in patients with glucagonoma.
NECROLYTIC MIGRATORY ERYTHEMA
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Necrolytic migratory erythema (NME) is a red, blistering rash that spreads across the skin. It particularly affects
the skin around the mouth and distal extremities; but may also be found on the lower abdomen, buttocks,
perineum, and groin. It is strongly associated with glucagonoma ,a glucagon, -producing tumor of the pancreas,
but is also seen in a number of other conditions including liver disease and intestinal malabsorption. When NME is
identified in the absence of a glucagonoma, it may be considered "pseudoglucagonoma syndrome". Less common
than NME with glucagonoma, pseudoglucagonoma syndrome may occur in a number of systemic disorders:
Celiac disease
Ulcerative colitis
Crohn’s disease
Hepatic cirrhosis
Hepatocellular carcinoma
Lung cancer, including small cell lung cancer
Tumors that secrete insulin or insulin growth factor 2
Duodenal cancer
The histopathologic features of NME are nonspecific and include:
@ epidermal necrosis
@ subcorneal pustules
@ confluent parakeratosis, epidermal hyperplasia, and marked papillary dermal hyperplasia in a psoriasiform
pattern
@ angioplasia of papillary dermis
@ suppurative folliculitis
@ The vacuolated, pale, swollen epidermal cells and necrosis of the superficial epidermis are most
characteristic. Immunofluorescence is usually negative
NECROLYTIC MIGRATORY ERYTHEMA
NECROLYTIC MIGRATORY ERYTHEMA
LESER-TRÉLAT SIGN
LESER-TRÉLAT SIGN
•
•
•
•
•
•
•
•
•
•
The sign of Leser-Telat is a skin disorder characterised by the abrupt appearance of multiple seborrheic keratoses that rapidly increase in
their size and number. It is caused by an associated cancer and often occurs with malignant acanthosis nigricans.
Multiple eruptive seborrhoeic keratoses There is much debate about the validity of the sign of Leser-Trélat as a true paraneoplastic
syndrome .Because seborrhoeic keratoses and cancer are both statistically more common in elderly people it is difficult to ascertain
whether the keratoses is due to the cancer (ie: a sign of Leser-Telat) or is a condition in its own right. However, the sudden eruption of
seborrhoeic keratoses in young patients points to a paraneoplastic process and should prompt an investigation for a hidden cancer.
causes the sign of Leser-Trélat
The cause of the sign of Leser-Trélat is unknown. It may possibly be due to the same unknown factors that induce malignant acanthosis
nigricans. It is thought that paraneoplastic syndromes are caused by the release of hormones from the tumor but this remains to be
proven.
The sign of Leser-Trélat has been linked to a variety of cancers but is mostly associated with an adenocarcinoma of the stomach or colon.
Other cancers where the condition has occurred include squamous cell carcinoma, lymphoma and leukaemia. The sign of Leser-Trélat is
rare, even among patients with cancer. The association with malignancy has remained controversial because seborrheic keratosis is a
common condition in the elderly which is the most affected age range.
Clinical manifestations. It presents as a sudden increase in the size and number of seborrheic keratoses. These are papular, verrucous,
usually well defined lesions of varying colors (brown, black or tan) which primarily affect the thorax and dorsum, followed by the
extremities, face, abdomen, neck and axilla . Pruritus and inflammation are frequent findings. Approximately two thirds of patients have
another paraneoplastic syndrome, of which ANM is the most common, occurring in one third of cases.
LTS is usually ignored by both doctors and patients, leading to a delay in the diagnosis of diseases that could be potentially curable. All
patients with LTS should be screened for neoplasms. Medical history and physical examination associated with complete blood count
(CBC), serum biochemistry, chest radiography, mammography, Pap smear, PSA screening, upper digestive endoscopy and colonoscopy
are required during this investigation.
Associated malignancies. Approximately half of all cancers associated with LTS are adenocarcinomas, present in the gastrointestinal
tract; gastric carcinoma is the most common, followed by colon , rectal cancer& Lymphoproliferative abnormalities. There are reports of
LTS in transitional cell carcinoma of the bladder, kidney tumors, prostate, lung, ovary and kidney cancer, and melanoma, as well as
lymphoproliferative neoplasias. Non-malignant conditions such as pregnancy and benign tumors may be rarely associated with LTS.
Histopathology. The histopathological pattern of the lesions does not differ when compared to that of patients without
malignancy.
Pathophysiology. The exact pathophysiology of the disease remains unknown. Neoplastic cells may secrete factors similar to EGF-α,
stimulating keratinocyte growth. Higher levels of EGF-α and IGF-1 are found in patients with LTS. Also, higher levels of TGF-α have
been found in the urine of a patient with LTS and melanoma; in this case, TGF-α levels became undetectable after removal of the tumor.
LESER-TRÉLAT SIGN
Seborrheic keratosis
Seborrheic keratosis
PARANEOPLASTIC PEMPHIGUS
PARANEOPLASTIC PEMPHIGUS
•
•
•
•
•
•
•
•
•
•
•
•
•
. The diagnostic criteria suggested for PNP can be divided into
@ major criteria : *polymorphous skin eruption, *concurrent internal neoplasia, *antibodies with an immunoprecipitation specific standard
@ minor criteria: *histological evidence of intraepithelial acantholysis, *DIF showing a linear pattern in an area of the basement membrane
with IgG and C3 deposition, and *indirect immunofluorescence using rat bladder epithelium as a substrate. Three major criteria or two
major and one minor are needed. Contrary to pemphigus vulgaris, in which DIF shows only intercellular deposition in epithelial cells, the
basement membrane is also affected in PNP.
Clinical manifestations. While the presence of lesions is the denominator among patients with PNP, the characteristics of the lesions
differ. The five clinical presentations of lesions associated with PNP include:
1.“Pemphigus-like": Flaccid blister (discrete), crusts over the raw exuding skin lesions
2."Pemphigoid-like": Tense blister(s) on brick red erythema
3. "Erythema multiforme-like": Severe polymorphic skin and/or mucous membrane lesions
4. "Graft-vs.-host disease-like": Widespread lichenoid eruption with severe mucous membrane involvement
5. "Lichen planus-like": Small red flat-topped scaly papulles
Oral involvement with painful stomatitis is seen in almost all cases and can often be the first symptom, being generally the least
responsive to treatment . Oral lesions may be severe, diffuse and affect the hypopharynx and esophagus; they may also involve the
conjunctival and anorectal mucosa. Skin manifestations range from papules and plaques similar to erythema multiforme, vesicles and
blisters that resemble pemphigus vulgaris or even pruritic plaques similar to lichen planus. Contrary to pemphigus vulgaris, there may be
acral and paronychial involvement. Some patients have respiratory complications such as bronchiolitis obliterans, with the potential risk of
respiratory failure. PNP is associated with high mortality rate secondary to sepsis, bleeding and respiratory failure.
Associated malignancies. Most associated malignancies develop in patients who are between 45 and 70 years old. Approximately 80%
are of hematological origin (B-cell lymphoproliferative disorders), such as non-Hodgkin lymphoma (42%), chronic lymphocytic leukemia
(29%), Castleman's disease, thymoma, Waldernstrom's macroglobulinemia and follicular dendritic cell sarcoma. In children and
adolescents, association with Castleman's disease is the most frequent. Minimal laboratory workout includes CBC, protein
electrophoresis, chest, abdomen and pelvis CT scan.
Histopathology. Suprabasal acantholysis and necrosis of keratinocytes are observed. In DIF, there is deposit of IgG (with or without C3)
in the intercellular spaces of the epidermis and/or basement membrane. IIF shows antibodies of the IgG type.
Pathophysiology. The exact etiology of the disease is unknown. It is believed that an immunological deregulation in antitumor antibodies
leads to the production of autoantibodies that bind to epidermal proteins (plakin family) present in desmosomes and hemidesmosomes
responsible for cell adhesion, thereby causing skin displacement. The search for malignancy should be conducted through a
comprehensive physical examination targeting the liver, spleen and lymph nodes
Paraneoplastic pemphigus
PARANEOPLASTIC PEMPHIGUS
Target antigens in paraneoplastic pemphigus (labelled in red) and their
locations. The plakins are present in both the desmosomes and
hemidesmosomes
.
PARANEOPLASTIC PEMPHIGUS
•
Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a
patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces
.
OTHER PARANEOPLASTIC DERMATOSES
OTHER PARANEOPLASTIC DERMATOSES
•
•
•
•
•
•
•
•
OTHER PARANEOPLASTIC DERMATOSES
Some other skin diseases are often associated with neoplasia, but with less associative strength than the paraneoplastic syndromes
previously described. We briefly describe the main syndromes below. Upon finding such dermatoses, the doctor should investigate
possible cancers.
Pityriasis rotunda. It is a rare disease characterized by multiple, well-defined circular macules that can be hyper or hypopigmented
and that are typically found in the trunk. One third of patients have an underlying disease, including tuberculosis, leprosy, liver and lung
diseases. Associated neoplasms include hepatocellular, gastric and esophageal carcinoma, prostate cancer, chronic lymphocytic
leukemia and multiple myeloma.
Dermatomyositis. It is an idiopathic inflammatory disease that affects the skin and muscles. Classical clinical findings include
heliotrope and Gottron's sign, malar erythema and poikiloderma in a "V" photodistribution on the thorax (with no history of sun exposure) known as shawl sign - associated with symmetric proximal paresis. Approximately 10% to 25% of cases are paraneoplastic. Incidence is
even higher in adults over 45 years, since dermatomyositis in children is not associated with malignancies. Clinical manifestations are the
same in the absence or presence of an underlying neoplasm. Ovarian, pulmonary (bronchogenic carcinoma), gastric (adenocarcinoma)
and genital carcinomas are the most often correlated.
Palmoplantar keratoderma. It is a disease characterized by alterations in keratinization, which may be inherited or acquired.
Different associations with malignancy have been described. The prototype of the inherited disease is Howell-Evan's Syndrome, which
has a 36-fold higher risk of development of oral or esophageal carcinoma. Skin lesions usually begin in childhood, although neoplastic
involvement occurs on average at 61 years of age. The pathogenesis of the syndrome has been linked to chromosome 17q24, a site of
keratin.
Pyoderma gangrenosum. It is a neutrophilic dermatosis that manifests as painful nodules and pustules with erythematous edges
and rapid evolution to deep ulcerations with undermined edges, whose debridement or surgical intervention may lead to worsening of the
lesion due to pathergy. The pretibial area is the most affected About 70% of cases are associated with an underlying condition, such as
inflammatory bowel disease and rheumatoid arthritis. Seven percent (7%) are associated with neoplasms, and malignant and
premalignant hematological diseases, such as myelodysplastic syndrome, myeloma, paraproteinemia (IgA) and leukemias, are the most
often reported.
Sweet Syndrome (acute febrile neutrophilic dermatosis). It is a process of systemic neutrophilic reactivation characterized by painful,
edematous, shiny erythematous nodules or plaques which usually occur in the head, neck and upper limbs. It is described in three
associations: classical or idiopathic form - associated with inflammatory bowel disease, infection of the upper respiratory tract and
pregnancy. post-drug; associated with malignancy (20%). Most neoplastic associations involve hematologic neoplasias, and acute
myelogenous leukemia and myelodysplastic syndrome are the main ones.
Other diseases classified as paraneoplastic syndromes are acquired ichthyosis, necrobiotic xanthogranuloma, multicentric reticulohistiocytosis, primary systemic amyloidosis, scleromyxedema and diseases included in the group of genodermatoses.
Pityriasis rotunda
Pityriasis rotunda
Dermatology Online Journal 15 (8): 14
Paraneoplastic Dermatomyositis
•
•
•
Dermatomyositis is an inflammatory myopathy featuring multiple skin changes before the onset of proximal muscle
weakness. Classically, dermatologic findings include a heliotrope rash (so-named for the purplish color of the
heliotrope plant) on the upper eyelids; an erythematous rash on the face, neck, back, chest, and shoulders; and
Gottron papules, a scaly eruption over the phalangeal joints that may mimic psoriasis. Approximately 10% to 25%
of cases are paraneoplastic. The malignancy correlated with dermatomyositis is breast cancer, ovarian cancer,
gastric cancer, lung cancer, malignant lymphoma, mediastinum cancer, liver cancer, prostate cancer, kidney
cancer, leukemia, and so on . Dermatomyositis accompanying malignant tumor is common in people between 4060 years, and the incidence was 15-50% . The biggest risk of dermatomyositis is associated with malignant tumor
and the older, the higher opportunity of tumor accompanyin
The diagnosis of dermatomyositis is suggested by an elevated level of creatine phosphokinase (which may be
followed to monitor response to therapy), characteristic findings on electromyography, and muscle biopsy findings
demonstrating a mixed B- and T-cell perivascular inflammatory infiltrate and perifascicular muscle fiber
atrophy. Because of the association between dermatomyositis and malignancy, expedited age-appropriate
examinations and tests to screen for cancer are warranted in all patients with dermatomyositis.Whether additional
cancer screening is indicated remains unclear. In a series of 40 patients with dermatomyositis or polymyositis, the
following clinical characteristics were significantly associated with malignancy: the presence of constitutional
symptoms, the absence of Raynaud phenomena, rapid onset of myositis, higher mean erythrocyte sedimentation
rate (48 vs 25 mm/h), and higher mean creatine kinase level (2840 vs 1346 U/L [to convert to μkat/L, multiply by
0.0167]). The authors concluded that patients with these features may benefit from a more extensive search for
malignancy, namely CT of the chest, abdomen, and pelvis.
Glucocorticoids are the mainstay of treatment for dermatomyositis, but paraneoplastic dermatomyositis often
requires additional immune-modulating therapies. In most cases, successful tumor-directed therapy will also
ameliorate symptoms; however, up to one-third of patients will have substantial residual motor impairment. In
contrast to dermatomyositis, polymyositis—an inflammatory myopathy without associated dermatologic findings—
is rarely associated with cancer.
Top 15 most uncommon illnesses ever
•
•
Also called orphan DiseasesDiseases, rare diseases are
those that are extremely uncommon and often have such
low prevalence that a common doctor would not run into
more than one case of that disease over a course of
years, if ever. There are more than 6,000 rare diseases
listed in the US Office of Rare Diseases today. There is
no single definition accepted yet to define the term rare
disease, but in the United States, a certain disease can
be considered rare if affects less than 200,000 people
and less than 1 in 2,000 people in European Union
Countries
Meleda disease (MDM)
Also called “mal de Meleda”, also called Mljet disease,
keratosis palmoplantaris and transgradiens of siemens,
(also known as “Acral keratoderma,” “Mutilating
palmoplantar keratoderma of the Gamborg-Nielsen type,”
“Palmoplantar ectodermal dysplasia type VIII”, and
“Palmoplantar keratoderma of the Norrbotten type”) is an
extremely rare autosomal recessive congenital skin
disorder in which dry, thick patches of skin develop on the
soles of the hands and feet, a condition known as
palmoplantar hyperkeratosis. MDM is most common on
the Dalmatian island of Mljet (or Meleda), thought to be
because of a founder effect. It is of autosomal recessive
inheritance. It may be caused by a mutation on the
SLURP1 gene, located on chromosome
Clinical features of pyoderma gangrenosum
Indian Dermatol Online J. 2012 ; 3(1): 7–1
•IBD: Inflammatory bowel disease
Pyoderma gangrenosum
•
•
•
•
•
•
•
Approximately 50% of patients with PG have an
associated systemic disease. These diseases
may precede, follow or occur simultaneously.
Depending upon the associated conditions PG
was also be classified as follows:
@ Parainflammatory (paraimmune) (associated
with IBD( inflammatory bowel disease), collagen
vascular diseases, arthritis, etc)
@ Paraneoplastic (associated with malignancy)
@ Hemotologic (leukemias, polycythemia)
@ Drug induced
@ Idiopathic
The most common associations are IBD, arthritis,
and hematologic diseases. PG associated with
IBD is characterized by ulcerative or pustular PG.
Oral and peristomal PG can also occur. PG in
association with myeloproliferative diseases may
present with bullous PG. In patients with HIV
infection, perineum is the most common site of
involvement and ulcers are often secondarily
infected with bacterial organisms
Pyoderma gangrenosum
•
•
•
Though the etiology is not well understood, the disease is thought to be due to immune system dysfunction, and
particularly improper functioning of neutriphils. In support of an immune etiology, a variety of immune mediators
such as IL-8, IL-1β, IL-6, interferon (IFN)-γ, G-CSF, TNF, matrix metallopaptidase (MMP)-9, MMP-10, and Elafin
have all been reported to be elevated in patients with pyoderma gangrenosum.
Also in support of an immune etiology is the finding that at least half of all pyoderma gangrenous patients suffer
from immune-mediated diseases. For instance, ulcerative colitis, rheumatoid arth& multiple myeloma (MM) have
all been associated with pyoderma gangrenosum. It can also be part of a syndromes such as PAPA syndrome.
One hallmark of pyoderma gangrenosum is pathergy, which is the appearance of new lesions at sites of trauma
.
•
Associations
•
•
The following are conditions commonly associated with pyoderma gangrenosum:
Inflammatory bowel disease:
•
–
–
•
Arthritides:
–
–
•
Rheumatoid arthritis
Seronegative arthritis
Hematological disease:
–
–
–
–
–
•
Ulcerative colitis
Crohn’s disease
Myelocytic leukemia
Hairy cell leukemia
Myelofibrosis
Myeloid metaplasia
Monoclonal gammopathy
Autoinflammatory disease:
–
–
Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome)
Granulomatosis with polyangiitis
Sweet Syndrome
• Approximately 20% of patients with Sweet syndrome have an
underlying cancer, most commonly acute myeloid leukemia or
another hematologic malignancy. The most commonly associated
solid tumors are breast, genitourinary, and gastrointestinal
cancers. The diagnosis of Sweet syndrome typically coincides with
an initial cancer diagnosis or recurrence. Sweet syndrome is
characterized by the sudden onset of painful, erythematous plaques,
papules, and nodules on the face, trunk, and extremities as well as
by neutrophilia and fever.
• First-line treatment includes systemic corticosteroids, colchicine, and
Lugol solution. In general, paraneoplastic Sweet syndrome is less
responsive to therapy than nonparaneoplastic cases, and treatment
of the underlying tumor rarely improves symptoms
Paraneoplastic Syndrome: Knocking on cancers door.