DR. GAMAL SULTAN

Cutaneous

Manifestations of

Internal Malignancy

and Paraneoplastic

Syndromes By

Dr. Gamal Sultan

INTRODUCTIONcutaneous manifestations are extremely valuable marker

because they may well be the presenting manifestation of an

underlying neoplasm.

Increased clinician awareness could prove beneficial for the

patient by promoting earlier screening and diagnosis, as well

as increased intervention measures, thereby significantly

affecting the chances of survival and/or improving the quality

of life of the patient DR. GAMAL SULTAN

DR. GAMAL SULTAN

CUTANEOUS METASTASIS OF MALIGNANCIES

CUTANEOUS SIGN & SYMPTOMS OF MALIGNANCY

CUTANEOUS PARANEOPLASTIC

SYNDROMES

Cutaneous Metastasis of Internal Malignancies

Cutaneous metastases from carcinoma are relatively uncommon in clinical practice, but they are very important to recognize

The incidence of cutaneous malignancy varies. In some autopsy studies of patients with metastatic carcinoma, as many as 9% of individuals were noted to have cutaneous metastases. Other studies suggest a range of 3-4%.

rarely the presenting sign but their re-appearance may be an indicator of disease recurrence.

DR. GAMAL SULTAN

The most common metastatic malignancies In woman

the breasts (69%), the colon (9%), melanomas (5%), the ovaries (4%), and the lungs (4%).

In men the lungs (24%), the colon (19%), melanoma (13%), and the

oral cavity (12%).

DR. GAMAL SULTAN

The mechanism for metastasisRegional spread by way of tissue most often occurs through body cavities, especially the peritoneal cavity. Transplantation can be caused by mechanical transport of tumor fragments by instruments during surgery or other invasive procedures.

Lymphatic and vascular routes are the most common pathways, Lymphatic spread is the most common pathway for the initial

spread of carcinoma. Hematogenous spread is commonly associated with

metastasis from sarcomas

DR. GAMAL SULTAN

Clinical Presentation of Cutaneous Metastases

They present as solitary or multiple nodules. The nodules are often nonpainful, round or oval, firm, mobile, and rubbery in texture. The nodules are usually flesh colored, ( from flesh colored to brown or blue-black).

tend to have a predilection for areas of old surgical scars

DR. GAMAL SULTAN

The scalp is a primary site of distant tumor metastases, with lesions that appear either nodular or as circumscribed areas of hair loss, known as alopecia neoplastica

DR. GAMAL SULTAN

The lymphatic obstruction from tumor cells leads to extensive thickening of the skin, and fibrosis of the dermis and subcutaneous tissue The term carcinoma en cuirasse is a hard and infiltrated plaque with a characteristic leathery or woody appearance

DR. GAMAL SULTAN

Sister Mary Joseph’s nodule

is a broad term that refers to any

malignant metastatic nodule near

the umbilical area, with the primary

sites of origin most commonly being

malignancies of the stomach, colon,

ovaries, pancreas, gallbladder, and

lymphomas

DR. GAMAL SULTAN

DR. GAMAL SULTAN

Common cutaneous sites for metastases and their probable primary sites

Scalp breast, lung,kidney

Neck oral SSC

Face oral SSC, lung,

kidney

Chest breast, lung, mela-

noma

Extremities melanoma, breast, lung, renal, intestinal

Umbilicus (Sister Mary Joseph's nodule)

stomach, colon, ovary, kidney, breast

Back lung

Cutaneous Signs and Symptoms Associated With

Internal Malignanciesnonspecific lesions associated

malignancies include:

pruritus petechiae, ecchymos

espallor ichthyosis

urticaria bullous eruptions

erythema nodosum alopecia

stomatitis phlebitis

DR. GAMAL SULTAN

PruritusGeneralized pruritus may be the initial symptom present in patients with solid tumors .

pruritus origin is complex. It can be either peripheral or central in origin.

The production of pruritogenic mediators such as histamine, serotonin, and cytokines stimulate the free nerve endings of specialized C fibers found in the skin

DR. GAMAL SULTAN

The use of corticosteroids or H2 receptor blockers,, is not useful in the treatment of pruritus associated with solid tumors. Twycross et al. proposed a treatment ladder for the management of pruritus in these patients, consists of using paroxetine DR. GAMAL SULTAN

A localized itch may offer a diagnostic clue to an underlying malignancy, for example:

(1) scrotal itch may be associated with prostate cancer;

(2) nostril itching associated with brain tumors infiltrating the floor of the fourth ventricle;

(3) vulval itch with cervical cancer;

(4) perianal itch with colon or rectal cancer

DR. GAMAL SULTAN

PARANEOPLASTIC SYNDROMES

They are defined as clinical syndromes involving non-metastatic systemic effects that accompany malignant disease

disorders that are triggered by an altered immune system response to a neoplasm. result from substances produced by the tumor, and they occur remotely from the tumor itself

The symptoms may be endocrine, neuromuscular or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature.

DR. GAMAL SULTAN

ACANTHOSIS NIGRICANS  (AN) manifests as a hyperpigmented, velvety thickening of the skin that usually occurs in the intertriginous zones, including the axillae, groin, neck, and inframammary folds.

DR. GAMAL SULTAN

Acanthosis nigricans can be classified into three different subgroups:

the hereditary benign acanthosis nigricans,

Acanthosis nigricans related to obesity

Acanthosis nigricans in an obese patient, it is usually benign and related to an increase in insulin resistance. A family history of endocrinopathies,as well as chronic steroid use.

malignant acanthosis nigricans

DR. GAMAL SULTAN

Malignant Acanthosis Nigricans Patients who have AN associated with malignancies also have skin changes involving the scalp, areolae, and

eyelids.

Most cases of paraneoplastic AN involve an adeno-carcinoma, most commonly one arising in the GIT (stomach or live) and less commonly in the (lungs, ovaries,

uterus, breasts, kidneys, prostate or

bladder)

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ACQUIRED ICHTHYOSIS conditions manifest with small, whitish to brownish, polygonal scales that lift up at the free edge and are widely distributed on the trunk and extensor surfaces of the extremities.

The palms and soles are usually spared. This condition is associated with a variety of chronic illnesses, including malignancy.

DR. GAMAL SULTAN

DR. GAMAL SULTAN

Associated noncancerous conditions Acquired immunodeficiency syndrome (AIDS) Systemic lupus erythematosus

Sarcoidosis

Autoimmune disease e.g., dermatomyositis and mixed connective-tissue disease

Endocrine abnormalities E.g., hyperparathyroidism and hypothyroidism

Malnutrition

Infectious etiologies - E.g., tuberculosis and leprosy

Use of certain medications - E.g., nicotinic acid, cimetidine, and clofazimine

DR. GAMAL SULTAN

Associated cancersAI is most strongly associated with Hodgkin lymphoma

Other AI-associated malignancies include Kaposi sarcoma,

cutaneous T-cell lymphoma, non-Hodgkin lymphoma,

leukemias, and solid tumors (including those arising in breasts, lungs, or bladder).

Rare cases of AI associated with graft versus host disease

(GVHD) have been reported after bone marrow transplantation.

DR. GAMAL SULTAN

Acrokeratosis paraneoplastica

(Bazex syndrome) symmetrical, scaly, violaceous plaques on the acral surfaces, with severe forms progressing to bullae. The lesions predominantly occur on the hands, feet, ear helices, nose tip, and scalp

DR. GAMAL SULTAN

Skin changes may spread to involve the knees, elbows, and malar surface of the face.

Alopecia and nail changes are common and can be early findings. Subungual hyperkeratosis, onycho-dystrophy, and white flaking of the nail surface.

DR. GAMAL SULTAN

Skin eruptions often precede detection of the cancer, with a reported median interval of as long as 1 year between the onset of skin changes and the diagnosis of malignancy.

The development of the lesions also tends to parallel the course of malignancy

The lesions may regress with successful cancer therapy and may recur with relapses, thus serving as a marker for status.

DR. GAMAL SULTAN

3 well characterized stages that parallel the dissemination of the underlying cancer

Stage 1: poorly defined psoriasiform plaques involving the ears, nose, nails, fingers, and toes; nail folds become dystrophic at this stage

Stage 2: larger and more proximal regions; violaceous keratoderma with central clearing is seen over the cheeks, palms, and/or soles

Stage 3: Characterized by involvement of the legs, knees, thighs, and arms

DR. GAMAL SULTAN

associated cancers Bazex syndrome appears to be exclusively associated with malignancy; therefore, its presence should prompt an extensive search for an occult cancer.

It is most commonly associated with squamous cell

carcinomas of the upper aerodigestive tract, including the tongue, floor of the mouth, palate, tonsils, pyriform sinus, larynx, pharynx, esophagus.

Cancers also reportedly; these include adenocarcinoma of

the colon and breast and Hodgkin lymphomas.DR. GAMAL SULTAN

Sign of Leser-Trélat defined as the rapid increase in the number and size of seborrheic keratoses in patients with an internal malignancy.

DR. GAMAL SULTAN

Lesions can develop anywhere, but they are most common in the usual distribution of seborrheic keratoses; ie, the chest and back (76% of cases).

Patients either are asymptomatic or have symptoms limited to pruritus (50% of cases).

DR. GAMAL SULTAN

Associated noncancerous conditions

acute drug eruptions

human immunodeficiency virus (HIV) infection

exfoliative erythroderma

benign neoplasms

pregnancy.

DR. GAMAL SULTAN

Associated cancers

most cases involve adenocarcinomas, especially those of the

stomach

lungs

colon

rectum

breasts. DR. GAMAL SULTAN

Tripe palmsalso known as acanthosis nigricans of the palms,, and acanthosis palmaris, is characterized by the appearance of hypertrophic ("velvety") papillation of the palms and soles, along with exaggerated dermatoglyphics and hyperkeratosis.

Tripe palms often occurs simultaneously with other paraneoplastic syndromes, including AN and the sign of Leser-Trélat.

DR. GAMAL SULTAN

The skin changes of tripe palms most often predate (60%) the diagnosis of cancer, but they may occur at any point in the course of the malignancy.

23% of lesions occur after the malignancy, and 17% coincide with it.

Lesions respond to successful cancer therapy, but they may persist for despite remission of the underlying tumor.

DR. GAMAL SULTAN

Associated cancers90% of cases are associated with malignancy

gastric and bronchogenic carcinomas are the most common.

A wide variety of tumor types, including cancers of the gastrointestinal tract, lungs, head and neck, and genitourinary (ovarian) system, have been reported;

Tripe palms in the absence of AN is more often associated with lung neoplasms

DR. GAMAL SULTAN

Extramammary Paget’s disease

most commonly seen in the anogenital region.

Evidence of perianal involvement has been reported to be associated with underlying cancer in 25–35% of patients, whereas only 4–7% of those with genital involvement are associated with cancer.

DR. GAMAL SULTAN

If evidence of perianal

involvement is found, the presence of rectal cancer

should be excluded.

if the genital area is affected, cancers from the urogenital or reproductive tracts should then be excluded .

DR. GAMAL SULTAN

Clinicians may confuse the diagnosis of extramammary Paget’s disease as eczema, candidiasis, leukoplakia,

or lichen simplex chronicus. Therefore, a thorough and pertinent patient history and assessment of possible risk factors for the development of cancer should be obtained.

DR. GAMAL SULTAN

Paraneoplastic pemphigus

autoimmune paraneoplastic syndromes. It is characterized by painful, intractable, erosive ulcerative stomatitis and a polymorphic cutaneous eruption consisting of erythema, papules, iris lesions, bullae, and erosions

DR. GAMAL SULTAN

2/3 of cases, paraneoplastic pemphigus occurs in patients with a known, preexisting neoplasm. However,

1/3 of patients develop the mucocutaneous disease before the neoplasm is detected.

DR. GAMAL SULTAN

Associated cancers Paraneoplastic pemphigus is most often associated with B-cell

lymphoproliferative disorders, especially non-Hodgkin lymphoma (80%). also linked to chronic

lymphocytic leukemia, Castleman disease, thymoma,

An association with solid tumors is extremely rare

DR. GAMAL SULTAN

Dermatomyositis DM is an inflammatory proximal myopathy with characteristic skin changes; it is often associated with an occult malignancy.

The rash is characteristic and diagnostic and usually accompanies or precedes the onset of the myopathy.

DR. GAMAL SULTAN

Skin manifestations of dermatomyositis

Heliotrope rash and Periorbital edema

(so named because of the similarity to the color of the blue-purple flower, the heliotrope) on the upper eyelids

DR. GAMAL SULTAN

DR. GAMAL SULTAN

Gottron papules

Violaceous, scaly papules over the interphalangeal and metacarpophalangeal joints that evolve into atrophic telangiectatic macules

DR. GAMAL SULTAN

Gottron sign

Scaling, erythematous to violaceous plaques over the elbows, knees and malleoli with follicular plugging

DR. GAMAL SULTAN

(poikiloderma)

A macular, red rash on the face and the V of the upper trunk that may become shiny and atrophic, with variable pigmentation and telangiectasias

DR. GAMAL SULTAN

The myopathy produces symmetrical weakness of the limb-girdle muscles and anterior neck flexors, with or without muscle tenderness.

This weakness progresses over weeks to months, with variable involvement of the pharynx, upper esophagus, or respiratory muscles.

DR. GAMAL SULTAN

Associated cancers

Most malignancies are detected within 2 ys of onset of DM.

approximately 25% of patients with DM already have or will develop cancer and risk increase for patients with DM is increased 6-fold over the general population.

The malignancies associated with DM are those common for ovarian, cervical, lung, and pancreatic and

gastric carcinomas, in addition to non-Hodgkin

lymphoma, DR. GAMAL SULTAN

Erythema gyratum repensLesions consist of dramatic, erythematous, concentric rings with scales, which cause the classic wood-grain appearance.

Lesions may be flat or slightly raised.

They are localized to the trunk and proximal extremities, sparing the feet, hands, and face.

DR. GAMAL SULTAN

The rings spread outward in a serpiginous

pattern at a rapid rate; the lesions may

advance at a rate of 1cm daily.

Patients universally report severe pruritus,

and concurrent hyperkeratosis of the palms

and soles has also been reported.

Marked peripheral eosinophilia may occur.

DR. GAMAL SULTAN

Associated noncancerous conditions EGR without a detectable malignancy, have in rare cases reported with:

tuberculosis,

CREST (ie, calcinosis cutis, Raynaud phenomenon, bullous dermatoses, esophageal motility disorder, sclerodactyly, bone marrow transplantation, telangiectasia) syndrome.

bullous pemphigoid,

pityriasis rubra pilaris,

psoriasis, to be associated with EGR. DR. GAMAL SULTAN

Associated cancers EGR is almost always (> 80%) indicative of an underlying malignancy

Cancers associated with EGR are

transitional cell carcinoma of the kidney

the lungs

esophagus

breasts.

DR. GAMAL SULTAN

Necrolytic migratory erythema

The skin and mucous membranes are affected, with painful, migratory, erythematous, polycyclic patches or plaques with superficial pustules, vesicles, or bullae being present.

DR. GAMAL SULTAN

The lesions are typically widespread, but they are accentuated in the intertriginous areas, lower abdomen, and proximal parts of the lower extremities.

It is often present in a triad with NME, glucose intolerance, and hyperglucagonemia.

The typical patient with NME is middle aged, has diabetes, and has the characteristic rash

DR. GAMAL SULTAN

The diagnosis of NME and glucagonoma syndrome is often difficult and usually occurs several years after the initial skin manifestations are noticed.

The most common attempts for treating a presumed

benign inflammatory dermatosis by using topical

antifungal agents or steroids. This approach is

unsuccessful, and patients eventually undergo diagnostic

skin biopsy, which reveals NME.

The differential diagnosis of NME includes non-neoplastic conditions such as acrodermatitis enteropathica, chronic mucocutaneous candidiasis, pemphigus foliaceus, and acquired zinc deficiency.

DR. GAMAL SULTAN

Confirming a diagnosis of is achieved by performing specific laboratory tests and imaging studies to localize the pancreatic tumor.

Elevated serum glucagon levels (and occasionally insulin levels),

an abnormal glucagon response to arginine infusion,

glucose intolerance, and

hypoaminoacidemia

Imaging studies are used to localize the pancreatic tumor.

Celiac arteriography, which reveals the characteristic hypervascularity of the tumor, is believed to be more sensitive than CT scanning for identifying the primary lesion.

DR. GAMAL SULTAN

Associated cancers

NME is unique among paraneoplastic syndromes in that it is almost always associated with a glucagon-secreting alpha-cell neoplasm of the pancreas,

although it may rarely occur in the presence of jejunal and rectal adenocarcinomas, villous atrophy of the small intestine, hepatitis B, or myelodysplastic syndrome.

Of patients with symptomatic glucagonomas, an estimated 67-90% have NME.

DR. GAMAL SULTAN

Sweet syndrome (Acute Febrile Neutrophilic

Dermatosis) Sweet syndrome is characterized by fever, neutrophilia, and sterile erythematous plaques or nodules.

Skin lesions most commonly involve the upper extremities and face and begin as tender, erythematous plaques or nodules. The lesions may evolve into vesicles, bullae, or pustules.

DR. GAMAL SULTAN

Extracutaneous manifestations are not infrequent and commonly involve the eyes, lungs, liver, kidneys, muscles, and bones.

Laboratory features include neutrophilia, anemia, and an elevated erythrocyte sedimentation rate.

DR. GAMAL SULTAN

The diagnosis of Sweet syndrome is based on the clinical presentation and characteristic findings at skin biopsy.

Histologic evaluation reveals a neutrophilic infiltrate in the dermis, without evidence of infection, vasculitis, or malignant cells.

Patients frequently have a positive perinuclear antineutrophil cytoplasmic antibody titer.

DR. GAMAL SULTAN

non-cancerous associasionCertain drug exposures: imatinib, all- trans -retinoic acid, granulocyte stimulating factor, and sulfa-based antibiotics

Autoimmune diseases: relapsing polychondritis 

Infections: with mycobacteria

Hematologic diseases: myelodysplastic syndrome

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Associated cancers

Sweet syndrome is associated with an underlying cancer in 20% of cases.

Approximately 80% of these cases involve hematologic malignancies; acute myeloid leukemia is most common.

Cases involving solid tumors are also described, usually in association with adenocarcinomas of the breast or gastrointestinal and genitourinary tracts

DR. GAMAL SULTAN

DR. GAMAL SULTAN