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Clinical Updates

Seemal Desai

Paraneoplastic Dermatoses

Seemal Desai

Thursday, September 19, 2013

Introduction

Paraneoplastic dermatoses are a heterogeneous group of non-inherited skin conditions that manifest an internal malignancy and may develop before a diagnosis of malignancy is determined.1 They may therefore aid the early detection of an underlying malignancy and it is important for dermatologists to be familiar with how these present in the clinic.

Classification of paraneoplastic dermatoses

Papulosquamous dermatoses are characterized by well-demarcated areas of papules and scales, typically on an erythematous background, including psoriasis, discoid lupus, and erythematous disorders.2 Malignant manifestations are typified by acanthosis nigricans (AN), tripe palms, and acrokeratosis paraneoplastica (Bazex syndrome).

AN manifests as hyperpigmented, velvety thickening of the skin in axillae, the groin, neck, and inframammary folds and usually coincides with the malignancy, but may also precede or follow diagnosis.1,3

Tripe palms is characterized by hypertrophic papillation giving a characteristic "velvety" appearance to soles and palms, often occurring simultaneously with other paraneoplastic disease such as AN and Sign of Lesser-Trélat.1,3 Importantly, the occurrence of tripe palms is thought to be highly predictive for a number of cancers often predating their diagnosis.3

Acrokeratosis paraneoplastica or Bazex syndrome, is exclusively associated with cancer, most commonly accompanying squamous cell carcinoma of the upper aerodigestive tract but it is also associated with adenocarcinoma of the colon and breast as well as Hodgkin lymphoma.1,3,4

Bazex syndrome (Figure 1) has a well-defined natural history comprised of three distinct stages: Erythrosquamous eruption on fingers and toes, violaceous keratoderma on lateral aspects of fingers and toes, and involvement of the trunk, extremities, and scalp.5 Interestingly, the development of these lesions tends to parallel the course of malignancy and has been shown to regress with successful cancer therapy, sometimes recurring upon cancer relapse, thus serving as a surrogate for cancer status.1

Figure 1 - Bazex syndrome

Desai 

 

Desai 2

 

Reactive erythemas such as erythema gyratum repens (EGR) and neutrophilic dermatoses like Sweet syndrome and necrolytic migratory erythema (NME) all have associations with underlying cancers; in more than 80% of cases, EGR is indicative of an underlying malignancy, often preceding the diagnosis by up to 2 years,1,6 and predominantly affecting males6 - by contrast, Sweet syndrome is associated with a malignancy in approximately 20% of cases,1 but in cases where Sweet syndrome is linked, it commonly occurs before or coincident with cancer diagnosis - indeed, up to 40% of patients have a diagnosis of cancer within one month of presentation.1,5,7

NME is almost always due to a rare glucagon-secreting alpha cell neoplasm of the pancreas called glucagonoma.1,8 Unfortunately, due to its usually delayed diagnosis, it is associated with metastatic disease.1

Finally, interface dermatitides describe a collection of inflammatory diseases of the interface between the epidermis and dermis and can be categorized as vacuolar or lichenoid with respect to their microscopical pattern.9 Some of these, for example, paraneoplastic pemphigus (a vesiculobullous disorder that may be characterized by the presence of an interface dermatitis), are strongly associated with an underlying malignancy, particularly those of haematological origin.1,5,10

 

Table 1: Morphological and oncological features of selected Paraneoplastic disorders. Adapted from Nguyen VQ et al. 1985; Chung VQ et al. 2006; and Lee A, 2009. 

Lesion

Appearence

Associated malignancy

Papulosquamous disorders
 

Acanthosis nigricans (AN) Hyperpigmented velvety thickening1,5,8 GI tract, lung carcinoma and uterus1,5,8
Tripe Palms Hypertrophic papillation of palms and soles1,5,8 GI tract and lung; head and neck1,5,8
Acquired ichthyosis Rare. Small white/brown polygonal scales lifting at free edge;1,8 can be distinguished from autosomal dominant AI from the fact it tends to spare flexures, palms, folds and soles8 Hodgkin lymphoma (70-80%), Kaposi sarcoma, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, leukemias, and solid tumors1,8
Acrokeratosis paraneoplastica (Bazex syndrome) Scaly, violaceous plaques, symmetrically distributed lesions over hands, feet, knees, nails, eyebrows, and ears; severe examples progress to bullae1,8 Exclusively associated with cancer, commonly accompanying squamous cell carcinoma of upper aerodigestive tract1,8
Sign of Leser-Trélat Rapid increase in number and size of seborrheic keratosis8 Adenocarcinoma of lung, colon, and breasts in the young; predictive value is questionable thanks to high prevalence in elderly populations1

Reactive erythemas and neutrophilic dermatoses
 

Erythema gyratum repens Polycyclic, geometric, or arciform plaques giving a wood grain appearance6 Carcinoma of the kidney, lungs, esophagus, and breasts1,8
Sweet syndrome Plum-colored nodules affecting head, neck, and dorsae of hands5,8 Associated with cancer (20%); majority of these are haematological malignancy5,8 
Necrolytic migratory erythema Erythematous papules forming patches evolving into vesicles, flaccid bullae, and pustules before becoming erosions and crusts1,8 Glucagonoma; associated with high prevalence of metastatic disease due to delay in diagnosis1,8

Interface dermatitides
 

Paraneoplastic dermatomyositis Eruption on exposed surfaces; pruritus of skin lesions; scaly scalp, diffuse hair loss5,11 Strongly associated with ovarian, lung, pancreatic, stomach, and colorectal cancer and NHL;5,11 treatment of the cancer normally helps to resolve skin changes5
Paraneoplastic pemphigus Pruritic polymorphous papules and patched on trunk5,10 75% associated with lymphoproliferative disease (42% NHL, 29% chronic lymphocytic leukemia)5,10

Dermal processes and miscellaneous diseases
 

Necrobiotic xanthogranuloma Purpuric yellow plaques in periorbital and flexural areas8 Monoclonal gammopathy, multiple myeloma8
Scleromyxedema Scleroderma-like thickening of skin associated colored or erythematous popular infiltrate8 Monoclonal gammopathy, multiple myeloma8
Cutaneous amyloidosis Macroglossia, purpura especially periorbital, and infiltrated papules8 Monoclonal gammopathy, multiple myeloma8
Hypertrichosis lanuginosa acquisata Development of soft downy hair on the face, within eyelashes and brows5 In men, most commonly associated with lung cancer and then colorectal cancer; in women, most common is colorectal and then lung and breast cancer. Skin manifestation appear late in disease, often after metastasis5

 

AN, acanthosis nigricans; GI, gastrointestinal; NHL, non-hodgkins lymphoma.

Evaluation and work-up

The relationship between some skin findings and an occult malignancy is, in some cases, clearly established. However, in cases where the connection is equivocal, the challenge for the clinician is deciding whether to implement full evaluation. Cancer screening is often a source of further anxiety for the patient, not to mention an arduous process of elimination - particularly when the skin condition could indicate one of several malignancies. In each case, a thorough history and physical examination should be combined with an age- and sex-appropriate cancer screen. Thus a typical work-up may include the following:

  • Physical exam, including thorough head and neck exam and a full body skin examination
  • Palpation for lymphadenopathy
  • Skin biopsy for H&E staining and tissue culture
  • Chest X-ray
  • Routine laboratory evaluation:
    • Complete blood count and metabolic panel
    • Urine analysis
    • Sedimentation rate, ANA count, certain lesion specific tests including LDH level, PSA for men and stool analysis for occult blood
  • Health maintenance screening:
    • Colonoscopy, mammography for women, urological evaluation including digital rectal examination for men

ANA, antinuclear antibody; H&E, hematoxylin & eosin; LDH, lactose dehydrogenase; PSA, prostate specific antigen

Conclusions

As dermatologists, we occupy a unique position with potential to diagnose underlying malignancies that other specialities could miss. Therefore, it is crucial that we always consider a malignancy when dealing with an atypical presentation. Never be afraid to order laboratory examinations if you suspect a malignancy and seek the advice of primary care providers or a specialist. As always, spending time with the patient to discuss potential diagnoses, and offering a thorough physical examination and history, will allow the clinician to better diagnose and potentially cure these conditions.

References

  1. Nguyen VQ, et al. Dermatologic Manifestations of Paraneoplastic Syndromes. Medscape. Available at http://emedicine.medscape.com/article/1095113-overview#a1. Last accessed 17 July 2013.
  2. Fox BJ and Odom RB. Papulosquamous diseases: a review. J Am Acad Dermatol 1985;12:597-624.
  3. Dourmishev LA and Draganov PV. Paraneoplastic dermatological manifestation of gastrointestinal malignancies. World J Gastroenterol 2009;15:4372-9.
  4. Cohen PR, et al. Tripe palm and malignancy. J Clin Oncol 1989;7:669-78.
  5. Chung VQ, et al. Clinical and pathologic findings of paraneoplastic dermatoses. J Am Acad Dermatol 2006;54:745-62.
  6. Eubanks LE, McBurney E and Reed R. Erythema gyratum repens. Am J Med Sci 2001;321:302-5.
  7. Kruzrock R and Cohen PR. Mucocutaneous Paraneoplastic Manifestations of Hematologic Malignancies. Am J Med 1995;99:207-16.
  8. Lee A. Skin Manifestations of Systemic Disease. Australian Family Physician 2009;38:498-505.
  9. USCAP virtual slide box. Available at http://www.uscap.org/site~/iap2006/slides09-1v.htm. Last accessed 17 July 2013.
  10. Robinson ND, et al. The new Pemphigus Variants. J Am Dermatol 1999;40:649-71.
  11. Hill CL, et al. Frequency of Specific Cancer types in Dermatomyositis and Polymyositis: A Population-based Study. The Lancet 2001;357:96-100.
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