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Slides for residents

Slides for residents. Dr,F iraji. Clinical History.

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Slides for residents

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  1. Slides for residents Dr,Firaji

  2. Clinical History • 52 year old white female presented for removal of multiple mucosal and cutaneous lesions. Over the course of her lifetime, the patient has had more than 30 surgical procedures to address her mucocutaneous as well as internal lesions. These procedures included removal of a large benign ovarian tumor at the age of 16, meningioma resection at the age of 37, removal of gastric and colonic polyps, history of goiter and most recently diagnosis of breast cancer for which patient has undergone left mastectomy and right lympectomy. Patient’s father and grandfather both have been diagnosed with the same genetic condition as our patient but have had less prominent manifestations of the syndrome.

  3. Physical Exam • Physical exam of the patient was significant for diffuse flesh colored mucocutaneous papules along with prominent cobblestoning of the oral mucosa (Figures 1-4).  Pathology showed a verrucous lesion consisting of lobular proliferation of bland cells with peripheral nuclear palisading. Lobules were surrounded by a prominent basement membrane.  All histological findings were consistent with a trichilemomma (Figures 5-7).  • Patient’s medical and family histories, cutaneous manifestations along with pathology were diagnostic of  Cowden syndrome

  4. Discussion • Clinical findings of Cowden or multiple hamartoma syndrome were first described by Costello in 1940 in a female patient who died from breast cancer at an early age.1  In 1963, a term Cowden syndrome was coined by Rachel Cowden, with family history of the disorder, presented with multiple cutaneous and mucosal lesions, fibrocystic disease of the breast and thyroid abnormalities.  

  5. Discussion • The gene responsible for the multiple hamartoma syndrome was mapped to chromosome 10 and then identified as PTEN.  PTEN which stands for phosphatase and tensin homolog deleted on chromosome 10, is a tumor suppressor gene which encodes a phosphatase that normally dephosphorylates serine and threonine residues thus opposing the activity of downstream AKT serine/threoninekinase.  When functioning normally, PTEN regulates cell cycle, cell migration, angiogenesis and apoptosis through various interconnecting pathways. Mutations in PTEN have been found in a number of malignancies most of which are common to Cowden syndrome including breast carcinoma, meningioma, endometrial carcinoma, ovarian tumors, renal cell carcinoma and melanoma.

  6. Discussion • The most prominent and common features of the Cowden syndrome are the mucocutaneoushamartomas (most often trichilemmomas) that present as facial papules and lead to cobblestone appearance of the mucosa in as many as 80% of the patients.Acral, including palmoplantarkeratoses, hemangiomas, lipomas, neuromas and xanthomas are other cutaneous lesions that can be seen in patients with this multiple hamartoma syndrome. • As the history of our patient demonstrates, all patients with Cowden syndrome must be regularly screened for breast, thyroid and endometrial carcinomas that are part of the International Cowden Consortium Diagnostic –Major Criteria.  Other malignancies associated with Cowden Syndrome but with less frequency include SCCs, BCCs, Merkel cell carcinomas, melanomas, lymphomas, hepatocellular and renal cell carcinomas. • Differential diagnosis of Cowden syndrome should always include a family of Hamartomatous Tumor Syndromes (PHTS) that also have been found to have PTEN gene abnormalities with variable frequencies. In this category is Lhermitte-Duclos disease,  Bannayan-Riley-Ruvalcaba Syndrome, Proteus Syndrome and VATER syndrome

  7. Clinical History • A 38 year-old white male presented with a 25-year history of multiple “warts” over his distal upper and lower extremities, inculding the dorsal hands and feet.  He stated that the lesions are asymptomatic and he often “pulls them off”.  Some moisturizers he had tried in the past help to soften the lesions, although nothing completely resolved them.  He had no significant past medical history or chronic medical diseases.  On further history, he stated that his father has similar lesions with a similar course. 

  8. Physical Exam • Physical exam revealed hundreds to thousands of 1-3mm gray-white verrucous papules with a “stuck-on” appearance over the patient’s hands, feet, and distal upper and lower extremities. (Fig. 1 and 2)  His head, neck, trunk, and groin were within normal limits. • Histopathology: • Biopsy revealed a verrucous lesion on low power with hyperkeratosis, acanthosis, and papillomatosis in a “church-spire” configuration. (Fig. 3 and 4)

  9. Discussion • Acrokeratosisverruciformis (AV) is a rare autosomal dominant genodermatosis first described by Gustav Hopf in 1931.  It is characterized by multiple flesh-colored to gray hyperkeratotic papules over the distal upper and lower extremities.  Lesions may also be reddish-brown or pigmented and present over the knees and elbows.  They usually appear in childhood, but may be present at birth or not appear until adulthood.  AV has been associated with degeneration to squamous cell carcinoma, but it is unclear whether sun exposure played a role in these cases (i.e., the lesions were incidental in the affected area). 

  10. Discussion • There are also associations of AV with epidermodysplasiaverruciformis and basal cell nevus syndrome, but these are controversial.  Histologically, the lesions are characterized by hyperkeratosis, acanthosis, and papillomatosis with a “church-spire” configuration, essentially undistinguishable from a stucco keratosis.  Recently it has been shown that some patients with AV have a mutation in ATP2A2, allelic to Darier’s Disease.  A genetic analysis of Chinese patients with AV showed no mutations in ATP2A2, however, which demonstrates genetic heterogeneity in this disorder. 

  11. Discussion • Treatments include:  1) destructive methods, such as keratolytics, cryotherapy, and laser ablation; and 2) medical treatments, such as topical and oral retinoids.  There is a report of clearing with oral acitretin, but the benefits of life-long therapy must be weighed against the risks of the medication.  The lesions will return after therapy is discontinued.

  12. Clinical History • 42 year old Caucasian male with past medical history significant for insulin dependent diabetes mellitus was referred from an outside dermatologist for “tough skin” on the posterior neck and upper back, which had been present for ten years. Due to this “tightness,” his skin did not form folds with movement of the neck, back, and shoulders. He reported no associated symptoms other than stiffness. Specifically, he had no respiratory or cardiac complaints. He had been previously biopsied by an outside dermatologist, yielding nonspecific findings, and a deeper biopsy was recommended.

  13. Physical Exam: • The patient was well developed, well nourished, and in no apparent distress. The skin of the posterior neck and upper back was firm, indurated, and mildly erythematous (Figure 1). He had no other cutaneous findings.

  14. Laboratory investigations: • CBC, LFT, BUN, and serum creatinine were normal. ANA was 18. HbA1c was 6.9. Serum protein electrophoresis was normal. • Histology:We performed a deep wedge biopsy of the posterior neck. Histology revealed an unaffected epidermis with a dramatic increase in dermal thickness. There was dermal fibrosis and edematous spaces between collagen bundles , corresponding to hyaluronic acid (mucin) deposition (Figures 5-6).

  15. Scleredemaadultorum of Buschke • Scleredema is a skin disease characterized by firm, nonpitting edema of the skin of the neck/face, back, shoulders, arms, and less commonly, the distal extremities.  The skin texture is firm and wood-like, and fails to form skin folds with movement of the affected body parts.  Except in diabetes-associated cases, there is no clear-cut demarcation from surrounding skin.

  16. Scleredemaadultorum of Buschke • Scleredema is seen in three settings: post-infectious (classic type of scleredema described by Buschke in 1902), diabetes-associated (which was the case with our patient), and with paraproteinemia (usually IgG kappa).  In the diabetes-associated form, males tend to outnumber females 10:1. The diabetes is usually late onset, insulin dependent, and poorly controlled, with associated neuropathy, retinopathy, atherosclerosis, and obesity. The lesions develop insidiously, persist for a long duration, and are generally refractory to therapy.  Unfortunately, tighter diabetic control does not influence disease course. 

  17. Scleredemaadultorum of Buschke • In contrast, the post-infectious type, which is seen more commonly in women, begins abruptly and spontaneously resolves within two years in most cases. Although Streptococcus is most commonly associated, other infectious etiologies have been described (influenza, measles, mumps).  Scarlet fever, tonsillitis, pharyngitis, otitis, furunculosis, erysipelas, and impetigo have been described.  Finally, it is important to recognize the association between scleredema and monoclonal gammopathies. In all patients presenting with the skin findings of scleredema, evidence for paraproteinemia should be sought.

  18. Scleredemaadultorum of Buschke • Given these clinical associations, patients presenting with skin findings of scleredema should undergo a workup including fasting blood sugar, hemoglobin A1c, serum protein electrophoresis, immunoelectrophoresis, antistreptolysin O (ASO) titer, bacterial culture, and erythrocyte sedimentation rate. 

  19. Scleredemaadultorum of Buschke • Scleredema can affect other organ systems, including the heart and upper aerodigestive tract. Tongue involvement can result in complaints of dysphagia or difficulty opening the mouth. Facial skin changes can impart a mask-like facies.  Cardiac arrthymias and pleural, pericardial, or peritoneal effusions are recognized complications.  Eye involvement (exopthalmos, opthalmoplegia, chemosis, eyelid induration) has also been reported.              Aside from diagnosing and treating any underlying disease process, some treatment options include electron beam therapy, bath or cream PUVA, UVA-1, high dose penicillin, cyclosporine, methotrexate, and extracorporeal photophoresis.  Given the risks of these treatments and the possibility for spontaneous resolution, conservative management is also appropriate in some cases. Physiotherapy also plays a role in management of scleredema.             In conclusion, scleredema is yet another example of a dermatologic manifestation of internal disease. Often, skin findings are the first manifestation of systemic disease. As dermatologists, we must therefore learn to recognize such associations and order appropriate screening tests for our patients.

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