Case 1-2012 — An 82-Year-Old Man with Persistent Ulcers on the Hands
N Engl J Med 2012; 366:166-174
- http://www.nejm.org/doi/pdf/10.1056/NEJMcpc1104568Article
- References
Presentation of Case
Dr. Sarah Gee (Dermatology): An 82-year-old man was admitted to this hospital because of persistent skin lesions on the hands. The patient had a history of diabetes mellitus and recurrent hidradenitis suppurativa. Five weeks before admission, he was admitted to another hospital because of drainage from a perineal abscess that was unresponsive to cephalexin. On examination, he reportedly had a small abrasion on his left hand, which he thought was caused by a dog bite. The administration of cephalexin was discontinued, and piperacillin–tazobactam and vancomycin were begun. During the following week, increasing erythema and an enlarging hemorrhagic bulla developed on the dorsum of the left hand and a diffuse, urticarial, and purpuric rash developed on the torso. Laboratory testing reportedly revealed thrombocytopenia. Débridement of the lesion of the left hand was performed; pathological examination of a specimen reportedly showed acute inflammation and granulation tissue. After débridement, the lesion worsened and similar lesions developed on the right hand, on the metacarpophalangeal joints. The lesions were reportedly painful to the touch and to manipulation, with ulceration extending to the tendons. Glucocorticoids were administered. On the 10th hospital day, a biopsy specimen of the skin of the right abdomen was obtained; pathological examination reportedly showed leukocytoclastic vasculitis and no microorganisms. The administration of piperacillin–tazobactam and vancomycin was stopped, as was subcutaneous heparin (begun during admission), and ciprofloxacin and linezolid were begun, in conjunction with a topical antimicrobial solution for the hands. The lesions expanded to include the proximal interphalangeal joints and became more erosive and painful. On the 13th day, the patient was transferred to a second hospital for evaluation and management of the skin lesions. At the second hospital, the patient reported weight loss of approximately 2.3 kg per week during the previous month and intermittent diarrhea. On examination, the temperature was normal. On the dorsal surfaces of the hands were well-demarcated, edematous, friable, erythematous-to-violaceous plaques, with gray discoloration at the margins (Figure 1AFigure 1
Clinical Photographs of the Patient.). Smaller violaceous, erythematous, edematous plaques were present on the trunk and thighs. A biopsy specimen of the skin on the dorsum of the right hand was obtained; pathological examination revealed a superficial and deep, dense, diffuse neutrophilic infiltrate. Staining for microorganisms was negative, and cultures were sterile. The serum level of sodium was 130 mmol per liter (reference range, 135 to 145), and levels of the other electrolytes were normal. Tests of liver function were normal, and testing for antibodies to the platelet factor 4–heparin complex was negative; other test results are shown in Table 1Table 1
Laboratory Data.. The administration of antibiotics was stopped, higher-dose systemic glucocorticoids were begun, and local wound care was performed, with partial improvement.
The patient was discharged home on the fifth day, taking prednisone (70 mg orally daily) with instructions to initiate a taper in 2 to 3 weeks. He also was prescribed an intensive wound-care regimen, with the assistance of a home nurse. Shortly after discharge, the prednisone dose was tapered from 70 mg daily to 40 mg daily, the administration of cyclosporine (300 mg daily) was begun, and intralesional triamcinolone acetonide (to a total of 60 mg daily) was injected.
Six days before admission to this hospital, a biopsy specimen of the skin on the dorsum of the right hand was obtained; pathological examination reportedly revealed neutrophilic dermatitis, with a suggestion of follicular perforation and folliculitis; no microorganisms were seen. The next day, levels of serum electrolytes, total bilirubin, total protein, globulin, and calcium were normal, as were tests of liver function; other laboratory-test results are shown in Table 1. Three days later, the lesions seemed improved; the cyclosporine dose was decreased to 100 mg orally daily, dapsone (100 mg daily) was started, and prednisone was maintained at 40 mg daily. During the next 2 days, the lesions on the patient's hands worsened. He was referred to this hospital and admitted because of increased pain and oozing of the lesions.
The patient reported feeling well except for his hands. He had a history of hidradenitis suppurativa, with recurrent abscesses, for more than 20 years, for which multiple antibiotics had been administered; diabetes mellitus, for which he had recently started taking insulin; hypertension; hyperlipidemia; cholelithiasis; a malignant melanoma of the back, which had been excised; macrocytic anemia with low folate levels; multinodular goiter; diverticulosis; microhematuria; chronic obstructive pulmonary disease; bradycardia, for which a cardiac pacemaker had been inserted; and bilateral leg edema. He had had herniorrhaphies and an appendectomy. Other medications included lisinopril and aspirin. He was allergic to penicillin. He was retired, lived with his wife, smoked cigarettes, and drank alcohol in moderation. He had no history of exposures to chemicals. There was no family history of similar skin lesions, autoimmune disorders, or inflammatory bowel disease.
On examination, the respiratory rate was 30 breaths per minute and the oxygen saturation was 97% while the patient was breathing ambient air; other vital signs were normal. There were violaceous, edematous, denuded plaques on the metacarpophalangeal joints of both hands and on both elbows (Figure 1B), as well as bilateral leg edema. The serum iron level was 50 μg per deciliter (9 μmol per liter; reference range, 45 to 160 μg per deciliter [8 to 29 μmol per liter]), iron-binding capacity 220 μg per deciliter (39 μmol per liter; reference range, 228 to 429 μg per deciliter [41 to 77 μmol per liter]), and ferritin level 540 ng per milliliter (reference range, 30 to 300, in men). The serum levels of electrolytes, calcium, magnesium, phosphorus, total protein and globulin, free thyroxine, lactate dehydrogenase, vitamin B12, folate, and glucose-6-phosphate dehydrogenase were normal, as were tests of liver function. Testing was negative for rheumatoid factor; evidence of hepatitis A, B, and C viruses; antiphospholipid antibodies; and lupus anticoagulant. Other test results are shown in Table 1. The administration of trimethoprim–sulfamethoxazole was begun. No Bence Jones proteins were detected in a concentrated urine specimen. Urinalysis revealed cloudy yellow urine, trace protein, 3+ occult blood, 20 to 50 red cells per high-power field, and 3 to 5 hyaline casts per low-power field.
On the fourth day, a diagnostic procedure was performed.
Differential Diagnosis
Dr. Daniela Kroshinsky: I am aware of the diagnosis in this case. This patient presented with a violaceous bullous lesion on the hand after a possible dog bite. The lesion expanded on débridement, and new lesions arose on the other hand. The cutaneous findings were accompanied by diarrhea and weight loss, but the patient was otherwise asymptomatic. The process was initially thought to be consistent with a necrotizing hemorrhagic cellulitis. The differential diagnosis that I would consider for these ulcerative, bullous, necrotic hand lesions includes infection (bacterial, mycobacterial, protozoal, fungal, or viral); a vasculitis (e.g., vasculitis associated with antineutrophil cytoplasmic antibodies [ANCA] or vasculitis of medium-size vessels); and neutrophilic dermatoses (e.g., pyoderma gangrenosum or Sweet's syndrome). Other blistering processes that often affect the hands but are not clinically consistent with this patient's presentation are porphyria cutanea tarda and epidermolysis bullosa acquisita.Infection
An infectious cause of the initial ulceration should be considered in view of the history of a dog bite, which can transmit several types of infectious organisms. The differential diagnosis would include bacterial infections (e.g., necrotizing cellulitis), mycobacterial infections (e.g., Mycobacterium ulcerans), protozoal infections (e.g., leishmaniasis), deep fungal infections (e.g., sporotrichosis), and viral infections (e.g., orf). Most of these causative agents are not endemic in the northeastern United States, and this patient reported no recent or remote travel to areas where they are endemic. The main bacterial infections to consider in association with dog bites are from staphylococci, streptococci, anaerobes, and pasteurella species. The aggressive nature of this patient's initial lesion also requires consideration of more aggressive organisms, such as clostridium. Many cases of necrotizing cellulitis result from local trauma and are more often seen in patients with a history of diabetes, which this patient has. Despite the pathological diagnosis of necrotizing cellulitis, there was no crepitus on examination of the patient or gas on imaging, although this finding is not seen in all forms of necrotizing cellulitis. He had no other signs of infection (e.g., fever or leukocytosis), he had no response to broad-spectrum antibiotics, cultures of the lesion were sterile, and his lesions worsened with débridement; in addition, lesions developed in nontraumatized areas in the absence of signs of systematized infection. For these reasons, infection seemed unlikely.Vasculitis
Certain forms of vasculitis can cause deep, painful ulceration, particularly vasculitis of medium-size vessels and the ANCA-associated forms of vasculitis. These were less likely diagnoses in this patient because of the previous biopsy specimen that lacked evidence of vasculitis, the absence of respiratory symptoms that would suggest necrotizing granulomatous inflammation of the upper and lower respiratory tracts, and the glomerulonephritis that would be present in Wegener's granulomatosis. The peak age at onset of this condition is 45 to 65 years, younger than this patient. Cutaneous polyarteritis nodosa is a condition of necrotizing vasculitis of medium-size vessels that is limited to the skin. It would be unlikely in this patient, since a manifestation is painful nodules that subsequently ulcerate, predominantly on the legs. Additional findings in cases of cutaneous polyarteritis nodosa include fever, myalgias, arthralgias, peripheral neuropathy, livedo reticularis, and atrophie blanche, all of which were absent in this patient. Repeat biopsy with close attention to any blood-vessel abnormalities and levels of cytoplasmic ANCA and perinuclear ANCA would help to rule out these forms of vasculitis.Neutrophilic Dermatoses
Pathergy
The patient's original lesion appeared to arise after minor skin trauma, and during the hospital stay, he had evidence of new skin lesions arising at sites of iatrogenic skin trauma. This phenomenon, known as pathergy, is an inflammatory response that develops after intradermal trauma and is manifested as erythematous-to-violaceous papules, plaques, and pustules, sometimes with secondary ulceration. A diagnostic test for pathergy is often used to confirm a suspicion of Behçet's disease — an 18-gauge needle is inserted at an angle through the dermis, and the appearance of lesions within 48 hours after insertion is indicative of a positive test. Pathergy occurs not only in Behçet's disease but also in acute febrile neutrophilic dermatosis (Sweet's syndrome), pyoderma gangrenosum, bowel-associated dermatosis–arthritis syndrome, and rheumatoid arthritis. I most often see pathergy associated with these conditions as an incidental finding on physical examination, manifesting as lesions arising at sites of intravenous catheter placement, venous sticks, skin biopsies, and other routine procedures that result in piercing of the dermis, as in this patient. The finding of pathergy should halt any further débridement or surgery, since these procedures would extend the process and would most likely result in an ongoing cycle of expansion and further débridement that could have catastrophic consequences.Pyoderma Gangrenosum
Pyoderma gangrenosum is a neutrophilic dermatosis that presents as a rapidly advancing painful ulcer, most often on the legs, with an irregular, violaceous or gunmetal gray, undermined border.1 An atypical form appears on the hands, arms, or face, with deep erosions or superficial ulcerations that have a violaceous or blue-gray, bullous or granulomatous-appearing border. This form has also been referred to as neutrophilic dermatoses of the hands, and the patient's clinical presentation is consistent with this variant. Up to 70% of cases of pyoderma gangrenosum are associated with an underlying condition, such as inflammatory bowel disease, rheumatoid arthritis, and hematologic diseases (e.g., acute myeloid leukemia or myelodysplastic syndromes, hairy-cell leukemia, or monoclonal gammopathy).1 This patient reported a recent history of diarrhea and weight loss, which raises the possibility of an underlying inflammatory bowel disease, although presentation at his age would be unusual. Chronic, atypical cases of pyoderma gangrenosum, like the one in this patient, are often associated with acute myeloid leukemia, myelodysplastic syndromes, and IgA monoclonal gammopathies.1 This patient has thrombocytopenia and anemia, raising concern for a primary bone marrow disorder. Another noteworthy clinical finding in this patient is his prompt response, at least initially, to systemic glucocorticoids. Criteria for the diagnosis of pyoderma gangrenosum have been proposed.1,2 Major criteria are rapid progression of a painful, necrolytic, cutaneous ulcer that has an irregular, violaceous, and undermined border and the ruling out of other causes of cutaneous ulceration. Minor criteria are a history that is suggestive of pathergy, the presence of a systemic disease associated with pyoderma gangrenosum, the histopathological finding of dermal neutrophilia, and a rapid response to systemic glucocorticoid treatment. This patient meets both major criteria and three of the four minor criteria for this diagnosis.Sweet's Syndrome
The diagnosis of acute febrile neutrophilic dermatosis (Sweet's syndrome) requires two major criteria (the abrupt occurrence of edematous erythematous-to-violaceous cutaneous lesions and a biopsy specimen that shows superficial edema and a deep, dense neutrophilic infiltrate without vasculitis) and at least two minor criteria (an associated underlying condition or exposure, fever, leukocytosis, and a rapid response to systemic glucocorticoid use). Like pyoderma gangrenosum, Sweet's syndrome is characterized by pathergy, as seen in this case. Also, 15% of adult cases of Sweet's syndrome are associated with hematologic neoplasms. The syndrome is also seen in patients who have solid-organ cancers, upper respiratory or gastrointestinal infections, human immunodeficiency virus infection, or inflammatory bowel disease; who have received vaccinations or other drugs (e.g., granulocyte colony-stimulating factor and all-trans retinoic acid); who have undergone bowel-bypass surgery; or who are pregnant. Sweet's syndrome typically does not induce the deep, progressive ulceration that was seen in this patient; however, localized Sweet's syndrome of the hands and atypical pyoderma gangrenosum (neutrophilic dermatoses of the hands) are sometimes considered to be the same entity.3 The patient did not have fever or leukocytosis, although he did have a response to glucocorticoids.Summary
In this patient who had violaceous, bullous, and necrotic ulcers of the hands and arms; pathergy; a biopsy specimen that revealed a dense neutrophilic infiltrate; and an absence of systemic symptoms, my diagnosis is atypical chronic pyoderma gangrenosum, probably in association with a hematologic neoplasm. I would proceed with a re-review of his biopsy specimens by the dermatopathology service and, if inconclusive, with a repeat biopsy. I would recommend further evaluation for disorders associated with pyoderma gangrenosum, including consultations from the hematology and gastroenterology services.Dr. Daniela Kroshinsky's Diagnosis
Atypical chronic pyoderma gangrenosum in association with a hematologic neoplasm.Pathological Discussion
Dr. Mai P. Hoang: Histologic sections of the skin biopsy specimen taken at the first hospital revealed a dense infiltrate of neutrophils in the dermis. The overlying epidermis shows acanthosis, and there is papillary dermal edema (Figure 2A and 2BFigure 2
Skin-Biopsy Specimen (Hematoxylin and Eosin).). Microbiologic cultures and special staining for microorganisms were negative. These findings are consistent with a diagnosis of pyoderma gangrenosum.
The following four distinctive clinical and histologic variants of pyoderma gangrenosum have been described: ulcerative, pustular, bullous, and vegetative.4 Lesions characterized by ulceration are often associated with a systemic disease, including arthritis, inflammatory bowel disease, and monoclonal gammopathy. Pustular lesions are characterized by subcorneal pustules, papillary dermal edema, a dense neutrophilic infiltrate, and an association with inflammatory bowel disease. The bullous lesions have subepidermal vesiculation and a dense dermal neutrophilic infiltrate and are associated with hematologic neoplasms. The vegetative lesions (or superficial granulomatous pyoderma) are characterized by pseudoepitheliomatous hyperplasia, dermal abscess, and palisading granulomatous reaction and are typically not associated with systemic disease.4 This case would fit best with the bullous variant, and thus a hematologic neoplasm should be suspected.
Dr. Robert P. Hasserjian: Bone marrow biopsy and aspiration were performed on the fourth hospital day. The biopsy specimen was normocellular for the patient's age and showed maturing myeloid and erythroid elements. Many megakaryocytes appeared dysplastic and small and had hypolobated nuclei and simplified nuclear contours (Figure 3AFigure 3
Biopsy Specimen of the Bone Marrow and Peripheral-Blood Smear.). The aspirate smear revealed frequent dysplastic myeloid cells, including many forms with hypogranulated cytoplasm and bilobed nuclei (pseudo-Pelger–Huët cells). Erythroid maturation was normal, and the percentage of myeloblasts (3%) was not increased. An iron stain of the bone marrow aspirate showed the presence of abundant storage iron and no ring sideroblasts. The peripheral-blood smear showed circulating immature myeloid elements (myelocytes and metamyelocytes) and pseudo-Pelger–Huët cells (Figure 3B); circulating blasts were not seen. These morphologic findings were thought to be highly suspicious for a myelodysplastic syndrome; this diagnosis was confirmed by bone marrow cytogenetic analysis, which revealed an abnormal, complex karyotype, including deletion of the long arm of chromosome 5 (Figure 3C).
On the basis of the presence of two morphologically dysplastic lineages (myeloid and megakaryocytic), the percentage of blasts in the bone marrow (<5%), and the percentage of blasts in the blood (<1%), this myelodysplastic syndrome was classified as refractory cytopenia with multilineage dysplasia, according to the 2008 World Health Organization classification.5 The presence of a complex karyotype is an adverse prognostic feature. The International Prognostic Scoring System (IPSS) for patients with myelodysplastic syndrome incorporates the percentage of blasts in the bone marrow, the number and degree of cytopenias, and the cytogenetic findings into a risk-group designation (low-risk, intermediate-1 risk, intermediate-2 risk, or high-risk). This patient's disease would fall in the intermediate-2 group; patients in this group have a median survival of approximately 1 year.6
Dr. Hoang: A variety of cutaneous manifestations have been reported in association with malignant tumors, including pyoderma gangrenosum, Sweet's syndrome, dermatomyositis, and necrobiotic xanthogranuloma. The two neutrophilic dermatoses — pyoderma gangrenosum and Sweet's syndrome — are seen most often in association with myeloid neoplasms, including myelodysplastic syndromes (as in this case), myeloproliferative neoplasms, and acute leukemias. Dermatomyositis, characterized by necrotic keratinocytes at the dermal–epidermal junction and marked dermal mucin deposition, is associated with lymphomas and ovarian carcinomas. Necrobiotic xanthogranuloma, characterized by granulomatous inflammation, cholesterol clefts, and striking multinucleated giant cells, is associated with paraproteinemia.
Discussion of Management
Dr. Kroshinsky: The diagnosis of atypical pyoderma gangrenosum had been made at the second hospital, and prednisone and cyclosporine had been prescribed, with a clinical response. Treatment of pyoderma gangrenosum involves wound care, including avoidance of trauma and débridement; treatment of any underlying condition; and immunosuppressive therapy.1 Although treatment of inflammatory bowel disease may induce remission of skin lesions in some patients, systemic immunosuppression is often required. The available agents, including glucocorticoids, dapsone, sulfapyridine, azathioprine, methotrexate, cyclophosphamide, cyclosporine, mycophenolate mofetil, tacrolimus, and tumor necrosis factor α (TNF-α) inhibitors, vary in their speed of onset of action, their side-effect profile, and their cost.1 In consultation with the clinical team, and because prednisone and cyclosporine had been effective before the attempt to taper them, we initially continued prednisone at 40 mg per day and increased the cyclosporine to 300 mg per day. Because the lesions showed no response, we added mycophenolate mofetil and tacrolimus topical gel. The lesions continued to progress, and new lesions appeared on the face and upper arms. On the eighth day, the patient began treatment with infliximab (a chimeric monoclonal antibody against TNF-α that blocks TNF-α action and induces apoptosis of T cells that express TNF-α), which has a rapid onset of action and has been reported to be helpful in cases of atypical pyoderma gangrenosum occurring on the hands and arms.7-9 Infliximab is preferred over other TNF-α blockers because of its rapid onset of action. The patient had a dramatic response, with improvement in all his lesions (Figure 1C). However, his overall clinical status deteriorated, with renal failure, volume overload, and pulmonary edema. Because the underlying hematologic disorder conferred a poor prognosis, the patient and his wife elected not to pursue aggressive treatment; in consultation with the palliative care service, care was transitioned to comfort measures only, and the patient died on the 29th hospital day. Dr. Eric S. Rosenberg (Pathology): Are there any questions or comments? A Physician: I have heard “team” mentioned during this conference. Would you describe how the team functions? Dr. Kroshinsky: At our hospital, the dermatology consult team consists of a full-time dermatologist who is assigned to the consult service with a resident. On behalf of this patient, the dermatology consult team dealt extensively with the team of caregivers, including the primary physicians and nurses and the consultants who helped interpret the test results that led to the diagnosis and the care plan.Anatomical Diagnosis
Pyoderma gangrenosum due to a myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia).This case was presented at the postgraduate course Dermatopathology Update, sponsored by the Harvard Medical School Department of Continuing Education and Department of Pathology, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Brigham and Women's Hospital. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.Source Information
From the Departments of Dermatology (D.K.) and Pathology (M.P.H., R.P.H.), Massachusetts General Hospital; and the Departments of Dermatology (D.K.) and Pathology (M.P.H., R.P.H.), Harvard Medical School — both in Boston.
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