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Notes: A 48-year-old woman presented with extensive facial ulceration of 1 year in duration. Based on the combination of the clinical appearance and a “nondiagnostic” biopsy taken elsewhere, the patient was started on oral prednisone at a dose of 40 mg/day, with a working diagnosis of pyoderma gangrenosum. According to the patient, the ulceration worsened over the 2 months whilst on prednisone and pain control was a major issue, controlled for the most part with oral oxycodone. One month prior to our evaluation of the patient, she was started on dapsone at 50 mg/day with no added benefit. Approximately 2 years prior to our evaluation, she developed raised, reddish, skin lesions on the abdomen and legs which recurred, but healed spontaneously each time after a few weeks.Her past medical history was remarkable for the remote use of intravenous drugs (which she had stopped for the past 20 years) and the past and continued use of alcohol on a daily basis. She had recently been tested elsewhere and was found to be positive for hepatitis C, but not human immunodeficiency virus (HIV). Examination revealed several ulcerations of the face and forehead, with an “apple jelly” coloration to the periphery and necrotic center. There was complete erosion of the nasal sidewall with apparent involvement of the septum (〈link href="#f1"〉Fig. 1). There were also scattered, smaller, nonulcerated, reddish to purplish lesions on the abdomen. Otolaryngologic examination revealed ulceration of the right ala and erosion of the nasal septum, but was otherwise unremarkable. No cervical or submental lymphadenopathy was noted.〈figure xml:id="f1"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD2035:IJD_2035_f1"/〉Facial ulceration at the time of initial evaluationRoutine laboratory tests showed the patient to be anemic, with a hemoglobin level of 11 g/dL (normal, 12–15.5 g/dL) and a white blood count of 13,300 (normal, 3500–10,500) The total bilirubin was normal at 1.0 mg/dL, but several liver function tests were elevated by 2–4 times the upper limit of normal, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (G-GT). Hepatitis C tests were abnormal, including antibody to hepatitis B core antigen (anti-HBc) and anti-hepatitis C virus (anti-HCV) antibodies, and hepatitis C-RNA was positive. Anti-hepatitis B surface antigen (anti-HBsAg) and antibody were negative. Human immunodeficiency virus (HIV) was negative. Antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA), serologic tests for syphilis, cryoglobulins and cryofibrinogens, renal function, and urinalysis were all either negative or normal. The chest X-ray showed bilateral pulmonary nodules, confirmed by computed tomography (CT) scan of the chest. Serologic tests for several fungal organisms, including Sporothrix and Cryptococcus, were negative. Tuberculin skin testing was negative.Two 4-mm punch biopsies were taken from the right cheek and from the right lower lateral abdomen near the hip. Biopsy of facial tissue cultures for acid-fast bacilli and fungal elements was negative. Bacterial culture revealed 1+Staphylococcus aureus and coagulase-negative Staphylococcus. Polymerase chain reaction (PCR) testing for herpes and varicella viruses was negative.Histologic examination of the skin biopsies revealed identical findings from both sites. There was parakeratosis, serum crust, and mild irregular epidermal acanthosis. Focal interfacial dermatitis was present and characterized by basal vacuolization and melanophages in the superficial dermis. Epidermotropism of atypical lymphocytes singly and in cell clusters was seen in the epidermis. In the papillary and reticular dermis, extending to the subcutaneous fat, there was a dense, diffuse, perivascular, interstitial, and periappendageal infiltrate composed of atypical lymphocytes, lymphocytes, histiocytes, plasma cells, and neutrophils. The atypical lymphocytes infiltrated the hair follicles with little associated spongiosis (pilotropism) (〈link href="#f2"〉Fig. 2). The atypical lymphocytes also surrounded and infiltrated the eccrine glands and blood vessels. Immunoperoxidase studies were performed on paraffin tissue and showed that the atypical lymphocytes were immunoreactive with CD3 (〈link href="#f3"〉Fig. 3) and βF1, but not with CD8, CD56, T-cell-restricted intracellular antigen-1 (TIA-1), or granzyme B. There was a reactive population of B lymphocytes immunoreactive with CD20. In situ hybridization for Epstein–Barr virus (EBV), performed on paraffin sections, was negative. Lung biopsy of several nodules was accomplished via video-assisted thoracoscopy and revealed a peripheral T-cell lymphoma. Gene rearrangement studies of skin and lung nodules showed similar T-cell clones and were positive for T-cell rearrangement by PCR (TCR PCR, T γ-chain positive).〈figure xml:id="f2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD2035:IJD_2035_f2"/〉Histopathology of a skin lesion. (a) Dense atypical lymphocytic infiltrate demonstrating pilotropism and epidermal involvement with little associated spongiosis (hematoxylin and eosin stain, × 200). (b) Higher power view better demonstrating the dense atypical lymphocytic infiltrate (hematoxylin and eosin stain, × 400)〈figure xml:id="f3"〉3〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD2035:IJD_2035_f3"/〉Strong CD3 immunoreactivity of the infiltrate (CD3 stain, × 200)The final diagnosis was peripheral T-cell lymphoma with pulmonary and skin involvement. There was no evidence for EBV infection.The patient returned home to receive treatment with four cycles of hyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone), followed by autologous stem cell transplantation. The facial erosions and ulcerations, as well as the systemic nodules, responded well to therapy, with only limited recurrence of the right lower lateral abdominal lesions, which were subsequently treated with radiation (〈link href="#f4"〉Fig. 4). The patient's clinical status 18 months after treatment is complete remission from lymphoma, but she has developed fulminant liver failure secondary to cirrhosis associated with hepatitis C.〈figure xml:id="f4"〉4〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD2035:IJD_2035_f4"/〉Facial lesions after completion of chemotherapy

Notes: The proband was evaluated for abdominal pain at age 61 years and found to have bilateral solid renal masses. He underwent a partial left nephrectomy. Two benign renal cysts were present, and two renal cell adenocarcinomas measuring 5.3 cm and 0.7 cm in greatest diameters were found. Histologically, both tumors contained both clear and granular cell types. He had a total right nephrectomy 2 months later. Fourteen or 15 lesions were scattered over the surface of this kidney, so an adrenal-sparing radical right nephrectomy was performed. On sectioning, the diameter of the largest tumor was 4 cm, and histologically this was described as renal cell carcinoma, clear cell type, Fuhrman grade II. One year later, the patient shows no evidence of recurrent disease.The proband's past medical history was notable for gastroesophageal reflux, degenerative disk disease, hyperlipidemia, and mild hyperglycemia. A genetics consultation was requested because of a family history of renal cancers in three maternal relatives (〈link href="#f3-1"〉Fig. 1). On examination, the proband was a nondysmorphic man of normal stature with no unusual findings, except for widespread skin findings (〈link href="#f3-2"〉Fig. 2). On his face were innumerable, small, slightly yellowish or flesh-colored papules on the forehead and especially over the cheeks. No intraoral lesions were seen. Around the neck were innumerable, dome-shaped, firm, ivory-colored papules ranging in size from 1 to 10 mm. Very tiny, similar papules were present over the trunk and in the antecubital area. Numerous acrochordons and some cherry angiomas were present. Several biopsies from the neck and upper back were obtained and were thought suggestive of papular mucinosis. The patient's mother had had a skin biopsy of a similar lesion from her face in 1947, interpreted as an adenoma sebaceum. No angiofibromas were evident on our patient's slides nor on physical examination.〈figure xml:id="f3-1"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-1"/〉Pedigree of family with Birt-Hogg–Dube Syndrome〈figure xml:id="f3-2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-2"/〉Photograph of the back of the neck of a 61–year-old man with Birt-Hogg–Dube SyndromeAt this point, diagnoses under consideration included von Hippel-Lindau disease (VHL), a familial chromosome no. 3 translocation, hereditary renal cell cancer (gene unknown), tuberous sclerosis (TS), or Birt-Hogg–Dube syndrome (BHDS). The patient underwent a variety of tests to evaluate these possibilities. He had no evidence of hemangioblastomas of the central nervous system, no liver or pancreatic cysts, no ocular findings for VHL or TS, and no hypomelanotic macules on skin exam. Chromosome analysis from peripheral blood showed a normal 46,XY karyotype. Direct DNA mutational analysis of the VHL gene detected no mutations. Additional biopsies from the patient's skin lesions were obtained, and tissue blocks from 1947 from his mother were resectioned (〈link href="#f3-3 #f3-4"〉Figs 3 and 4). Upon further review, multiple fibrofolliculomas were found in both mother and son in skin biopsies. In aggregate, these data established a diagnosis of BHDS.〈figure xml:id="f3-3"〉3〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-3a"/〉〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-3b"/〉(A) Skin biopsy from the upper back of the proband showing a dome shaped papule with abundant mucin in the papillary dermis. Follicular changes are suggestive of fibrofolliculoma. (H&E, 12.5X). (B) Mucinosis in the papillary dermis is highlighted with alcian blue stain (ABPAS, 25X)〈figure xml:id="f3-4"〉4〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-4a"/〉〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-4b"/〉(A) Fibrofolliculoma seen on skin biopsy of a facial papule from the mother of the proband (H&E, 25X). (B) Fibrofolliculoma from the mother of the proband with sebaceous gland enlargement and mucin deposition highlighted by alcian blue stain (ABPAS, 25X)In addition to the renal cancers, the patient's and/or cousin's medical record reported that others in the family had the same skin manifestations, including his mother, maternal grandmother, maternal uncle, and two maternal first cousins by report. Cousin III.6′s medical record showed a clinical diagnosis initially of ‘‘sebaceous hyperplasia’' and upon skin biopsy was said to have ‘‘innumerable trichoepitheliomas over his face’'. He was treated with liquid nitrogen with good results. Unfortunately, we were not able to obtain tissue for review on the other renal cancers in relatives. Additional findings of note are a spontaneous pneumothorax in our patient's daughter and melanoma in our patient's brother and son. This family has been invited to participate in genetic studies underway at the National Cancer Institute.

Notes: Cutaneous granulomatous vasculitis is an uncommon histopathologic finding that has been associated with lymphoproliferative disorders, systemic vasculitis, autoimmune inflammatory diseases, and infection. To define further the concept of cutaneous granulomatous vasculitis and to emphasize its clinical importance, we reviewed biopsy material from 8 patients seen from 1985 through 1992. All biopsies showed evidence of blood vessel damage with fibrinoid change or hemorrhage (or both) and granulomatous inflammation in and around vessel walls. Special stains for microorganisms were negative in all cases. Associated medical disorders included neuropathy (2 patients), sarcoid-like disease (2), systemic vasculitis (1), lymphoma and suspected lymphoma (1 each), and associated herpes simplex virus (1). T-cell gene-rearrangement studies were negative in a patient with suspected lymphoma. Granulomatous cutaneous vasculitis is most commonly associated with lymphoma and systemic vasculitis. In selected cases, infection should be considered as an underlying cause.

Notes: Background  The clinical mucocutaneous manifestations of glucagonoma syndrome are recognized easily when they occur in the classic pattern of acral or periorificial lesions evolving in recurrent crops, with an annular and migratory distribution, in a patient with diabetes mellitus who has had recent weight loss and anemia. Not infrequently, noncharacteristic clinical and histopathologic features are observed and, in these cases, the diagnosis of pancreatic neoplasm may be delayed.Aim  To review the clinical and histopathologic features of cutaneous manifestations of glucagonoma syndrome.Methods  The clinicopathologic features of 13 patients (eight women) with widespread or localized cutaneous eruption as a manifestation of islet cell pancreatic carcinoma with marked glucagon secretion (glucagonoma) were reviewed.Results  The definitive diagnosis of the cutaneous eruption was established at the time of diagnosis of the pancreatic neoplasm (three patients) or afterwards (10 patients). In nine patients, the mucocutaneous manifestations preceded the diagnosis of the pancreatic neoplasm by 1 month to 3 years (mean, 12 months). In only eight biopsy specimens were the histopathologic features considered to be suggestive or characteristic of necrolytic migratory erythema. Diffuse parakeratosis, that occasionally arose abruptly from normal epidermis, was observed in 12 biopsy specimens. By the time necrolytic migratory erythema was diagnosed, the pancreatic carcinoma had metastasized to the liver, regional lymph nodes, or bone in 12 patients.Conclusion  Increased awareness of the polymorphic mucocutaneous and nonspecific histopathologic features of glucagonoma syndrome is needed to avoid unnecessary delay in the diagnosis of this syndrome.

Notes: Background  Isolated or predominantly hand involvement in Sweet's syndrome, pyoderma gangrenosum, or pustular vasculitis is a rare presentation in the spectrum of neutrophilic dermatoses and is often associated with an occult malignancy or other systemic inflammatory disorder. When these disorders occur on the hands, they are often clinically indistinguishable, but they can sometimes be separated histologically by the presence of papillary dermal edema (Sweet's syndrome), ulceration and necrosis (pyoderma gangrenosum), or vasculitis (pustular vasculitis). These distinctions may be arbitrary, however, and reflect differences in the temporal course of the disease and in the degree of inflammation at the time of biopsy.Methods  We report four cases of neutrophilic dermatosis affecting the hands and a review of the literature for similar cases.Results  Of the four patients presented, two had associated carcinomas and one had myelodysplasia in transition to leukemia. The cutaneous symptoms preceded the finding of an occult malignancy. Thirty-two reported cases of neutrophilic dermatoses presenting on the hands showed clinicopathologic features similar to those in our series. Taken together, the mean age at diagnosis was 60.5 years, and 58% of the patients were female. Twenty-five per cent (nine patients) also had myelodysplasia or leukemia, 14% (five patients) ulcerative colitis, 6% (two patients) carcinoma, 6% (two patients) Crohn's disease, and 6% (two patients) seropositive arthritis.Conclusions  These cases illustrate the importance of recognizing that neutrophilic dermatoses may present uniquely or predominantly on the hands. This presentation is distinctive, and prompt diagnosis may prevent unnecessary medical or surgical therapy and may lead to the earlier diagnosis and treatment of an associated malignancy or other systemic disorder.

Notes: A 76-year-old man receiving long-term prednisone therapy for rheumatoid arthritis had a four-part intertrochanteric fracture after a fall. The patient underwent an open reduction with internal fixation and dynamic hip screw placement. Two months later, when the patient presented with significant pain and difficulty ambulating, radiographs revealed dissociation of the compression screw from the femoral head. At the time of removal of failed hardware, a total hip replacement procedure was aborted when intraoperative findings were consistent with infection. Thorough irrigation and debridement were performed, with placement of antibiotic-impregnated cement spacers. One month after a 4-week course of intravenous cefazolin, the patient underwent left total hip arthroplasty. Intraoperative cultures grew methicillin-resistant Staphylococcus aureus and Corynebacterium jeikeium. A 4-week course of intravenous vancomycin was followed by long-term antibiotic suppression with long-term minocycline (100 mg twice daily).Six months after starting minocycline, the patient noticed a blue-gray discoloration of the forearms. During the next 4 months, the pigmentation progressed considerably. He was admitted to Mayo Clinic for a myocardial infarction. Three-vessel coronary artery disease was discovered, necessitating bypass grafting. Before surgery, dermatology was consulted. A main concern of the primary service was the discoloration representing ecchymoses in a surgical candidate with a possible bleeding diathesis.Cutaneous examination revealed slate gray, ill-defined patches in the preauricular, flank, upper thigh, and shoulder areas. Similar patches coalesced on the upper and lower extremities (〈link href="#f17131"〉Fig. 1). There was no scleral or mucous membrane involvement. Histologically, minocycline pigmentation with pigment-laden macrophages and free dermal pigment in the papillary and superficial reticular dermis stained positive with Prussian blue and Fontana-Masson (〈link href="#f2"〉Fig. 2). Minocycline was discontinued, and the patient was started on trimethoprim-sulfamethoxazole double strength once daily for long-term antimicrobial therapy.〈figure xml:id="f17131"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1713_2:IJD_1713_f1"/〉Minocycline-induced slate gray discoloration of the (a) arms and (b) shins〈figure xml:id="f2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1713_2:IJD_1713_f2"/〉Pigment-laden macrophages and free dermal pigment. (Hematoxylin-eosin; original magnification ×600)