Benefits and limitations of belatacept in 4 hand-transplanted patients.

Belatacept (cytotoxic T-lymphocyte-associated protein 4 Ig) is an emerging treatment in kidney transplantation. Lack of nephrotoxicity and possibly an inhibitory effect on the development of donor-specific antibodies (DSAs) make it an interesting agent in hand transplantation. To reduce calcineurin inhibitor immunosuppression and preserve kidney function, we have added belatacept to the therapeutic regimen of 4 hand-transplanted patients at month 4 and at 6, 9, and 13 years after hand-forearm transplantation. Patients received 5 mg/kg belatacept every 2 weeks, and the dosing interval was extended to 4 weeks after 5 applications. Belatacept was initially well tolerated in all cases. Two patients were weaned to a low-dose tacrolimus monotherapy together with monthly belatacept applications. One patient is taking belatacept with lowered tacrolimus and sirolimus trough levels. A fourth patient had significant levels of DSAs at time of conversion and progressed to a severe necrotizing rejection early despite an unaltered baseline immunosuppression. Finger skin necrosis and histologic signs of severe chronic allograft vasculopathy eventually led to amputation of the graft. Implementation of belatacept can be beneficial in hand transplantation. However, our findings indicated both potential and caution and reflection of the immunologic state at the time of conversion.

[Clinical presentation of cutaneous adnexal tumors]. / Klinik der Hautadnextumoren.

Cutaneous adnexal lesions can sometimes be clinically diagnosed even by an experienced clinician or a differential diagnosis can at least be narrowed down. However, clinical findings alone cannot replace histological investigations and diagnosis or make them superfluous. This expertise is based on an algorithm which first differentiates inflammatory pseudo-tumors, such as ruptured infundibular cysts (atheroma) from authentic neoplastic adnexal lesions. In a second step criteria of regularity and/or chaos, such as asymmetry, irregular border, color variation and/or destruction with exulceration help to evaluate the dignity. In a third step criteria of differentiation allow the characterization of lesions varying in size from macules to papules, plaques, nodules and tumors to the subgroups of adnexal differentiation. Infundibular differentiation is characterized by comedones and is skin-colored, yellow or white and hard. Follicular differentiation notifies hair and is skin-colored, pearl-like to occasionally brown-black and variably hard. Sebaceous differentiation signifies lobulation and is yellow to skin-colored or red and soft. Apocrine lesions are reddish and fleshy. Eccrine differentiation shows either papillary reddish-brown (differential diagnosis viral warts) or skin-colored hard lesions. Multiple, monomorphous lesions are characteristic of syndromes, such as Spiegler-Brooke-Fend, Birt-Hogg-Dubé, Muir-Torre, and Gorlin-Goltz.One peculiarity of adnexal lesions is their potential to form cysts. Cysts with horny or hairy material are skin-colored to yellow, with glandular fluid fluctuation, a bluish character, and with illumination a Tyndall phenomenon becomes obvious, while ruptured cysts reveal an erythematous-reddish, ill-defined foreign body reaction. Brown to bluish-gray and black color is seen by the presence of melanocytes with melanin in lesions with mostly follicular differentiation. Strong vascularization and bleeding are reddish, soft, spongy and compressible and in due course variably dark due to the presence of hemosiderin.

Cutaneous epithelioid angiomatous nodule: different views or interpretations in the analysis of ten new cases.

Classification schemes proposed for vascular lesions are the subjects of significant controversy. Cutaneous epithelioid angiomatous nodule (CEAN) was described in 2004, but there is no agreement as to whether this is a distinct entity or a type of either epithelioid hemangioma or angiolymphoid hyperplasia with eosinophilia. We present a typical case of CEAN and discuss nine other cases from our institution. We then provide two opposing viewpoints concerning its classification.

Gallbladder sarcoma: a clinicopathological study of seven cases from the UK and Austria with emphasis on morphological subtypes.

BACKGROUND: Primary sarcoma of the gallbladder (PGBS) is rare, with only 40 cases reported in the literature. Most of these have been diagnosed as leiomyosarcoma. We aimed to evaluate the histological features of a case series of this rare tumor and correlate these with clinical features. DESIGN: Cases recorded as "gallbladder sarcoma" from different institutes were reviewed and the clinicopathological features of these cases were recorded. Only primary gallbladder wall mesenchymal tumors were included. Epithelial tumors, mixed tumors (carcinosarcoma or sarcomatoid carcinoma), and tumors extending into the gallbladder from the abdomen or sarcoma with other known primaries were specifically excluded. RESULT: PGBS occurred in one male and six females with a median age of 70 (range 64-82) years. Patients presented with acute or chronic cholecystitis, abdominal pain, weight loss, and pruritus. They were generally found to have elevated alkaline phosphatase and bilirubin, and leukocytosis. Tumors ranged from 1.1 to 4 cm with a median size of 3 cm. Most PGBS arose in the body but one arose in the fundus. All tumors were associated with ulcerated mucosa. Based on morphological and immunohistochemical features of the PGBS, there were three myxofibrosarcomas (malignant fibrous histiocytoma, MFH, storiform pleomorphic), one leiomyosarcoma (LMS), one angiosarcoma (AS), and two liposarcomas (LS). All patients received cholecystectomy and three received adjuvant chemotherapy. Follow-up revealed that six patients died of the disease 6 weeks to 2 years after diagnosis and one died of unrelated causes. CONCLUSION: PGBS are rare and mainly occur in the gallbladder body in middle-aged females. They generally present with acute cholecystitis and have a very poor prognosis. A variety of sarcoma types are found with MFH being the predominant variant.

Superficial acral fibromyxoma: a clinicopathological study of new 41 cases from the U.K.: should myxoma (NOS) and fibroma (NOS) continue as part of 21st-century reporting?

BACKGROUND: Superficial acral fibromyxoma (SAF) remains poorly recognized by general pathologists and dermatopathologists, partly attributable to its relatively uncommon occurrence and recent documentation. OBJECTIVES: To examine a series of SAF and document the U.K. experience with this new entity. METHODS: We reviewed 771 tumours reported between 1970 and 2006 in seven different U.K. hospitals and coded as myxoma, not otherwise specified (NOS), fibroma (NOS) or dermatofibroma (NOS) presenting at acral sites. Forty-one cases of SAF were studied. RESULTS: The patients comprised 27 men and 14 women, age range 19-91 years (mean 50, median 47), presenting with a solitary mass or nodule with a mean size of 1.92 cm. The common clinical sites were the toes (n=29) and fingers (n=11) as well as the palm (n=1), with more than 75% of cases close to or involving the nail bed. All cases presented with a painless mass except for four cases where pain was the presenting complaint. A history of trauma was reported in only two cases. Histologically, all cases presented as proliferation of spindle-shaped and/or stellate cells with a storiform and fascicular pattern embedded in a fibromyxoid/collagenous stroma with conspicuous mast cells. Multinucleated cells were observed (n=22), increased number of blood vessels in the stroma and extravasation of red blood cells (n=4). The characteristic immunophenotype was CD34+, CD99+/-, epithelial membrane antigen+ focally/-, S100-, desmin-, smooth muscle actin-, HMB45- and cytokeratin-. CONCLUSIONS: We describe a large series of 41 cases of SAF showing that it is a distinct entity with typical clinical, histological and immunohistochemical features. Follow-up was available only in 12 patients, precluding a firm comment on recurrence. However, complete excision and follow-up review is recommended.

A new variant of mastocytosis: report of three cases clinicopathologically mimicking histiocytic and vasculitic disorders.

Cutaneous mastocytosis (CM) or urticaria pigmentosa is characterized by abnormal proliferation and accumulation of mast cells. Clinically, CM usually presents as symmetrically distributed red-brown macules or papules that develop weals, erythema and often pruritus on stroking (Darier's sign). The histological hallmark of the disease is an increase in oval to spindle-shaped mast cells in the dermis located around blood vessels and skin appendages. We describe three patients with a new clinicopathological type of CM, which clinically mimics a histiocytic disorder and histologically mimics leucocytoclastic vasculitis (LV). Three infants (two boys and one girl) developed generalized reddish-yellow-brown macules of 3-10 cm with occasional scaling and crusting on the trunk and extremities without further symptoms or organ involvement except variable itching. Histology revealed diffuse and dense dermal infiltrates of eosinophils, neutrophils and nuclear debris with perivascular accentuation, imitating LV. This infiltrate masked large epithelioid cells, positive for macrophage markers, which by special histochemical stains for metachromatic granules turned out to be mast cells. This is the first report of this new variant of CM, which may cause considerable diagnostic difficulties both clinically and histopathologically.

[Epithelioid sarcoma of the hand, a seldomly recognized tumor]. / Das Epithelioidsarkom der Hand, selten primär richtig diagnostiziert.

BACKGROUND: The epithelioid sarcoma of the hand is often misdiagnosed. This tumor occurs most frequently in children and young adults, has an uncharacteristic course, and carries a high risk for local recurrence and metastases. The characteristic histopathology is helpful in establishing the correct diagnosis. Differential diagnosis includes synovialoma, fibromatosis and Dupuytren's contracture. Multinodular appearance is not uncommon. PATIENTS AND METHOD: Three young patients (one male and two female) were operated on the hand for treatment of Dupuytren's contracture, synovialoma and fibromas, respectively. The necessity for surgical revision in these patients led to a reevaluation of the primary histological data. The original diagnosis having been found to be incorrect, the correct diagnosis was established namely, epithelioid sarcoma. RESULTS: Surgical revision was performed, which involved partial amputation of the extremity. None of the patients underwent adjuvant radio- or chemotherapy. The patients were followed-up for ten, four and two and a half years, respectively. They are currently free of recurrences. CONCLUSION: Prognosis depends on the size and the location of the tumor. Adequate treatment requires early radical excision; amputation may be required if the primary tumor is located in the fingers or treatment of recurrent growth. The tumor tends to metastasize via the lymphatic system. Patients must be monitored with yearly lung X-rays since recurrence or metastasis may occur many years after the initial diagnosis and treatment.

[Pathological examination of breast biopsy specimens]. / Pathologische Aufarbeitung von Mammabiopsaten.

No differences for long-term disease free survival could be found between breast conserving surgery and mastectomy. Most importantly is the fact that this therapy presents a significantly higher risk for local recurrence. The characterisation of this risk is one of the most important things to do. These findings result in a widespread change in treatment of breast cancer patients. Consequently an increase in interdisciplinary working between radiologists, surgeons and pathologists could be found. Histological examinations are necessary for diagnosis and exactly evaluation of the tumor extension. Microscopic evaluation of the resection margin is of most important interest, because there is a direct connection between local recurrence and tumor infiltration of the resection margin. We performed our investigations by the use of a standardized complete embedding method with the possibility of three-dimensional reconstruction, on a cohort of 280 patients. Additionally this method allowed the detection of all relevant findings on one hand and on the other hand an evaluation of all resection margins. Our results showed a breast conserving therapy including tumor free margins was performed in 67% of the patients. But there was a second resection necessary in 57% of the cases. An extensive tumor distribution as the detection of multifocal tumor spread was the reason for mastectomy in 33%. Our findings point out the necessarily of the histological examination in the line of the complete embedding method of the breast biopsy material in order to analyse the tumor including resection margin evaluation.

Combined dermatofibroma: co-existence of two or more variant patterns in a single lesion.

AIMS: Based on a series of 25 cases, we define and characterize combined dermatofibroma, a tumour comprising two or more variant patterns of dermatofibroma in a single lesion. METHOD AND RESULTS: Dermatofibroma may present with a wide variety of architectural, cellular or stromal peculiarities. Architectural peculiarities include deep penetration, atrophy, collarette formation, fascicular to plexiform architecture, massive haemorrhage, prominent haemangiopericytoma-like vascularity and palisading; cellular peculiarities the presence of epithelioid cells, clear cells, granular cells, prominent myofibroblastic differentiation and atypical giant cells ('monster cells'); or stromal peculiarities such as prominent sclerosis, mucin, haemosiderin and cholesterotic deposits. In combined dermatofibromas two or more of these features are seen in complex or inhomogenous combination such as the silhouette of a deep penetrating dermatofibroma with an 'ordinary' storiform pattern in the upper and granular cell differentiation in the lower part of the lesion; or a dermatofibroma with ordinary features in the upper, prominent sclerosis in the middle and clear cells in the lower portion of the lesion; or the characteristic epidermal collarette and cells of epithelial cell histiocytoma with a plexiform ('neurothekeoma-like') architecture surrounded by a myxoid stroma with spindle-shaped to stellate cells. Clinically, these lesions preferentially occur on the lower extremities of young to middle-aged females, frequently with the diagnosis of a fibrohistiocytic lesion. Apart from one recurrence follow-up was uneventful in all other cases. Immunohistochemically, lesions are consistently positive with KiM1p, variably positive for factor XIIIa, smooth muscle specific actin and with KP1 (CD68), NK1C3 and E9. CONCLUSION: Recognition of combined dermatofibroma allows the histopathologist to apply a confident benign label to unusual lesions which might otherwise elude diagnosis, or tempt description of 'new' entities and to avoid a misdiagnosis of malignancy.

Differential expression of CD34 and Ki-M1p in pleomorphic fibroma and dermatofibroma with monster cells.

Pleomorphic fibroma (PF) and dermatofibroma with monster cells (DFMC) are characterized by the presence of numerous cells with large atypical nuclei. Despite cytologic similarities, the two entities are likely to be unrelated, but their histogenesis is poorly understood. In this study, we examined six cases of PF and eleven cases of DFMC by immunohistochemistry using antibodies against vimentin, alpha-smooth muscle actin, S-100 protein, CD34, factor XIIIa, and the pan-monocytic marker Ki-M1p. Strong vimentin expression was seen in all tumors, whereas none of them expressed S-100 protein. PF consistently exhibited CD34 staining but appeared to be depleted of Ki-M1p positive cells compared with the surrounding normal skin. Conversely, all cases of DFMC contained numerous Ki-M1p positive cells including atypical multinucleate cells, but virtually no CD34 reactivity was observed. A weak staining for alpha-smooth muscle actin was occasionally seen in a subset of the cells of both entities. Our results indicate that PF and DFMC are histogenetically distinct entities that may arise from two different types of dermal dendritic cells defined by their reactivity for CD34 and Ki-M1p, respectively. Immunohistochemistry using these two antibodies permits an easy and reliable discrimination between PF and DFMC.

Myxoid dermatofibroma.

AIMS: This report presents seven cases of a rare variant of dermatofibroma, characterized by marked mucinous stromal changes. METHODS AND RESULTS: In this retrospective clinicopathological study, lesions preferentially occurred on the lower extremities of young to middle-aged females. Clinical (differential) diagnoses included: dermatofibroma (two cases), cyst, tophus, ganglion and neurofibroma. Histology revealed well circumscribed, faintly stained dermal to subcutaneous lesions which contained abundant stromal mucin. A variable amount of spindle-shaped cells, occasional lymphocytes and fine collagen fibres were also seen. Epidermal hyperplasia above as well as storiform arrangement of spindle cells and some sclerotic collagen at the periphery of the lesion indicated the fibrohistiocytic origin. Individual histopathological features included: bizarre giant cells, perifollicular arrangement and seas of mucin with pseudovascular clefts in one case each. Immunohistochemically, all lesions were positive for KiM1p (> 50% of the cells). Moreover, two lesions showed moderate reactivity for factor XIIIa (10-25%), one each with NK1C3 (> 90%) and smooth muscle actin (50%), but were otherwise negative with a broad panel of markers. Electron microscopy in one case revealed large pools of mucin interspersed by a moderate number of fibrocytes with fine fibrillary collagen. CONCLUSION: This series confirms myxoid dermatofibroma as a rare variant of fibrohistiocytic tissue response; our series also indicates that many of these lesions might be misinterpreted as cutaneous myxoma.

[Intestinal invagination due to endometriosis of the terminal ileum]. / Darminvagination durch Endometriose des terminalen Ileums.

HISTORY AND CLINICAL FINDINGS: A 39 year old female patient presented with nausea and crampy abdominal pain in the right lower quadrant. INVESTIGATIONS: Physical examination showed a markedly distended abdomen with a diffuse pain, punctum maximum in the right lower part of the abdomen and reduced peristalsis. Plain abdominal x-rays revealed slightly dilated loops of small bowel with air-fluid levels. Abdominal ultrasound revealed thickening of the bowel wall of the distal ileum and some free fluid. To exclude Crohn's disease, Sellink-computer tomography was performed, which also showed thickening of the wall of the terminal ileum and dilated bowel loops proximal to the underlying stenosis. DIAGNOSIS, TREATMENT AND COURSE: Intraoperatively, the terminal ileum was thickened by scar tissue and subtotally invaginated. Histologic investigation of the resected specimen showed submucosal endometriosis. CONCLUSION: Endometriosis of the small bowel should be considered carefully in the differential diagnosis of female patients of reproductive age who suffer from symptoms of ileus, dysmenorrhea and sterility.