Non-Hodgkin lymphoma with exclusive involvement of the heart and the gastrointestinal tract.

An extranodal high-grade B-cell lymphoma, centroblastic type, with exclusive involvement of the heart, stomach and small bowel was detected at post-mortem examination following the death of an 80-year-old man. Autopsy revealed massive cardiomegaly with a total heart weight of 1800 g owing to an intramyocardial tumour involving the right ventricle, and multiple mucosal tumour plaques and nodules in the stomach and small bowel. The case highlights the difficulties of diagnosing cardiac lymphoma clinically even in the presence of a large tumour mass.

Spontaneous or interferon-gamma-induced T-cell infiltration, HLA-DR and ICAM-1 expression in genitoanal warts are associated with TH1 or mixed TH1/TH2 cytokine mRNA expression profiles.

The purpose of the study was to investigate the cytokine gene expression patterns and immunohistochemical characteristics of genitoanal warts in order to obtain a clue as to the immunological mechanisms possibly relevant for wart regression or persistence. We analysed surgically removed warts from 11 patients, 2 of whom were immunosuppressed. Lesions of five of the nine otherwise healthy individuals were additionally treated with intralesional interferon-gamma (IFN gamma) prior to surgery. Invasion of CD4+ T cells into the papillomas and HLA-DR and ICAM-1 expression on keratinocytes were found in two otherwise healthy patients and were intensified by intralesional IFN gamma in four of five patients. The mRNA expression patterns in seven of eight non-recurrent warts were compatible with a predominant TH1 or mixed TH1/TH2 cytokine profile. In contrast, in recalcitrant warts of three patients (one healthy, two immunocompromised) histological signs of immunore-activity and TH1-like cytokine mRNA expression were not detected. In recurrent warts of a renal transplant patient, IL-4 and IL-5 mRNA expression was repeatedly found suggesting a predominant TH2 response. In conclusion, immunoreactivity to genitoanal warts such as T-cell infiltration, HLA-DR and ICAM-1 expression was associated with a predominant TH1 or mixed TH1/ TH2 cytokine mRNA expression profile.

Prominent myofibroblastic differentiation. A pitfall in the diagnosis of dermatofibroma.

Myofibroblastic differentiation occurs in 10-20% of all dermatofibromas, affecting < 25% of cells. We report on a series of 36 dermatofibromas collected from > 1,500 fibrohistiocytic lesions (2%), with more prominent (> 25%) myofibroblastic differentiation characterized by markedly slender and elongated spindle cells positive for smooth muscle markers. While most of the lesions did not otherwise differ from ordinary dermatofibromas, three cases (0.2%) from the neck-shoulder region of male adults showed extensive myofibroblastic features (> 90%). Clinically, these three lesions measured approximately 1 cm and had a firm consistency, with the differential diagnosis of some fibrohistiocytic tissue response. Histologically, densely packed cells and prominent, partially nodular, stromal sclerosis with focal palisading of nuclei indicate some overlap with other rare variants of fibrohistiocytic tissue response, such as cellular benign and palisading cutaneous fibrous histiocytoma. Yet, these features together with focal whorled nesting of more epithelioid cells (one case) also caused considerable diagnostic problems to exclude other myofibroblastic as well as (malignant) spindle cell lesions such as (palisaded) myofibroblastoma, dermatofibrosarcoma protuberans, and neurothekeoma. Immunohistochemically, all lesions were markedly (> 90%) labeled for smooth muscle markers (HHF35, anti-SMA) and with NK1C3 (CD57), while a broad panel for other spindle cell tumors, such as pan-keratin, S100 protein, EMA, desmin, CD34, CD31, and KiM1p, were negative. Electron microscopy of two cases revealed prominent endoplasmic reticulum and Golgi complex, numerous intermediate filaments, attachment plaques, and focal basal lamina formation. No recurrence was seen during a follow-up of 9 (two cases) and two years, respectively.

p53 abnormalities are rare events in neuroendocrine (Merkel cell) carcinoma of the skin. An immunohistochemical and SSCP analysis.

The aim of the present study was to assess a possible role of the tumour suppressor gene p53 in neuroendocrine (Merkel cell) carcinoma of the skin with regard to tumour development and tumour progression. p53 was investigated in a series of routinely processed Merkel cell carcinomas, with application of four different p53 antibodies (CM-1, PAb1801, DO7, and PAb240) to 25 carcinomas and screening for p53 mutations of exons 4-8 by single-strand conformation polymorphism (SSCP) analysis in 9 cases. All 25 tumours in the present series showed the characteristic microscopic and immunohistochemical features of Merkel cell carcinoma of the skin. In 5 of the 25 Merkel cell carcinomas investigated 5-10% of tumour cell nuclei showed a positive p53 reaction with at least one anti-p53 antibody. A few scattered p53 positive nuclei were found in an additional 9 cases. The remaining 11 cases completely lacked p53 immunostaining. SSCP analysis of exons 4-8 revealed no significant alterations in the mobility shift of the single strand DNAs in the five cases with 5-10% p53-immunoreactive tumour nuclei or in five cases lacking p53 accumulation significant. Our results suggest that alterations of the p53 gene play only a minor part in the development or progression of Merkel cell carcinoma of the skin.

Non-Langerhans cell histiocytoses. A new unifying concept.

Based on our series of 111 cases of non-Langerhans cell histiocytoses, we present a new unifying concept for this rare group of disorders. The common denominator is the monocyte/ macrophage, which presents with various histologic features probably due to the influence of cytokines. Non-Langerhans cell histiocytoses are classified according to the predominant mononuclear (vacuolated, spindle-shaped, xanthomatized, scalloped, and oncocytic) and/or multinucleate (Touton, ground-glass appearance, Langhans, and foreign body) histiocytic cell types. Variable mixtures of these cell types produce common polymorphous patterns with prominence of vacuolated, spindle-shaped, and xanthomatized histiocytes in juvenile xanthogranulomas and of scalloped and oncocytic histiocytes in adult xanthogranulomas. Rarely, unusual monomorphous reaction patterns are observed: mostly vacuolated histiocytes are seen in the mononuclear variant of xanthogranulomas, (early benign cephalic histiocytosis, and generalized eruptive histiocytoma. Xanthomatized histiocytes predominate papular xanthoma and rarely xanthoma disseminatum, whereas spindle-shaped histiocytes are evident in spindle cell xanthogranuloma and progressive nodular histiocytosis, scalloped histiocytes are evident in most cases of xanthoma disseminatum, and finally oncocytic histiocytes are evident in reticulohistiocytoma and multicentric histiocytosis. Immunohistochemical, ultrastructural, and clinical findings can rationally be adjusted to this unifying concept of non-Langerhans cell histiocytoses. The time course of lesions, the age of the patients, and the presence or absence of underlying internal diseases are, or may, at least partially, be related to and thus explain variations on the theme of the non-Langerhans cell histiocytic reaction.

Aneurysmal and haemangiopericytoma-like fibrous histiocytoma.

AIM: To describe the clinicopathological features of 33 aneurysmal fibrous histiocytomas (AFH), including five cases with a haemangiopericytoma-like pattern. METHODS: Thirty three cases of AFH were studied by using routine histology and immunohistochemistry for factor XIIIa, the "cell activity marker" E9 (anti-metallothionein), NK1C3 (CD57), smooth muscle actin (SMA), factor VIII, ulex europaeus agglutinin, JC70A (CD31), and QBEND10 (CD34). The time dependent variation in histopathological features was evaluated by statistical methods (Pearson chi 2, likelihood ratio chi 2). RESULTS: Of the AFHs, 29 of 33 occurred on the extremities of adults (age range 30 to 50 years), six of which were associated with rapid growth, probably caused by trauma, and pain. Twenty one lesions were thought to be vascular and/or melanocytic lesions, including two melanomas, because of a bluish-black and/or cystic appearance. Histologically, large areas of haemorrhage, up to 50% of the tumour bulk, lacking an endothelial lining were seen in otherwise typical fibrous histiocytomas. Five cases resembled nodular stages of Kaposi's sarcoma. Variable haemosiderin deposition in histiocytes (18/33) and giant cells (11/33) was suggestive of haemosiderotic histiocytoma. A haemangiopericytoma-like pattern was seen in five otherwise indistinguishable cases. On immunohistochemistry, variable reactivity was seen for factor XIIIa (18/30), with E9 (18/30), NK1C3 (19/30), and for SMA (14/30), but labelling for vascular markers was not detected. Early lesions without iron deposition were factor XIIIa positive; late lesions with iron deposition were factor XIIIa negative. Labelling for SMA correlated with prominent sclerosis. CONCLUSION: AFHs, including a haemangiopericytoma-like variant, have a characteristic time dependent histological and immunophenotypic profile, clearly different from nodular type Kaposi's sarcoma.

Clear cell dermatofibroma. Case report of an unusual fibrohistiocytic lesion.

A case of clear cell dermatofibroma is presented. Clinically, a 41-year-old woman exhibited a hard brown nodule on her instep that was assumed to be a dermatofibroma. Histologically, more than 90% of the lesion was composed of clear cells. Epidermal hyperplasia and a storiform arrangement of spindle cells and sclerotic collagen in some foci at the periphery of the lesion indicated the fibrohistiocytic origin. Moreover, prominent vascularity and some bizarre giant cells in the lower part of the lesion were reminiscent of multinucleate cell angiohistiocytoma. Of a broad panel of antibodies, the lesion was positive only for Factor XIIIa (and vimentin). Ultrastructurally, clear-cell changes corresponded to a mostly translucent cytoplasm, focally with some endoplasmic reticulum and prominent lysosomal structures. A review of 1,496 dermatofibromas seen during the last 15 years at our institute revealed 12 cases (1%) with similar clear-cell changes in a minor part of the infiltrate (less than 10%). The differential diagnosis includes metastases of renal-cell carcinoma, which exhibit more atypia and mitoses and are positive for epithelial cell markers; clear-cell sarcoma, a lesion of tendons or aponeurosis with some moderate cytoplasmic melanin deposition and immunoreactivity with HMB-45; and various non-X histiocytic disorders, such as the predominantly vacuolated type of juvenile (or adult) xanthogranulomas or papular xanthoma, with a mixed infiltrate of various types of mononuclear and multinucleate histiocytes positive with a variety of macrophage markers.

Dermal spindle cell lipoma: plexiform and nodular variants.

We report on eleven cases of a distinctive dermal spindle cell lipoma characterized by a mixture of mature adipocytes and spindle-shaped cells in a fibromucinous background. Six lesions showed a moderately well circumscribed plexiform pattern, five a well demarcated nodular pattern with compression of surrounding connective tissue and prominent stromal fibrosis. Clinically, the plexiform type mostly occurred in the thigh-groin-buttock area and the nodular type in the head-neck or acral location. While plexiform lesions were predominantly seen in middle-aged females, nodular types occurred in young adults of either sex. No recurrence was seen in five patients with follow-up. The tumour cells were vimentin positive and a thin cytomplasmic rim of S-100 protein positivity was seen in mature adipocytes. Ultrastructural studies revealed lipoblastic differentiation of spindle-shaped cells with lipid droplets and basal lamina formation. Dermal spindle cell lipomas seem to be the dermal counterpart of the most subcutaneously located spindle cell lipoma.

Solitary and generalized variants of spindle cell xanthogranuloma (progressive nodular histiocytosis).

Twelve cases of solitary spindle cell xanthogranuloma, seven of which had originally been misdiagnosed as dermatofibroma/benign fibrous histiocytoma, were clinicopathologically compared with four cases of progressive nodular histiocytosis, a rare generalized non-X histiocytic disorder. Clinically, a single brown-yellowish papule or nodule is characteristic of solitary spindle cell xanthogranuloma, multiple generalized lesions of progressive nodular histiocytosis. Solitary spindle cell xanthogranuloma occurs with decreasing frequency on the head, neck, upper trunk, or occasionally the extremities of young adults (aged 20-40 years), progressive nodular histiocytosis mostly on the trunk of older patients (aged 40-60 years), both without sex predilection. Histologically, both entities are characterized by predominance (> 90%) of spindle-shaped histiocytes arranged in a storiform pattern. Other mononuclear (vacuolated, xanthomatized, scalloped, oncocytic) and multinucleate (Touton) histiocytes are also regularly seen. Immunohistochemically, both entities exhibit a macrophage/dendritic cell lineage positive for KP1/Ki-M1p (CD68), HAM 56 and factor XIIIa as well as for smooth muscle specific actin and HHF35. Ultrastructurally, dense, regularly laminated, myeloid or pleomorphic cytoplasmic inclusions may be found, but no Birbeck granules are present. This study documents that both solitary spindle cell xanthogranuloma and progressive nodular histiocytosis are distinct entities within the spectrum of a xanthogranulomatous reaction characterized by predominance of spindle-shaped histiocytes.

Atrophic variants of dermatofibroma and dermatofibrosarcoma protuberans.

Dermal atrophy of more than 50% of the locoregional dermis may be the predominant histopathological feature in dermatofibroma and dermatofibrosarcoma protuberans. This may cause diagnostic difficulties. In the present study 26 cases of atrophic dermatofibroma were compared with three cases of atrophic dermatofibrosarcoma protuberans. Clinically, both conditions mostly occurred on the (upper) trunk of females. While atrophic dermatofibroma usually presented as a reddish, umbilicated lesion (0.5-1cm), often suspected to be a basal cell carcinoma, atrophic dermatofibrosarcoma protuberans showed irregularly arranged tan-brown plaques (3-6 cm). Histologically, atrophic dermatofibroma showed a regular silhouette with a smooth nodular (9/26) or scalloped lower margin with an intervening lace-like pattern of superficial fatty tissue infiltration (17/26) and variable sclerosis: atrophic dermatofibrosarcoma protuberans showed a deep, irregular infiltration of fatty tissue in a lacelike/honeycomb and/ or multilayered pattern, but no sclerosis. Immunohistochemically, atrophic dermatofibroma was mostly negative with QBEnd 10 (CD34;24/26), variably positive for factor XIIIa (20/26) and metallothionein (11/26). Labelling for factor XIIIa and metallothionein was usually seen in 'early' (metabolically active) lesions, while 'late' sclerotic ones were negative. In contrast to atrophic dermatofibroma all three atrophic dermatofibrosarcoma protuberans showed a consistently uniform profile: CD34 positive, factor XIIIa and metallothionein negative. Our study delineates atrophic dermatofibroma and atrophic dermatofibrosarcoma protuberans as distinct entities clearly distinguishable from each other by clinicopathologic criteria.

Monophasic cellular variant of infantile myofibromatosis. An unusual histopathologic pattern in two siblings.

Infantile myofibromatosis (IMF) is a distinct clinicopathologic entity characterized by solitary or multicentric tumors present at birth or in early infancy with a typical biphasic (central hemangiopericytoma-like, peripheral leiomyoma-like) histologic pattern. We present a case of IMF in two siblings with onset of disease in late childhood. Histology of the primary as well as several later tumors was characterized by a monophasic cellular appearance with a prominence of tiny capillaries initially suggesting an unusual vascular tumor. Diagnosis was established by the development of more characteristic biphasic lesions during the course of disease. Immunocytochemistry (Ulex, factor VIII, JC/70A [CD31], PAL-E, BMA120, EN4, QBEnd10 [CD34], SMS actin) and ultrastructural studies showed no (marked) differences between different types of IMF. The monophasic cellular pattern should be recognized as an unusual histologic manifestation of IMF, in particular in patients outside the classical setting or presentation.

Adjuvant treatment of recalcitrant genitoanal warts with systemic recombinant interferon-alpha-2c.

Seventeen male patients with recalcitrant genitoanal warts, who had been unsuccessfully treated with classical destructive modalities for 16 months on average, were included in an open uncontrolled trial. The treatment regimen consisted of caustic and/or surgical measures as judged optimally suited in the individual cases, combined with an intermittent systemic low-dose adjuvant interferon-alpha-2c regimen (3 or 6 5-day-courses with intervals of 2 weeks) followed by a 1-year-observation period. At the end of interferon treatment, no patient had clinically visible warts but 10 still had subclinical acetic acid positive lesions. At the end of the 1-year-observation period, clearance of both warts and acetowhite lesions was observed in 4 patients (23.5%), whereas acetowhite lesions persisted in 4 others (23.5%). Recurrence of clinically visible lesions, always within the acetowhite areas, was observed in 9 (53%) patients. Interferon may thus have been effective in suppressing clinical recurrences of genitoanal warts, but its potency to eradicate subclinical papillomavirus infection was disappointing.