Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis.

Adult-onset urticaria pigmentosa/mastocytosis in the skin almost always persists throughout life. The prevalence of systemic mastocytosis in such patients is not precisely known. Bone marrow biopsies from 59 patients with mastocytosis in the skin and all available skin biopsies (n=27) were subjected to a meticulous cytological, histological, immunohistochemical, and molecular analysis for the presence of WHO-defined diagnostic criteria for systemic mastocytosis: compact mast cell infiltrates (major criterion); atypical mast cell morphology, KIT D816V, abnormal expression of CD25 by mast cells, and serum tryptase levels >20 ng/ml (minor criteria). Systemic mastocytosis is diagnosed when the major diagnostic criterion plus one minor criterion or at least three minor criteria are fulfilled. Systemic mastocytosis was confirmed in 57 patients (97%) by the diagnosis of compact mast cell infiltrates plus at least one minor diagnostic criterion (n=42, 71%) or at least three minor diagnostic criteria (n=15, 25%). In two patients, only two minor diagnostic criteria were detectable, insufficient for the diagnosis of systemic mastocytosis. By the use of highly sensitive molecular methods, including the analysis of microdissected mast cells, KIT D816V was found in all 58 bone marrow biopsies investigated for it but only in 74% (20/27) of the skin biopsies. It is important to state that even in cases with insufficient diagnostic criteria for systemic mastocytosis, KIT D816V-positive mast cells were detected in the bone marrow. This study demonstrates, for the first time, that almost all patients with adult-onset mastocytosis in the skin, in fact, have systemic mastocytosis with cutaneous involvement.

Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD).

In a substantial number of patients with systemic mastocytosis (SM), an associated clonal haematological non-mast cell lineage disease (AHNMD) is detectable. Although most of these patients display KIT mutations, especially KIT(D816V), little is known about their exact frequency and their distribution in AHNMD subtypes. We examined 48 patients with SM-AHNMD for the presence of mutant KIT in the SM and AHNMD components of the disease. Mast cells and AHNMD cells were obtained from immunostained bone marrow sections by laser microdissection and examined by melting point analysis of nested-PCR products. KIT(D816V) was found in AHNMD cells in the vast majority of patients with SM-chronic myelomonocytic leukaemia (CMML, 89%). Unexpectedly, KIT(D816V) was far less frequently detectable in AHNMD cells in patients with SM-myeloproliferative neoplasm (MPN, 20%) and SM-acute myeloid leukaemia (AML, 30%). None of the patients with lymphoproliferative AHNMDs displayed KIT codon 816 mutations in AHNMD cells (0/8). In FIP1L1/PDGFRA-positive chronic eosinophilic leukaemia (CEL), neither the SM nor the CEL component of the disease exhibited the KIT mutation. Our findings demonstrate that KIT codon 816 mutations are variably present in AHNMD cells in patients with SM-AHNMD, depending on the subtype of AHNMD. The high frequency of KIT(D816V) in neoplastic mast cells and leukaemic myelomonocytic cells in SM-CMML may point to a common precursor in these patients, and may have implications for the biology of the disease and the development of KIT-targeting therapies.

Coexistent parathyroid adenoma and thyroid papillary carcinoma in pregnancy.

BACKGROUND: Primary hyperparathyroidism in pregnant women is a rare antenatal complication. Maternal symptoms include nephrolithiasis, bone disease, pancreatitis, hyperemesis, muscle weakness, mental status changes, and hypercalcemic crisis. Fetal complications comprise intrauterine growth retardation, low birth weight, preterm delivery, intrauterine fetal death, postpartum neonatal titanic crisis, and permanent hypoparathyroidism. CASE: A 23-year-old gravida was referred to our clinic with severe hyperemesis and weight loss at 32 gestational weeks. She was diagnosed with primary hyperparathyroidism because of parathyroid adenoma and treated with surgery where a synchronous thyroid papillary carcinoma was detected. After right parathyroidectomy and right subtotal lobectomy of the thyroid, the patient was stable and laboratory and clinical findings normalized. The fetus' state was monitored via reassuring non-stress cardiotocography and repeated sonographic exams until birth. Delivery was induced at 35 weeks of gestation because of preeclampsia. CONCLUSION: Parathyroid adenoma in pregnancy is a rare maternal condition with potential impact on the advancing pregnancy. Generally, a surgical approach is recommended with thorough inspection of the thyroid gland so that any irregular structure might be removed during the same surgical intervention for diagnostic reasons. In this reported case, a coexistent papillary carcinoma of the thyroid was detected accidentally and removed successfully.

Basal cell carcinoma with neuroendocrine differentiation arising in a scar: A case report.

Basal cell carcinoma (BCC), the most common cutaneous malignant tumor, may display neuroendocrine differentiation in very rare instances. We here describe a case of a BCC with neuroendocrine differentiation that arose in a scar resulting from a trauma 75 years earlier. Neuroendocrine differentiation was proven by immunohistochemistry and electron microscopy. The simultaneous occurrence of BCC development in a scar and neuroendocrine differentiation is quite rare.

Sarcoma of follicular dendritic cells with features of sinus lining cells--a new subtype of reticulum cell sarcoma?

Dendritic cell neoplasms of the World Health Organization classification comprise Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, and dendritic cell sarcoma, not otherwise specified. Several studies based on immunohistochemical and ultrastructural analysis tried to further clarify the origin of these neoplasms which are thought to derive from mesenchymal or bone marrow precursors. Lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1) was recently described as a marker for lymphatic endothelium which is expressed on normal liver blood sinusoid lining cells, spleen endothelium, activated tissue macrophages, blood vessels in the lung, endothelial cells of lymphatic sinuses, and in fibroblastic reticular cells in lymph nodes. We present a case of LYVE-1-positive reticulum cell neoplasm in an axillary lymph node. To the best of our knowledge, there has been no report about LYVE-1 expression in histiocytic or dendritic cell neoplasms so far. Due to the assumed specificity of this antibody, we propose designation of this reticulum cell sarcoma as lymphatic sinus lining cell sarcoma which might finally represent another subtype of reticulum cell sarcomas.

Delineation of patterns of bone marrow mast cell infiltration in systemic mastocytosis: value of CD25, correlation with subvariants of the disease, and separation from mast cell hyperplasia.

In most cases, the diagnosis of systemic mastocytosis (SM) is based on histomorphologic evaluation of the bone marrow. We analyzed mast cell (MC) infiltration patterns in 57 cases of SM and 31 cases of mast cell hyperplasia (MCH). Tryptase immunohistochemical analysis was used for MC detection and CD25 to distinguish neoplastic from normal MCs. The following infiltration patterns were found: I, diffuse interstitial; II, focal, dense; III, focal, dense with an additional diffuse component, located preferentially around focal infiltrates; IV, focal, dense with an additional diffuse component evenly distributed throughout; and V, diffuse, dense. In 29 cases of MCH, MCs formed the type I pattern. The majority of SM cases exhibited patterns II to V; type IV was the most frequent (n = 36). Type V was seen in 3 cases of MC leukemia and 1 case of smoldering SM. In 1 case of SM, type I infiltration was found; the SM diagnosis was based on 3 minor SM criteria. Our data show that the infiltration pattern in SM correlates with the disease subtype and should be recognized as an important aspect in the histomorphologic evaluation of the bone marrow.

CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens.

The diagnosis of systemic mastocytosis (SM) is based primarily on the histologic and immunohistochemical evaluation of a bone marrow trephine biopsy specimen. Although mast cell (MC) specific antigens like tryptase and chymase are detectable in routinely processed tissue, no immunohistochemical markers that can be used to discriminate between normal and neoplastic MCs are yet available. We have investigated the diagnostic value of an antibody against CD25 for the immunohistochemical detection of MCs in bone marrow sections in 73 patients with SM and 75 control cases (reactive marrow, n = 54; myelogenous neoplasms, n = 21) and correlated the results with the presence of c-kit mutations. While MCs in almost all patients with SM (72 of 73) expressed CD25, none of the control samples contained CD25-positive MCs. Irrespective of the SM subtype, most of neoplastic MCs expressed CD25. In 3 patients with advanced MC disease, pure populations of neoplastic MCs were obtained and found to express CD25 mRNA by RT-PCR analysis. In addition, all patients with CD25-positive MCs contained c-kit mutations, while all control cases exhibited wild type c-kit. CD25 therefore appears to be a reliable immunohistochemical marker for the discrimination of neoplastic from normal/reactive MCs, with potential as a diagnostic tool in SM.

Whole cell ELISA for measuring anti-tumour effects of immunotherapies in a mouse tumour model of ALCL.

The use of whole cell vaccines to augment anti-tumour immunity has been explored throughout the last century. Using the recently established TS1G6 ALCL mouse model, we compared the ability of whole cell vaccines with different combinations of CpG oligodeoxynucleotides, Diphteria-, Pertussis- and Tetanus-vaccine (DPT) to enhance the immunogenicity of tumour cells. We have therefore developed a whole cell ELISA that detects the systemic anti-tumor-cell antibody response. CpG oligodeoxy-nucleotides can induce production of different TH1-cytokines and stimulate immune effector cells. Diphteria-, Pertusis- and Tetanusvaccine, injected together with irradiated tumor cells into Diphteria-, Pertussis- and Tetanus-preimmunized mice were used to serve as a target for the host's existing memory response and thus enhance the immunogenicity of the tumour cells by induction of a local inflammation. The combined application of oligodeoxynucleotides, the vaccines and irradiated tumor cells into preimmunized mice quickly induced very high titers of tumour cell-specific antibody response. We conclude that this therapy may be a new attractive part of a tumour immunization strategy.

[Aleukemic mast cell leukemia (formerly: "malignant mastocytosis"): an extremely rare form of leukemia. A case report and simultaneously a contribution to revised classification of mastocytosis]. / Aleukämische Mastzellenleukämie (vormals: "maligne Mastozytose"): Eine extrem seltene Leukämieform. Ein Fallbericht und gleichzeitig ein Beitrag zu einer revidierten Klassifikation der Mastozytosen.

The term mastocytosis denotes a heterogeneous group of rare hematological disorders characterized by abnormal accumulation of mast cells. While cutaneous mastocytosis is relatively frequent mast cell leukemia belongs to the rarest forms of human leukemia. In the following we present the case of an aleukemic mast cell leukemia and shall discuss the revised classification of mastocytosis based on the "Year 2000 Working Conference on Mastocytosis" held in Vienna, Austria. A 48 year-old caucasian man presented with a four-week history of diarrhea, obstipation, vomiting, rash, and mild fever. Clinical inspection revealed a disseminated itching rash and a mild hepatomegaly. Red and white blood cell counts were within the normal range. Levels of the alkaline phosphatase and serum histamine were significantly increased. There was no splenomegaly or lymphadenopathy. Cytologic and histologic investigation of the bone marrow revealed a marked increase in atypical mast cells. Since only a few circulating mast cells could be detected in a cytospin preparation of the blood, the diagnosis of an aleukemic mast cell leukemia was established. About four weeks after the diagnosis had been established, the patient died with signs of a hemorrhagic shock due to a massive gastrointestinal bleeding. Autopsy revealed widespread mast cell infiltration of bone marrow, spleen, liver and lungs, but also a small, deeply penetrating, non-specific duodenal ulcer. In conclusion, despite of presentation with signs of a primary gastrointestinal disorder, the patient was found to suffer from an exceedingly rare aleukemic mast cell leukemia ("malignant mastocytosis") and died after a total duration of the disease of only about three months.

BCL6-translocations affect the phenotype of follicular lymphomas only in the absence of t(14;18)IgH/BCL2.

BACKGROUND: The translocation t(14;18)IgH/BCL2 is the molecular hallmark of follicular lymphomas (FL). A subset of cases harbours translocations involving the BCL6-gene locus. This study aimed to determine the frequency of BCL2- and BCL6-translocations in FL and to identify morphological and immuno-histochemical features with respect to the presence of BCL2- and BCL6-translocations. MATERIALS AND METHODS: Fluorescence-in-situ-hybridisation (FISH) was used to determine the BCL2- and BCL6-translocation status of 102 FL and these were compared to morphological and immunohistochemical parameters. RESULTS: Lymphomas with BCL6- and BCL2-translocations were very similar to t(14;18)-positive lymphomas without BCL6-translocations. In contrast, t(14;18)-negative lymphomas with BCL6-translocations were amongst others of higher grade, less often CD10-positive, involved the bone marrow less frequently and did not infiltrate the lymph node capsule. CONCLUSION: BCL2- and BCL6-translocations correlate with particular phenotypes of follicular lymphomas. BCL6-translocations seem to affect the phenotype only when they are not accompanied by BCL2-translocations.

Pulmonary lymphangioma.

We report on the very rare case of a 49-year-old man with a large solitary pulmonary lymphangioma. Rapid growth of the tumor led to dyspnea and pain. A chest roentgenogram and computed tomography scan revealed a large 18 x 12-cm space-occupying cystic lesion in the posterior mediastinum. The tumor was resected by lateral thoracotomy. Histopathology revealed a pulmonary cystic lymphangioma.

Chromosomal aberrations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma unspecified: A matrix-based CGH approach.

Angioimmunoblastic T-cell lymphoma (AILT) is a histopathologically well-defined entity. However, despite a number of cytogenetic studies, the genetic basis of this lymphoma entity is not clear. Moreover, there is an overlap to some cases of peripheral T-cell lymphoma unspecified (PTCL-u) in respect to morphological and genetic features. We used array-based comparative genomic hybridization (CGH) to study genetic imbalances in 39 AILT and 20 PTCL-u. Array-based CGH revealed complex genetic imbalances in both AILT and PTCL-u. Chromosomal imbalances were more frequent in PTCL-u than in AILT and gains exceeded the losses. The most recurrent changes in AILT were gains of 22q, 19, and 11p11-q14 (11q13) and losses of 13q. The most frequent changes in PTCL-u were gains of 17 (17q11-q25), 8 (involving the MYC locus at 8q24), and 22q and losses of 13q and 9 (9p21-q33). Interestingly, gains of 4q (4q28-q31 and 4q34-qtel), 8q24, and 17 were significantly more frequent in PTCL-u than in AILT. The regions 6q (6q16-q22) and 11p11 were predominantly lost in PTCL-u. Moreover, we could identify a recurrent gain of 11q13 in both AILT and PTCL-u, which has previously not been described in AILT. Trisomies 3 and 5, which have been described as typical aberrations in AILT, were identified only in a small number of cases. In conclusion, CGH revealed common genetic events in peripheral T-cell lymphomas as well as peculiar differences between AILT and PTCL-u.

First-trimester sonographic diagnosis of distal urethral atresia with megalourethra in VACTERL association.

Congenital megalourethra is a rare disorder. We present an early case diagnosed in the first trimester. Prenatal ultrasound showed a megalourethra with a normal fetal bladder, hyperechogenic cystic right kidney and single umbilical artery. After termination of pregnancy, necropsy confirmed all sonographic findings and revealed other malformations (spina bifida occulta, anal atresia, tracheo-oesophageal fistula, brachydactylia) resulting in the diagnosis of VACTERL association. The prenatal diagnostician should seek histological examination firstly to confirm his findings and secondly to avoid missing associations and inherited malformations.