Kaposi's sarcoma and cytomegaloviral ileocolitis complicating long-standing Crohn's disease in an HIV-negative patient.

A 67-yr-old woman with a 25-yr history of Crohn's disease, maintained on near-continuous corticosteroids (prednisone 10 mg daily) over a 6-yr period, underwent ileocolic resection for obstruction. Pathology revealed Crohn's disease, multiple nodules of Kaposi's sarcoma, and cytomegalic inclusion bodies with confirmation of cytomegalovirus by shell vial immunofluorescence. Testing for HIV serum antibody has been repeatedly negative. Crohn's disease, Kaposi's sarcoma, and cytomegalovirus have been clinically in remission for 5 yr.

Concurrent malakoplakia and papillary urothelial carcinoma of the urinary bladder.

A case of malakoplakia and papillary urothelial carcinoma of the urinary bladder is reported. In this case, malakoplakia was an incidental finding in a biopsy of the urinary bladder of a 74-yr old female, who presented with hematuria. The biopsy showed a low-grade papillary urothelial carcinoma in close association with malakoplakia. This is a rare association of these lesions.

Gene-enhanced tissue engineering: applications for wound healing using cultured dermal fibroblasts transduced retrovirally with the PDGF-B gene.

The treatment of difficult wounds remains a considerable clinical challenge. The goal of this study was to determine whether genetic augmentation of dermal cells on resorbable matrices can stimulate the healing process, leading to increased tissue repair in a rat full-thickness excisional wound repair model. The human platelet-derived growth factor B (PDGF-B) gene was the initial gene chosen to test this hypothesis. The human PDGF-B gene was obtained from human umbilical vein endothelial cells (HUVEC) by reverse transcriptase-polymerase chain reaction, cloned into retroviral vectors under control of either the cytomegalovirus promoter or the rat beta-actin promoter, and introduced into primary rat dermal cells. In vitro results demonstrate that rat dermal cells are transduced and selected readily using retroviral vectors, and engineered to secrete PDGF-B at a steady-state level of approximately 2 ng per milliliter culture per 1 million cells per 24 hours. Seeding of the gene-modified cells onto polyglycolic acid (PGA) scaffold matrices and introduction into the rat model resulted in substantially increased fibroblast hypercellularity over control wounds at both 7 and 14 days posttreatment. Our results demonstrate that gene augmentation of rat dermal fibroblasts with the PDGF-B gene introduced into this animal model via PGA matrices modulates wound healing and suggests that experimentation with additional genes for use separately or in combination with PDGF-B for additional, improved wound healing is warranted.

Estrogen and progesterone receptors: their role in postsclerotherapy angiogenesis telangiectatic matting (TM).

BACKGROUND: Postsclerotherapy neoangiogenesis telangiectatic matting (TM) occurs in up to 24% of individuals treated by sclerotherapy. Although the etiology is unknown, obstructive flow factors, angiogenic factors, estrogen, inflammatory, and endogenous factors have all been postulated to play a role in its pathogenesis. OBJECTIVE: The aim of the study was to ascertain the presence or absence of estrogen and progesterone receptors in postsclerotherapy TM lesions and thus substantiate their possible role in the pathogenesis of TM. METHODS: Ten women, median age 37.7 years, were included in the study population who developed TM following a single sclerotherapy treatment session employing Sotradecol 0.25% for class I-II telangiectasia/venulectasia. Four of 10 patients had a history of previous hormonal therapy or pregnancy in the previous 12 months prior to entering into the study. Three millimeter punch biopsies were taken at 12 weeks posttreatment and assayed for estrogen and progesterone receptors by the ERICA and PRICA (estrogen/progesterone immune cytochemical assay) techniques. RESULTS: Zero of 10 patients were positive for estrogen/progesterone receptors as assayed by the ERICA/PRICA technique in biopsied sites of postsclerotherapy TM. CONCLUSION: Although estrogen and progesterone may play an indirect role in the development of postsclerotherapy TM via vasodilatory or secondary angiogenic or cytokine release mechanisms, they do not appear to play a primary role in promoting postsclerotherapy neoangiogenesis as demonstrated in this study.

The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy.

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague-Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.

Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years.

We summarize our experience with 238 cases of Langerhans cell granulomatosis (LCG), 198 of whom were followed for a median period of 10.5 years. Our patients did well unless overtreated, and no deaths were attributed to the disorder itself. The disease may appear in unifocal or multifocal form, and treatment is based on this fact. Virtually all patients recovered completely except for occasional residual orthopedic problems or residual diabetes insipidus. Several of the patients underwent subsequent pregnancies without difficulty. The granulomas primarily occur in bone, but lung, skin, and lymph nodal involvement is not uncommon. Involvement of thyroid, thymus, and other sites is rare. The hallmark of the disease is the accumulation of Langerhans cells (LCs). We review the pathology of LCG by histology, electron microscopy, and immunolabeling. LCs originally were identified in squamous epithelium, but these cells are part of the widespread system of dendritic cells. The latter cells, which arise from CD34+ progenitors, are specialized and efficient antigen-presenting cells for T-cell-mediated immunity. In LCG, however, the major associated cells are not T cells, but mature eosinophils: hence the original name eosinophilic granuloma. Confusion about terminology has been based upon the scanty and rather crude pathology reports in the original literature. The term histiocytosis X was meant to cover a spectrum of three diseases--eosinophilic granuloma, Hand-Schüller-Christian disease (HSC), and Letterer-Siwe disease (LS)--but HSC and LS have no basis in pathology and hence the terms are meaningless. The term HSC has become a synonym for multifocal eosinophilic granuloma (LCG). The term LS has been used in reporting a number of benign, malignant, or unknown conditions. We prefer the term LCG to avoid confusion with the term histiocytosis X because there is evidence that the LC is not a member of the mononuclear phagocyte system and hence not a tissue macrophage, and because the use of the term "histiocyte" has become a convenience in much of the literature when reporting incompletely understood diseases.

Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity.

The term "nevoid malignant melanoma" (nevoid MM) is used here to describe rare nodular malignant melanomas that may escape detection in routine histological sections due to the lack of a prominent intraepidermal component, sharp lateral circumscription and evidence of partial maturation with descent in the dermis. Nevoid MM mimic ordinary compound or intradermal melanocytic nevi when the melanoma cells are small, or Spitz's nevi when the cells are large. The patterns of HMB-45 staining in 12 nevoid MM were compared with those in 107 melanocytic nevi. HMB-45 staining was strong in the dermal component of the nevoid MM, even in the absence of a junctional component. In common acquired and congenital nevi, the upper dermal component stained less than the junctional component of the lesion. The deepest components of these nevi were negative. Spitz nevi and cellular blue nevi had positive dermal cells, even without a junctional component. Additional staining for a proliferation marker, such as cyclin (PCNA) or Ki-67 (with the antibody MIB-1), can help further in distinguishing a nevoid MM from a Spitz's nevus. Melanoma has strong nuclear staining throughout the lesion. In contrast, Spitz's nevi have more staining at the top of the lesion than at the bottom. The patterns of HMB-45 and MIB-1 staining can be used along with standard histologic criteria for the diagnosis of nevoid MM. Clinicopathologic correlation is needed to distinguish some metastatic melanomas from primary nevoid MM.

Cytology of cervical chordoma in cerebrospinal fluid from a child. A case report.

The cytologic findings on cerebrospinal fluid examination of cervical chordoma in a 2-year-old girl are presented. The major cell type was a small, isolated, hyperchromatic cell with sharply defined nuclear membrane and granular cytoplasm. However, the characteristic cell of this neoplasm, the so-called physaliferous cell with typical bubbly cytoplasm, was also noted. Cytologic findings were compared to biopsy findings, with a good correlation of tumor morphology. Clinical follow-up revealed unusually aggressive tumor behavior, and the patient died a year later despite intensive chemotherapy. The differential diagnosis of the condition is also discussed.

Immediate vs. salvage resection after local treatment for early rectal cancer.

PURPOSE: There is an increasing awareness of local procedures to treat early stage rectal cancer. Abdominoperineal resection (APR) or low anterior resection (LAR) has been recommended if adverse pathologic findings are encountered in the local excision specimen. No data compare the impact on survival of "immediate" resection for adverse features vs. "salvage" resection for clinical recurrence. METHODS: We reviewed retrospectively 155 patients who underwent initial curative treatment of invasive rectal cancer by excision (91), snare-cautery (44), and fulguration (20). RESULTS: Twenty-one patients underwent APR/LAR immediately after initial local treatment, whereas another 21 patients underwent salvage APR/LAR for local recurrence. The disease-free survival after APR/LAR was 94.1 percent for the immediate group and 55.5 percent for the delayed group (P < 0.05). CONCLUSION: This decreased survival observed after delayed resection supports the recommendation for immediate APR/LAR when adverse pathologic features are present in the excision specimen.

Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site.

Adenocarcinomas of the proximal stomach including the gastroesophageal junction are extremely virulent cancers which are increasing rapidly in incidence. Stage-for-stage proximal gastric cancers have a worse prognosis than do tumors of the body or antrum of the stomach. To further explore biological differences based on site, we studied 80 patients with locally advanced primary tumours of the proximal (n = 40) and distal stomach (n = 40) for amplification of the HER-2/neu proto-oncogene. None of 40 patients with proximal lesions had overexpression of HER-2/neu, whereas four of 40 (10%) distal adenocarcinomas had a 16-24-fold gene amplification (P = 0.04). In the adenocarcinomas from two patients, gene rearrangements were found in addition to amplification. HER-2/neu gene product p185 over-expression was found only in the amplified cases. All four patients with distal tumors and amplification had rapid progression of disease (median survival: 4.3 months). While it is unclear why HER-2/neu amplification is seen only in distal tumors, these data further support the hypothesis that biological differences between proximal and distal lesions are present. As is the case for other tumours, HER-2/neu amplification is associated with a poor prognosis for the individual patient.

Crohn's disease and colorectal carcinoma: rectal cancer complicating longstanding active perianal disease.

OBJECTIVES: Reports of Crohn's disease (CD)-associated colorectal carcinoma are being cited in the medical literature with increasing frequency. Our aim was to identify subgroups of patients with risk factors that may account for this. METHODS: We reviewed the medical records of 16 patients with the simultaneous diagnosis of CD and colorectal carcinoma and, in addition, reviewed previously reported cases of CD-associated colorectal carcinoma. RESULTS: Eight male and eight female patients presented with 18 carcinomas: four right colon, four transverse, two descending colon, and eight rectal lesions. Median age at presentation was 48 yr. The mean duration of CD before presentation of carcinoma was 19.7 yr. Two lesions were discovered in strictured bowel segments. Two patients had multiple cancers. One had simultaneous cecal and left colon adenocarcinomas. The other underwent resection of a right colon lesion and 5 yr later presented with transverse colon carcinoma. Eight patients had rectal cancer; all were diagnosed preoperatively. Six of these patients had a history of severe perianal CD. Six had undergone multiple incision and drainage procedures for perirectal abscesses and fistulas. Two developed malignancies in defunctionalized rectal stumps. One of these patients presented with simultaneous squamous rectal carcinoma and papillary bile duct cholangiocarcinoma. CONCLUSIONS: Gastrointestinal malignancy in association with CD has been reported. Symptoms of chronic inflammatory disease may obscure clinical manifestations of occult malignancy and thereby delay diagnosis. Crohn's patients with long-standing anorectal or perianal disease and stricture may well warrant surveillance endoscopy and biopsy of involved areas with the hope of earlier detection and treatment of these rectal cancers.

Recurrent deletions involving chromosomes 1, 5, 17, and 18 in colorectal carcinoma: possible role in biological and clinical behavior of tumors.

We have employed cytogenetic and restriction fragment length polymorphism (RFLP) analysis to identify a full spectrum of cytogenetic and molecular alterations associated with initiation and progression of "sporadic" colorectal cancer and also to correlate the alterations with biological and clinical behavior of the tumors. The study series included 63 colorectal cancers, 47 primary and 16 metastatic recurrences. Cytogenetic analysis was successful in 48 tumors (76%) of which 44 (91%) were abnormal. Of these 44 tumors, clonal abnormalities were identified in 43, whereas chromosomes from one tumor were unsuitable for complete analysis. Each of these abnormal tumors displayed heterogeneity with regard to extent and complexity of recurrent chromosomal abnormalities. Numerical losses of chromosomes 17 and 18 (20-34%) and gains of chromosome 7 (28%) were significantly higher. The four most frequent structural rearrangements on the other hand, involved specific regions of chromosomes 1p, 5q, 17p, and 18q. The shortest regions of overlap of these rearrangements or losses were located at 1p36, 5q21-22, 17p13 and 18q21- > ter. RFLP analysis directed at 1p, 5q, 17p and 18q identified allelic deletions of these regions in 39 tumors (64%) which included 17 normal and 11 cytogenetic failures. Of all the informative tumors, 32%, 37%, 31%, and 63% showed allelic losses at chromosomes 1p, 5q, 17p and 18q respectively. The two methods of analysis (cytogenetics and RFLP) employed to identify genetic alterations were complementary; probes for chromosome 1 and 18 showed the greatest degree of concordance, whereas probes for chromosomes 5 and 17 provided relatively higher rate of discordance with cytogenetic results. These differences could be attributed mainly to three reasons: 1) a limited number of probes used for RFLP analysis; 2) contamination of tumor cells with normal cells, and 3) either mutational inactivation or deletion of specific alleles not closely linked to the probes used. Regardless of these limitations, however, the combined use of cytogenetic and RFLP identified genetic alterations in a large number of tumors and help elucidate the role of hyperdiploidy and/or relative deficiency of a given chromosomal segment in expression of recessive mutations. In addition, alterations of either chromosomes 1 or 17 predicted poorer survival for the patients with primary colorectal cancer (p = 0.03).

Intestinal microsporidiosis. Report of five cases.

Five cases of intestinal microsporidiosis are reported, including one case of a heterosexual female acquired immunodeficiency syndrome (AIDS) patient, three homosexual males, and one bisexual male AIDS patients with detailed description of their clinical course. These five cases underscore the severity of immunodeficiency in patients with microsporidiosis. All patients had multiple opportunistic infections and a CD4 cell count below 100/microliters long before diarrhea developed. This is the first kinetic study of helper T-lymphocytes in cases of microsporidiosis. Diagnosis was made by duodenal biopsies stained with Brown and Brenn or Gram-Weigert technique (confirmed by electron microscopy) and by stool smears stained with a modified trichrome technique. However, the best preparation was plastic sections stained with toluidine blue, which demonstrated both the spores and plasmodia clearly. In our evaluation, Giemsa stain was also acceptable for identification of microsporidian spores in both intestinal biopsies and stool smears, but there was a failure to identify the organism on hematoxylin and eosin, acid-fast, periodic acid-Schiff, and Gomeri's methenamine silver stained preparations. Therapeutic attempts using albendazole, metronidazole, octreotide, and zidovudine (AZT) failed to eradicate microsporidia in these patients.

Giant myofibroblastoma of the male breast.

Myofibroblastoma of the breast is a rare, benign neoplasm, seen predominantly in men. The gross appearance is that of a well-circumscribed nodule, characteristically small, seldom exceeding 3 cm. We report a case of giant myofibroblastoma measuring 10 cm and weighing 169 g in the breast of an 83-year-old man. Light microscopic, immunohistochemistry, and electron microscopic features are described. Histologically, these neoplasms may exhibit a varied cellularity that can be misinterpreted as sarcoma. However, they lack marked cellular pleomorphism, tumor necrosis, and mitosis and are characteristically composed of plump and long bipolar, spindly cells arranged in swirling fascicles with intervening broad collagen bands. As we report, immunostaining is strongly positive for vimentin, desmin, and muscle common antigen and negative for cytokeratins and S-100-associated protein. Electron microscopy shows predominantly cells suggestive of myofibroblastic differentiation. The patient has remained free of disease 2 years after mastectomy.

[Molecular biology and immunohistochemical studies of Her2/neu oncogene in stomach cancer]. / Molekularbiologische und immunhistochemische Untersuchungen zum Her2/neu-Onkogen beim Magencarcinom.

In 58 gastric carcinomas the expression of the Her2/neu gene product p185 was immunohistochemically analyzed. Fresh tumor tissue for molecular studies was available in 25 cases. The results were correlated with various pathohistological and prognostic factors. A 16-32fold Her2/neu amplification was found in 20% of the tumors (n = 5). The oncogene product p185 was detected at the basement membrane in 38% of the tumors (n = 22). Amplification and p185 overexpression occurred in intestinal, but not diffuse type carcinomas (p < 0.001). p185 expression was independent from tumor site and tumor stage, but correlated with pT-stage (p < 0.001). Overall prognosis was influenced by tumor stage and R-classification, but not by p185 expression. Multivariate analysis, however, defined patients with stage IIIA/B and IV and R0-resection who had a poorer survival in case of p185 expression (p < 0.05). Her2/neu amplification and p185 overexpression appear to be characteristic molecular events in intestinal type gastric carcinogenesis and may help in identifying a subgroup of patients at increased risk for shorter survival.

Aggressive natural killer cell lymphoma/leukemia. A recently recognized clinicopathologic entity.

We report a comprehensive study of a case of aggressive natural killer cell lymphoma/leukemia, which is characterized by young male predominance, rapidly progressive clinical course, and presence of lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. The leukemic phase is frequently preceded by pancytopenia. The diagnostic clues are the detection of cytoplasmic granules in tumor cells on Wright-Giemsa-stained tissue imprints or smears and a selective loss of T-cell antigens. Immunophenotyping is decisive in making the final diagnosis by showing positive natural killer cell markers (CD16, CD56, and/or CD57), CD2, CD11c, and Ia, but negative CD3, T-cell receptor heterodimers, terminal deoxynucleotidyl transferase, and B-cell markers. Genotyping always shows germline configuration in both immunoglobulin and T-cell receptor genes. The unique feature in this case is its presentation as a testicular lymphoma, which has not been previously reported. Polymerase chain reaction was performed in this case but failed to detect human T-cell leukemia virus type I/II provirus. It is important to recognize this new entity as it is a highly aggressive disease with a rapidly progressive clinical course and fails to respond to any chemotherapeutic regimen available.

Usefulness of carcinoembryonic antigen monitoring despite normal preoperative values in node-positive colon cancer patients.

PURPOSE: The aim of our study was to determine to what extent serial carcinoembryonic antigen (CEA) monitoring is helpful in detecting colorectal cancer recurrence in patients if their preoperative serum CEA is normal. Additional major objectives of this study were to correlate CEA immunohistochemical features of the primary tumor with serum CEA levels at the time of tumor recurrence in node-positive colorectal cancer patients with low preoperative CEA values. METHODS: One hundred fourteen node-positive colorectal cancer patients with preoperative serum CEA levels of < 5.0 ng/ml undergoing clinically curative operations were studied. Primary tumors were evaluated for tissue CEA using the same monoclonal antibody as used for serum CEA determinations utilizing the avidin-biotin-peroxidase immunohistochemical technique. RESULTS: The exact preoperative serum CEA value did not correlate with tumor grade, immunohistochemical CEA intensity or pattern. In the 32 patients who developed recurrent cancer, the serum CEA at recurrence was greater than 5 ng/ml in 44 percent. All such patients had CEA present in their primary tumor. There was no correlation with the exact preoperative serum CEA, the intensity of the primary tissue CEA, or the localization of such CEA and subsequent serum elevation at recurrence. CONCLUSION: Serum CEA is a useful marker in the detection of recurrent colorectal cancer despite normal preoperative values.

[DNA analysis in stomach cancer--correlation of aneuploidy with tumor site]. / DNA-Analyse beim Magencarcinom--Korrelation von Aneuploidie mit der Tumorlokalisation.

The DNA status and the proliferative activity was determined in 37 gastric carcinomas applying computerized image analysis. Aneuploidy was found in 51.4% (n = 19) of the tumors. Comparing diploid and aneuploid lesions the latter ones had statistically significant increased DNA amount, DNA index and proliferative rate (7.4 pg, 1.03 and 16.4% versus 12.8 pg, 1.78 and 30.7%; p < 0.05). Aneuploidy occurred more frequently in tumors at proximal sites (p < 0.05), but was not associated with histological type, differentiation and tumor stage. The prognostic impact of DNA aneuploidy remains controversial, since tumor aggressiveness per se is not directly related to aneuploidy.