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The records of 63 patients surgically treated for liposarcoma at the Cleveland Clinic between 1975 and 1995 were examined. Both metastatic disease (Enneking stage IIl) and an abdominal location were found to be poor prognosticants for survival. Age, gender, or tumor size, setting, or grade did not have any prognostic significance. The 5-year disease-specific survival for extremity tumors was 92% (95% confidence interval [CI]; range: 84%-100%), while general 5-year survival for extremity tumors was 66% (95% Cl; range: 48%-85%).

Context.—A large percentage of cases of perianal Paget disease are associated with an internal cancer, most commonly rectal adenocarcinoma. Immunostains for cytokeratin 7, cytokeratin 20, and gross cystic disease fluid protein 15 are useful in identifying cases associated with rectal adenocarcinoma. The Paget cells and rectal adenocarcinoma cells of these lesions typically have a cytokeratin 7+/cytokeratin 20+/gross cystic disease fluid protein 15− immunophenotype. It is not known whether rectal adenocarcinoma unassociated with perianal Paget disease has the same cytokeratin profile as rectal adenocarcinoma associated with perianal Paget disease. Objective.—To evaluate the immunohistochemical cytokeratin 7 and 20 profile of resected rectal adenocarcinoma unassociated with perianal Paget disease as well as that of normal anal glands from hemorrhoidectomy specimens. Design.—We performed immunohistochemistry for cytokeratins 7 and 20 on tissues from 30 cases of rectal adenocarcinoma unassociated with perianal Paget disease and 12 hemorrhoidectomy specimens from 12 cases with normal anal glands. We defined positive staining as any immunoreactivity within the neoplastic cells. Results.—Twenty-six of 30 cases of rectal adenocarcinoma (87%) had a cytokeratin 7−/cytokeratin 20+ immunophenotype, similar to the immunophenotype of cases of nonrectal large intestine adenocarcinoma. In 4 cases (13%), neoplastic cells coexpressed cytokeratins 7 and 20. Anal glands stained strongly for cytokeratin 7 but were negative for cytokeratin 20 in all cases, and the anal transitional zone mucosa had a similar immunophenotype. Conclusions.—Rectal adenocarcinoma unassociated with perianal Paget disease has a cytokeratin profile similar to that of nonrectal large intestine adenocarcinoma. These data suggest that rectal adenocarcinoma unassociated with perianal Paget disease has a different cytokeratin profile than rectal adenocarcinoma associated with perianal Paget disease.

Esophageal leiomyomas are rare. We report the clinicopathologic features of one of the largest series of esophageal leiomyomas from a single institution. We retrospectively reviewed the Cleveland Clinic pathology database (1985-2010) for patients with a diagnosis of esophageal leiomyoma(s). Clinicopathologic features of 30 cases from 28 patients were analyzed. The group included 15 females and 13 males with a mean age at diagnosis of 56 years. These include 9 excisions, 9 esophagectomies, and 12 endoscopic biopsies. Only one partial esophagectomy was performed solely for a symptomatic 14-cm leiomyoma; the remainder of the resections (n= 8) were for other indications, including esophageal cancer (Barrett's esophagus-related adenocarcinoma and squamous cell carcinoma) and emergent esophageal perforation, with leiomyoma being an incidental finding. One patient (2.5%) had two synchronous leiomyomas (14 cm and 0.3 cm). Tumor size ranged from 0.1 to 14 cm (mean = 2.0 cm). Mean tumor size among symptomatic patients was 5.2 cm, as compared with 0.4 cm in asymptomatic patients. Dysphagia was the most common complaint in symptomatic patients (71.4%). Sixty-nine percent of the tumors were located in the distal and middle thirds of the esophagus, with most (69.6%) arising from muscularis propria. Histologically, these tumors were composed of bland spindle cells with low cellularity, no nuclear atypia, or mitotic activity. Only one case (14 cm) showed focal moderate cellularity and nuclear atypia, with low mitotic activity (1/10 high power field). Immunohistochemical studies showed tumor cells were positive for smooth muscle actin, and negative for CD34 and CD117. Follow-up information was available for 22 patients (78.6%), and none had adverse events related to leiomyoma. In summary, esophageal leiomyoma is a rare benign tumor of the esophagus. Patients with larger tumors were more likely to have symptoms. The majority of the tumors were in the lower and mid-esophagus, and arose from muscularis propria. These tumors behave in a clinically benign fashion.

The aim of this study was to determine preoperative clinical factors associated with subsequent diagnosis revision to Crohn's disease (CD) following total proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) or indeterminate colitis (IC) patients.Presumed UC and IC patients undergoing IPAA from a large single-institution prospective database with change of diagnosis to CD were identified and compared with patients without diagnosis change.A total of 2814 patients (47% male, median age 37 years) with presumed UC (85%) or IC (15%) underwent primary IPAA. At a median follow up of 9.6 years, 184 (7%) had the diagnosis revised to CD from histopathological examination of the colectomy specimen immediately in 97 (53%) or at a median interval of 36 months in 87 (47%). CD and UC/IC patients had had a similar operative technique, length of stay and 30-day morbidity. The postoperative CD diagnosis was associated with a preoperative diagnosis of IC (P0.0001) and perianal fistula (P = 0.002). Patients with a delayed diagnosis of CD were associated with a 3-stage procedure (P0.0001, OR = 2.8) (95% CI = 1.8-4.4), colonic stricture (P = 0.04, OR = 2.9 [95% CI = 1.1-7.4]), perianal fistula (P = 0.02, OR = 2.9 [95% CI = 1.2-7.2]), oral ulceration (P = 0.009, OR = 3.8 [95% CI = 1.2-9.6]) and younger age (P0.0001, OR = 0.048 [95% CI = 0.011-0.19]).A few patients having IPAA for presumed UC/IC were subsequently diagnosed to have CD which was associated with perianal fistula and the diagnosis of postoperative preoperative IC. The delayed diagnosis of CD was associated with a three-stage procedure, colorectal stricture, anal fissure, mouth ulceration and younger age.

The behaviour of leiomyosarcoma is site-related and there are few data on such tumours located in the head and neck. We studied the clinicopathological features of these lesions.Cases diagnosed as leiomyosarcoma of the head and neck were retrieved from the archives of three institutions. Immunohistochemistry was performed and follow-up information was obtained. There were seven men and six women, aged 21-73 years, and lesions involved the neck (n=3), maxilla (n=4), buccal area (n=3), and maxillary sinus, nose, and pharynx (n=1 each). Tumours ranged from 10 to 80 mm. All tumours showed at least focally typical histological features of leiomyosarcoma with perpendicularly arranged fascicles of smooth muscle cells with blunt-ended nuclei, eosinophilic cytoplasm and paranuclear vacuoles. They expressed muscle-specific actin (8/9), smooth muscle actin (7/9), and desmin (10/12). Follow-up information was available on nine patients. All had surgery, with radiation and/or chemotherapy in seven. Three (27%) recurred at 6-24 months; in one case twice. Five (56%) had metastases, including the three with prior recurrences at 1-128 months. Five (including two who received adjuvant therapy) were disease-free at a median of 47 months, one was alive with metastatic disease at 24 months), and three were dead of disease (median 13 months).Head and neck leiomyosarcomas are rare and aggressive neoplasms which metastasize. Adjuvant therapy has limited effect.

A specific TLS-CHOP fusion gene resulting from the t(12;16) is present in at least 95% of myxoid liposarcomas (MLS). Three common forms of the TLS-CHOP fusion have been described, differing by the presence or absence of TLS exons 6-8 in the fusion product. Type 5-2 (also known as type II) consists of TLS exons 1-5 fused to CHOP exon 2; type 7-2 (also known as type I) also includes TLS exons 6 and 7 in the fusion, whereas type 8-2 (also known as type III) fuses TLS exons 1-8 to CHOP exon 2. We sought to determine the impact of TLS-CHOP fusion transcript structure on clinical outcome in a group of well-characterized MLS cases. We also analyzed P53 status, because this parameter has been found to have a significant prognostic impact in other sarcomas with chromosomal translocations.We analyzed TLS-CHOP fusion transcripts by reverse-transcription PCR using RNA extracted from frozen tissue in 82 MLS confirmed previously to harbor a CHOP rearrangement either by Southern blotting or by cytogenetic detection of the t(12;16). Parameters analyzed included age, location, size, percentage of round cell (RC) component, areas of increased cellularity, necrosis, and surgical margins. In 71 (87%) cases, adequate tumor tissue was available for immunohistochemical analysis of P53 status, using DO7 antibody. The Kaplan-Meier method, log-rank, and Cox regression tests were used for survival analyses.Most MLS were10 cm (73%), arising in the thigh (70%), and localized at presentation (89%). RC component was5% in 47 (57%) cases andor =5% in 35 (43%). The TLS-CHOP fusion transcript was type 5-2 in 55 (67%), type 7-2 in 16 cases (20%), and type 8-2 in 8 (10%). One tumor had a unique variant fusion, between exon 6 TLS and exon 2 CHOP. Two other cases (2%) showed an EWS-CHOP fusion transcript. Overexpression of P53 (defined asor =10% nuclear staining) was detected in 12 (17%) cases. High histological grade (defined asor =5% RC; P0.01), presence of necrosis (or =5% of tumor mass; P0.05), and overexpression of P53 (P0.001) correlated with reduced metastatic disease-free survival in localized tumors. The presence of negative surgical margins (P0.01) and extremity location (P = 0.02) were found to be significant in predicting local recurrence in the entire group as well as localized cases by univariate and multivariate analysis. Although there was no significant correlation between TLS-CHOP transcript type and histological grade or disease-specific survival, an association was found between the P53 status and type 5-2 fusion (P0.01).In contrast to some other translocation-associated sarcomas, the molecular variability of TLS-CHOP fusion transcript structure does not appear to have a significant impact on clinical outcome in MLS. Instead, high histological grade (or =5% RC), presence of necrosis, and P53 overexpression are predictors of unfavorable outcome in localized MLS.

Cutaneous spindle cell squamous cell carcinoma (SSCC) is a challenging diagnosis since it may be difficult to distinguish from spindle cell melanoma, leiomyosarcoma and atypical fibroxanthoma. Furthermore, it may be difficult to demonstrate epithelial differentiation by a traditional immunohistochemical panel. We performed an expanded immunohistochemical evaluation of ultrastructurally documented SSCC to assess its utility in diagnosing this entity.We identified 16 cases of SSCC that were composed predominantly of spindle-shaped cells and with ultrastructural evidence of epithelial differentiation (i.e. at least rudimentary cell junctions). Immunohistochemical analysis using antibodies to a variety of cytokeratins (AE1/3, K903, CK5/6) and S-100 protein was performed. The extent of immunostaining was graded on a scale of 0 to 4+ (0: no staining; 1+:or =25%; 2+: 26-50%; 3+: 51-75%; 4+:75%).Of the 16 cases, 6 expressed AE1/3 (38%), 8 expressed K903 (50%) and 11 (69%) expressed CK5/6. Six cases were positive for all three CK markers and two cases were positive for both K903 and CK5/6 but negative for AE1/3. Three cases (19%) stained for CK5/6 without any staining for AE1/3 or K903. Five cases (31%) were negative for all epithelial markers. The extent of CK5/6 staining was either similar to or greater than K903 staining in 7 of 8 cases that stained with both markers. All 16 cases were negative for S-100 protein.Including CK5/6 in the initial battery of immunostains performed on a cutaneous spindle cell neoplasm can help demonstrate epithelial differentiation in SSCC, even in the absence of AE1/3 or K903 staining. However, some cases of cutaneous SSCC can only be confirmed ultrastructurally, as up to one-third may not show evidence of epithelial differentiation using an expanded immunohistochemical panel.

Accurate tumour classification is critical for meaningful epidemiological studies in the assessment of cancer incidence rates and trends. Differentiating primary gastric carcinoma from oesophageal carcinoma can be difficult, especially when tumours are large and involve both the oesophagus and stomach. Furthermore, adenocarcinomas of both organs typically are of intestinal histological type and arise in a background of intestinal metaplasia. Consequently, histological markers that reliably distinguish Barrett's-related oesophageal adenocarcinoma from gastric adenocarcinoma would be useful. Cytokeratins (CK)7 and 20 are cytoplasmic structural proteins with restricted expression that help to determine the origin of many epithelial tumours including those of the gastrointestinal tract. The aim of this study was to determine the utility of co-ordinate CK7 and 20 expression in the distinction of Barrett's-related oesophageal adenocarcinoma from gastric adenocarcinoma arising in a background of intestinal metaplasia.CK7 and 20 immunostaining was performed on randomly selected surgical resection specimens from patients with Barrett's-related oesophageal adenocarcinoma (n = 30) and intestinal type gastric adenocarcinoma (n = 14) arising in a background of intestinal metaplasia. A CK7+ CK20- immunophenotype was demonstrated in 27 of 30 (90%) patients with Barrett's-related oesophageal adenocarcinoma and only three of 14 (21%) gastric adenocarcinomas. The sensitivity, specificity and positive predictive value of a CK7+/20- immunophenotype for a diagnosis of Barrett's-related oesophageal adenocarcinoma was 90%, 79%, and 90%, respectively.A CK7+/20- tumour immunophenotype is associated with Barrett's-related oesophageal adenocarcinoma and may be useful in accurate tumour classification, thus facilitating improving epidemiological evaluation of tumours at the oesophagogastric junction.

Fibromatoses of the extremities are rare and often recalcitrant to treatment. We evaluated the clinical and pathologic features of a group of extremity fibromatoses treated by surgical excision with or without adjuvant therapy to determine if any clinical or pathologic parameters were predictive of clinical outcome.Thirty-six extremity fibromatoses were evaluated. A number of clinical and histologic features were correlated with risk of local recurrence.The cohort included 19 females and 17 males with ages ranging from 11-72 years (mean: 35 years), with 12 tumors of the upper and 24 tumors of the lower extremity. Tumors ranged in size from 1.5-15.5 cm (mean: 7.5 cm).Histologically, 26 were infiltrative, 3 had pushing borders and 7 had both. Mitotic counts ranged from 0-5/50 high-power fields (mean: 0.74). Surgical margins were positive in 22 cases. Seventeen patients were treated with postoperative adjuvant therapy including radiation therapy and tamoxifen. Follow-up information was available in 34 cases (from 1-202 months; mean: 83 months). Nineteen patients (56%) had recurrences, including 11 with multiple recurrences (range to first recurrence: 5-61 months; mean 23 months). Seventy-one percent of patients with a positive surgical margin and clinical follow-up had a local recurrence, compared to 31%with a negative surgical margin (P0.05). None of the other clinical or histologic parameters correlated with the risk for local recurrence.Local control in fibromatoses of the extremities remains problematic. Aside from positive surgical margins, none of the other clinical or histologic parameters evaluated in this study were useful in predicting the risk of local recurrence.

The gastric cardia is a microscopic zone that is normally found in the most proximal portion of the stomach, although cardiac-type mucosa may arise in the distal esophagus as a metaplastic phenomenon secondary to gastroesophageal reflux disease (GERD). Inflammation of the native gastric cardia is strongly associated with Helicobacter pylori infection, although there may be a second form of 'carditis' in which metaplastic cardiac-type mucosa becomes inflamed secondary to GERD. Intestinal metaplasia of the cardia may be difficult to recognize because of the difficulty in accurately identifying the esophagogastric junction by endoscopy and the histologic similarities of intestinal metaplasia in the proximal stomach and distal esophagus. However, cytokeratin 7 and 20 immunoreactivity patterns appear to be useful in distinguishing between these forms of intestinal metaplasia. The preponderance of data suggests that intestinal metaplasia of the cardia is associated with H. pylori infection as opposed to GERD, and preliminary data suggest a lower risk of progression to dysplasia and adenocarcinoma when compared to intestinal metaplasia of the distal esophagus.

Desmoplastic small round cell tumor (DSRCT) is a unique, highly aggressive neoplasm that chiefly affects male adolescents and young adults. This tumor is characterized by nests of small undifferentiated cells that show immunohistochemical evidence of epithelial, mesenchymal, and neural differentiation. We report two cases of DSRCT that lacked immunohistochemical evidence of epithelial differentiation, but were found to have the fusion transcripts characteristic of this tumor. Both patients (a 41-year-old male and a 31-year-old female) presented with large intra-abdominal masses. After diagnostic biopsy, both were treated with multi-agent chemotherapy. One patient expired 18 days after diagnosis, and the other is currently alive 28 months later. Histologically, both tumors had the characteristic features of DSRCT and were composed of small round cells with hyperchromatic nuclei and scanty cytoplasm. In one of the cases, perinuclear intracytoplasmic hyaline inclusions were seen. Immunohistochemically, neither case expressed any of the epithelial markers tested, including AE1/AE3, CAM 5.2 and EMA. Both tumors were diffusely immunoreactive for desmin with a prominent globoid "dot-like" pattern of staining in one case. Both tumors stained for vimentin, neuron specific enolase, and synaptophysin, but were negative for CD99, muscle-specific actin, and myogenin. Reverse transcriptase-polymerase chain reaction revealed EWS-WT1 fusion transcripts characteristic of this neoplasm. In conclusion, we describe two cases of DSRCT that lacked immunohistochemical evidence of epithelial differentiation but had histologic and other immunohistochemical features which suggested this diagnosis. The ability to confirm the diagnosis of this rare tumor using molecular genetic techniques is particularly useful in those cases with unusual histologic or immunophenotypic features.

We report an unusual case of an ovarian tumor arising in a 22-year-old female that showed histologic, immunohistochemical, and ultrastructural features of myofibroblastic differentiation. The mass was found incidentally and upon excision was 9.0 cm in its greatest dimension and almost entirely replaced the left ovary. The patient is alive without evidence of disease 21 months after excision. Histologically, the tumor was encapsulated and composed of cytologically bland spindled cells arranged into a variety of patterns, similar to those found in both solitary fibrous tumor and hemangiopericytoma. Immunohistochemically, the cells stained strongly for smooth muscle actin and muscle-specific actin, with only focal and weak staining for CD34. Stains for S-100 protein, desmin, and AE1/AE3 were negative. Ultrastructurally, the neoplastic cells showed clear-cut evidence of myofibroblastic differentiation. The differential diagnostic considerations, including solitary fibrous tumor and hemangiopericytoma, are discussed.

The incidence rates of gastric cardia and esophageal adenocarcinomas are increasing, but data suggest that carriage of cagA(+) Helicobacter pylori strains may protect against development of Barrett's esophagus and esophageal adenocarcinoma. Our aims were to examine the relationship between pre-malignant and malignant lesions in the gastric cardia and serum antibodies to H. pylori antigens in patients with and without complications of Barrett's esophagus. The prevalence of carditis was 40% in controls compared with 13% in patients with complicated or uncomplicated Barrett's esophagus and cardia adenocarcinoma (p0.001). Cardia intestinal metaplasia (IM) and atrophy were present and concordant in 28% of controls but less frequent in patients with Barrett's alone or with dysplasia/adenocarcinoma (0% for each, p0.001). Carriage of cagA(+) strains was present in 34% of patients with carditis and significantly associated with increased frequency and severity of cardia inflammation, IM, and atrophy but not with adenocarcinoma. IgA and HspA seropositivity were significantly increased in H. pylori-colonized patients with carditis compared to persons with normal cardia histology (p/= 0.005) but not in persons with esophageal disease or cardia adenocarcinoma. We conclude that carriage of cagA(+) H. pylori strains and induction of particular serological responses are significantly associated with marked histological findings in the gastric cardia but not with adenocarcinoma of either the gastric cardia or esophagus.

Induction chemoradiotherapy before esophagectomy for esophageal carcinoma seems to improve patient survival. Given the toxicity of this regimen, it would be useful to predict those patients likely to benefit. p53 is known to mediate apoptosis in response to DNA damage, but there are few data evaluating the relationship between p53 expression and chemoradiosensitivity in human tissues. We immunohistochemically evaluated p53 protein expression in 95 biopsy specimens from patients with esophageal carcinoma before chemoradiotherapy. p53 expression was correlated to the pathologic response identified in subsequent esophagectomy specimens. p53 immunoreactivity was recorded semiquantitatively using the following scale: neg,5%; 1+, 5-25%; 2+, 26-50%; 3+, 51-75%; 4+,or = 76%. Pathologic response in esophagectomy specimens was categorized as overt residual tumor (ORT), minimal residual tumor, and no residual tumor. Of the 95 patients, 64 had adenocarcinoma, and 31 had squamous cell carcinoma. Of those with adenocarcinoma, 46 (72%) of 64 were positive for p53. Thirty-seven (80%) of 46 p53+ patients had ORT, compared with 4 (22%) of 18 p53- patients (P.001). There was no correlation between the degree of p53 staining and pathologic response. Of those with squamous cell carcinoma, 13 (42%) of 18 were positive for p53. Three (23%) of 13 p53+ patients had ORT, compared with 4 (22%) of 18 p53- patients (P = .96). Our data indicate that overexpression of p53 protein is associated with decreased responsiveness to induction chemoradiotherapy in patients with esophageal adenocarcinoma but that no such association exists in patients with esophageal squamous cell carcinoma.

Data are limited on leiomyosarcomas within the abdomen and retroperitoneum, particularly if one discounts those associated with the gastrointestinal (GI) tract. Recently, some authors proposed that certain tumors in this location are more appropriately termed extra-GI stromal tumors, given their histologic resemblance to GI stromal tumors as opposed to conventional soft tissue leiomyosarcomas. We evaluated the clinical and pathologic features of 17 cases of leiomyosarcoma (16 retroperitoneal, one intra-abdominal) and recorded the tumor size, predominant cell type, tumor cellularity, nuclear pleomorphism, extent of tumor cell necrosis, and number of mitotic figures per 10 high power fields (MFs/10HPFs). Cases were only included for study if the excised tumor did not arise from abdominal or pelvic viscera or major blood vessels, if adequate clinical follow-up was available, and if the tumor unequivocally resembled conventional soft tissue leiomyosarcoma, both by light microscopic and immunohistochemical examination. The cohort included 16 women and 1 man, and ages ranged from 44 to 72 years (median, 60 yr). Tumors ranged in size from 6.5 to 29.5 cm (median, 13.5 cm). Fifteen tumors were composed predominantly of spindled cells, one tumor was composed predominantly of epithelioid cells, and one tumor was composed of an admixture of spindled and epithelioid cells. Follow-up intervals ranged from 4 to 169 months (median, 47 mo). Fifteen (88%) of seventeen patients developed an adverse outcome, defined as the development of metastatic disease or death due to tumor. Patients whose tumors had greater than 10 MFs/10HPFs had significantly shorter intervals to either metastasis or death than did those whose tumors had 10 or fewer MFs/10HPFs (8.4 mo vs. 42 mo; P = .003). No other features correlated with time to adverse outcome. In conclusion, the majority of patients with leiomyosarcomas located within the abdomen or retroperitoneum progress to metastatic disease or die from their tumor. The only feature that is significantly associated with a shorter interval to either metastasis or death is more than 10 MFs/10HPFs.

Poorly differentiated synovial sarcoma (PDSS) is a round cell sarcoma that may be difficult to distinguish from other round cell sarcomas, such as peripheral primitive neuroectodermal tumour (pPNET), on histological examination alone. Furthermore, these two tumours may show overlapping immunophenotypes, as some cases of PDSS express CD99, and, on the other hand, pPNET may express epithelial markers. The goal of this study was to determine the utility of cytokeratin (CK) subsets in distinguishing between these two lesions.We evaluated 13 cases of pPNET with RT-PCR detected EWS/FLI-1 fusion transcript and 21 cases of PDSS for the immunohistochemical expression of CK7 and CK19. All cases of PDSS had areas of recognizable monophasic or biphasic synovial sarcoma that expressed at least one epithelial marker. Thirteen of 21 (62%) PDSS stained with AE1/AE3. CK7 and 19 were expressed in 11 (52%) and nine (43%) cases, respectively. Although six of 19 (32%) PDSS demonstrated cytoplasmic staining for CD99, none showed a membranous pattern of immunoreactivity. In contrast, 12 of 13 (92%) pPNET showed strong membranous immunoreactivity for CD99. Four tumours (31%) showed focal staining with AE1/AE3, two of which (15%) stained for CK19. CK7 was not detected in any of the pPNETs.Although AE1/AE3 may be found in up to 31% of cases of pPNET, the expression of CK7 makes this diagnosis less likely.

Plexiform neurofibroma (PNF) is an important part of the diagnostic criteria for neurofibromatosis type 1 (NF1) and is a known precursor lesion of malignant peripheral nerve sheath tumor (MPNST). We studied the clinicopathologic features of 54 cases of PNF for which the hematoxylin- and eosin-stained slides and paraffin blocks were available and adequate clinical follow-up could be obtained. In addition, in all cases, a representative section of the PNF and, when present, MPNST, was evaluated immunohistochemically with an antibody for p53 (DO7). The cohort included 28 male patients and 26 female patients, with an age range from 4 to 79 years (mean, 27 yr). Of these 54 patients, 46 (85%) met the strict diagnostic criteria for NF1. Thirty-nine patients had PNF alone; 15 patients had an MPNST arising from the PNF (PNF/MPNST). Those patients with PNF/MPNST tended to be older (38 yr vs. 22 yr) and to have larger tumors (10.5 cm mean vs. 7.4 cm mean) than those with PNF alone. In 9 patients (23%) of 39 with PNF alone, local recurrence developed, whereas in 7 patients (47%) of 15 with PNF/MPNST, recurrent MPNST developed, and metastases developed in 3 (20%) of the 15. Immunohistochemically, only 1 case (2.5%) of 39 cases of PNF alone stained for p53. On the other hand, 12 (80%) of 15 cases of PNF/MPNST showed p53 immunoreactivity in the MPNST component, 2 of which also showed staining in the PNF areas. In conclusion, we found that the vast majority of patients with PNF met the strict diagnostic criteria for NF1. The immunohistochemical detection of intranuclear p53 protein is common in the malignant areas of PNF/MPNST but is rare in the PNF regions. The rarity of p53 staining in the PNF regions precludes its use in predicting those tumors that are likely to progress to MPNST.

Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is a premalignant condition, because these patients are at increased risk of adenocarcinoma. Neuroendocrine neoplasms (NENs) have rarely been described in this setting. We evaluated 14 cases of NEN arising in a setting of IBD. All of the tumors arose in areas involved by IBD, and all showed immunohistochemical or ultrastructural evidence of neuroendocrine differentiation. The cohort included seven men and seven women (range, 28-71 yr; median, 43 yr). Eight patients had Crohn's disease (CD), and six had UC. Duration of disease ranged from 4 months to 50 years (median, 15 yr), with one of unknown duration. Of the eight patients with CD, five had ileocolitis, one had ileitis, one had colitis, and in one case, the extent of disease was unknown. Of the six patients with UC, four had extensive UC, one had left-sided UC, and the extent of UC was unknown in one case. Reasons for surgery included CD complications (five patients), refractory disease (three patients), dysplasia/carcinoma (five patients), and incontinence (one patient). The NENs were well differentiated in 11 cases and poorly differentiated mixed adenocarcinoma/small cell carcinomas in 3 cases. Tumor sites included the rectum (six cases), appendix (four cases), small bowel (two cases), and sigmoid colon (two cases). High-grade dysplasia was present in adjacent mucosa in four cases, and low-grade dysplasia was present in distant mucosa in two cases. Two patients with poorly differentiated NENs died from the disease at 3 and 11 months after tumor excision. All of the other patients were alive without tumor as of last follow-up. We concluded that NENs rarely arise in a setting of IBD. Most are well-differentiated tumors and are clinically indolent. Dysplasia is found in adjacent mucosa in more than one-third of cases, suggesting that neuroendocrine differentiation might evolve from multipotential cells in dysplastic epithelium.

Recent changes in the epidemiology of esophageal carcinoma now recognize adenocarcinoma as the predominant histologic cell type. Barrett's esophagus and dysplasia in this epithelium identify patients who are at risk of developing invasive adenocarcinoma. This neoplasm is not a single entity with a consistently poor prognosis, and disease stage is important for determining therapy. These findings offer the potential for further development of therapeutic regimens. Endoscopic esophageal ultrasound is an accurate and reproducible staging tool. It allows the physician to determine clinical stage and modify treatment. T2 N0 M0 or lesser stage tumors have acceptable surgical cure rates, and patients should undergo immediate resection. Patients with more advanced T3 or N1 tumors have a potential for cure but do poorly with surgery alone. These patients should be considered for multimodality therapy. Palliative therapy should be given to patients with hematogenous metastatic disease. Treatment stratification by stage proves that esophageal carcinoma is not a uniformly fatal disease without hope for cure.

Dedifferentiated liposarcoma (DDL) has been defined as a tumor composed of well-differentiated liposarcoma (WDL) associated with or progressing to a nonlipogenic, high-grade sarcoma. One might expand this definition of DDL to include low-grade dedifferentiation (LGDD), because tumors with LGDD alone are capable of metastasizing. We studied 20 cases of retroperitoneal WDL with or without LGDD and/or high-grade dedifferentiation (HGDD) to semiquantitate the amount of WDL, LGDD, and HGDD in each case and to correlate the amounts of these components with clinical outcome. For each case, a composite estimate of each of these components was obtained. Thirteen patients (65%) of 20 had an adverse outcome (AO). Within this group, metastatic disease developed in 3 patients, 2 of whom had areas of HGDD (40% and 20%) in their initial excisions, whereas 1 patient had 30% LGDD and 0% HGDD. Of the patients with AOs, 12 (92%) had LGDD areas, 4 (31%) had HGDD areas, and 1 (8%) had pure WDL. Of the seven patients without AOs, three had recurrences, but metastatic disease did not develop in any. All of these seven patients had some element of WDL, five (71%) had LGDD areas, two (29%) had HGDD areas (20% in both cases), and two (29%) had pure WDL. There was no significant difference in clinical outcome between those patients with WDL and those with WDL/LGDD or WDL/LGDD/HGDD. We conclude that recurrences develop in most patients with retroperitoneal WDL and that most of these patients die as a result of local effects of the tumor. Metastases are rare and may occur in patients with tumors with either LGDD, HGDD, or both but do not occur in pure WDL. Neither the amount of LGDD nor HGDD correlates with clinical outcome. LGDD areas, as defined in this study, are commonly seen in de novo retroperitoneal WDLs.

Achalasia is an esophageal motility disorder of unknown etiology. Several studies suggest possible herpes or measles virus etiology, but results are inconclusive. The aim of this study was to test whether herpesvirus (HV), measles (MV), or human papilloma virus (HPV) sequences could be detected in myotomy specimens from a wide spectrum of achalasia patients, using the polymerase chain reaction (PCR) technique. Myotomy specimens from 13 achalasia patients, esophagectomy specimens from nine esophageal cancer patients, and autopsy specimens from six fetuses were studied with the PCR technique. Paired oligonucleotide primers of HV (HSV-1 and 2, CMV, EBV, VZV, and HHV-6), MV and HPV sequences and exon 3 of the HPRT gene were used for the PCR DNA amplification. Amplified products were resolved on agarose gels and stained with ethidium bromide. All specimens yielded the appropriate-sized products for exon 3 of the HPRT and viral controls. No amplified products were seen in the achalasia specimens or controls corresponding to any of the virus sequences tested. The absence of HV, MV, and HPV sequences suggests that these viruses are not associated with achalasia but does not exclude the possibility of a previously unidentified virus as a causal agent. Further studies aimed at identifying an unknown viral agent as a cause for achalasia are warranted.

Giant cell fibroblastoma (GCF) is a rare mesenchymal neoplasm, which is classified as a fibrohistiocytic tumor of intermediate malignancy owing to its propensity for local recurrence, although metastasis has not been documented. Prior reports have linked GCF to dermatofibrosarcoma protuberans (DFSP), given overlapping clinical and histologic features.This report documents three additional cases of GCF that further support the contention that this lesion is histogenetically related to DFSP.All three lesions occurred on the trunk of patients whose ages were 4, 28, and 38 years. One case that histologically resembled a GCF on initial excision recurred with areas of both GCF and DFSP. A second recurrence was composed entirely of DFSP. Another case contained areas of both GCF and DFSP, as well as a focus that was felt to be undergoing fibrosarcomatous change. The third case consisted entirely of GCF. Immunohistochemically, all three lesions showed intense immunoreactivity for CD34 in the GCF component. CD34 also strongly marked the cells in those cases with a DFSP component.Although GCF may not represent the "juvenile form" of DFSP, as previously suggested, the evidence strongly supports a histogenetic relationship between these two lesions, even though the cell of origin remains obscure.

Plexiform schwannomas are relatively rare, benign peripheral nerve sheath tumors, which usually arise in either the dermis or subcutaneous tissue, although rare cases originate in skeletal muscle or other deep somatic soft tissue sites. These tumors may occur singly or as multiple lesions and may be localized to one anatomic site or diffusely distributed. Rare cases have been associated with "schwannomatosis" as well as type 1 neurofibromatosis (von Recklinghausen's disease). We report an unusual case of multiple cutaneous plexiform schwannomas associated with bilateral acoustic neuromas as well as other intracranial and intraspinal neoplasms. In addition, we examine the relationship between the various forms of cutaneous schwannoma, particularly the plexiform variant, and both types 1 and 2 neurofibromatosis; we also examine several purported cases of schwannomatosis.

Patients with ulcerative colitis, particularly long-standing ulcerative pancolitis, have an increased risk of developing carcinoma of the hepatobiliary tract. However, only 14 cases of carcinomas localized to the gallbladder have been associated with ulcerative colitis. Of 57 cases of gallbladder carcinomas seen at this institution, we found 3 cases in patients with ulcerative colitis, all of whom had undergone total proctocolectomy. All three patients had pancolitis, two with high-grade dysplasia, and one with low-grade dysplasia. All three gallbladders harbored an invasive adenocarcinoma. The nonneoplastic gallbladder mucosa showed a background of acalculous chronic lymphoplasmacytic cholecystitis in two cases. One of these patients also had a liver biopsy which showed changes of primary sclerosing cholangitis. Because cholecystectomy adds little to the operative morbidity and mortality of total proctocolectomy, it might be advisable to perform both operations when the latter is indicated for high-grade dysplasia in ulcerative colitis.

The bcl-2 proto-oncogene encodes a protein that blocks programmed cell death (apoptosis). Although bcl-2 has been shown to be involved in the development of follicular lymphoma via a chromosomal translocation t(14;18), little is known about its function in non-hematolymphoid neoplasms. The bcl-2 protein is normally expressed in the regenerative crypt compartment of the colon, small intestine, and stomach, and has been found to be abnormally overexpressed as an early event in the dysplasia-carcinoma sequences of both ulcerative colitis-related and gastric neoplasias. This study was undertaken to evaluate the role of bcl-2 in the Barrett's metaplasia-dysplasia-carcinoma sequence. Thirty-six esophageal resection specimens were studied, using a monoclonal antibody to the bcl-2 protein on fixed paraffin-embedded specimens. Barrett's mucosa was present in each specimen: low-grade dysplasia in 35, high-grade dysplasia in 34, intramucosal carcinoma (IMC) in 23, and submucosal carcinoma in 13. In addition, a section of the gastric resection margin was evaluated for bcl-2 immunoreactivity in each case. In all cases, the regenerative compartment of the gastric mucosa in the resection margins stained for bcl-2; however, no immunoreactivity was seen in any of the cases of Barrett's mucosa with or without dysplasia or carcinoma. We conclude that, in contrast to its role in gastric neoplasia, bcl-2 alterations are not an important molecular marker in the neoplastic progression of Barrett's mucosa.

We report a case of a giant bilateral extra-adrenal myelolipoma. To our knowledge this is only the second reported case of either giant or bilateral extra-adrenal myelolipoma and the first in which both features are present. The tumor is also notable for having areas of fibromyxoid degeneration histologically similar to those seen in low-grade fibromyxoid sarcomas. This feature, previously unreported, expands the differential diagnosis of extra-adrenal myelolipomas.

Achalasia is characterized by failure of relaxation of the lower esophageal sphincter and absence of progressive peristalsis in the esophageal body. Few data are available regarding the morphologic features of achalasia, in particular its histologic progression. The esophagi of 42 patients with achalasia treated with total thoracic esophagectomy were examined histologically in order to systematically identify morphologic features of clinically unresponsive achalasia and to determine what could be learned about the disease's evolution. In all cases, myenteric ganglion cells within the esophageal body were markedly diminished, with 20 specimens having none. Twenty specimens had residual ganglion cells in the proximal esophagus, and 15 specimens had a few randomly distributed ganglion cells in the mid- and distal portions of the esophagus. Inflammation within myenteric nerves, present in all cases, generally consisted of a mixture of lymphocytes and eosinophils, occasionally with plasma and mast cells. Focal replacement of myenteric nerves by collagen occurred in all cases, and there was almost complete replacement in several cases. Actual destruction of the residual ganglion cells was not seen. The resected esophagi also shared extramyenteric morphologic features. Some features probably stemmed from physiologic obstruction, such as muscular hypertrophy, mainly of the muscularis propria (all cases), with secondary degeneration and fibrosis (29 cases), and eosinophilia of the muscularis propria (22 cases). Other changes, probably resulting from chronic stasis of ingested materials in the lumen, included diffuse squamous hyperplasia (all cases), lymphocytic mucosal esophagitis (28 cases), lymphocytic inflammation of the lamina propria and submucosa with prominent germinal centers (all cases), and submucosal periductal or glandular inflammation with complete loss of submucosal glands in half of the cases. One patient had high-grade squamous dysplasia, and another had superficially invasive squamous cell carcinoma. A third group of changes was probably due to previous esophagomyotomy, including abnormal gastroesophageal reflux, as shown by pH reflux testing (13 cases) and Barrett's mucosa (four cases). In one case of Barrett's there was low-grade dysplasia. Clinically unresponsive, surgically resected achalasia has almost total loss of ganglion cells, and widespread destruction of myenteric nerves has already occurred. The only active component is myenteric inflammation. However, it cannot be determined whether this inflammation is a manifestation of ongoing nerve destruction or whether it is a secondary phenomenon.

Although many histologic criteria have been utilized to help distinguish benign from malignant adrenocortical tumors, it still may be difficult to assess the biologic potential of a given tumor. We evaluated 19 adenomas and 15 primary carcinomas with the avidin-biotin complex peroxidase method utilizing formalin-fixed, paraffin-embedded tissues with monoclonal antibodies for proliferating cell nuclear antigen (PC10) and Ki-67 (MIB 1) to determine if staining for these antigens could be used to help differentiate benign from malignant adrenocortical neoplasms. We also evaluated whether these markers could be used as prognostic indicators. Labeling indices for both PCNA and Ki-67 were determined by enumerating 1000 tumor cells, and expressed as a percentage of cells with nuclear staining. A PCNA and a Ki-67 score was obtained by the product of the staining intensity (0-3+) and the extent of nuclear staining, expressed as an estimate of the percentage of cells staining. Both PCNA and Ki-67 score and labeling index were correlated with mitotic counts, histologic diagnosis, and clinical outcome. Follow-up period for patients ranged from 4 months to 12 years with a mean of 25 months. Mitotic counts correlated with histologic diagnosis and clinical outcome. Both Ki-67 score and labeling index were significantly higher in malignant than in benign tumors, and correlated with mitotic counts and clinical outcome. There was a strong correlation between Ki-67 score and labeling index, indicating that Ki-67 score may be a more rapid and equally accurate method of estimating proliferative index of a tumor. PCNA score and labeling index did not correlate with histologic diagnosis or clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a case of primary renal carcinoid, which is a very rare neoplasm: to our knowledge, only 19 cases have been previously reported. The tumor displayed histologic features typical of carcinoid tumors from other sites, including growth in nests and ribbons, uniform cells with finely granular, eosinophilic cytoplasm, and stippled chromatin. Electron microscopy confirmed the presence of membrane-bound dense-core granules. Immunohistochemical analysis revealed staining for chromogranin A, neuron-specific enolase, Leu-7, and synaptophysin, as well as pancreatic polypeptide. An interesting finding was the positive staining for prostatic acid phosphatase, while staining for prostate-specific antigen was negative. Although prostatic acid phosphatase is commonly seen in primary gastrointestinal hindgut carcinoids, in this case a primary hindgut carcinoid was ruled out by clinical examination and endoscopy. The patient developed metastases to the liver, but was well and without symptoms 15 months after diagnosis.

The 21-aminosteroids represent a new class of compounds that serve as potent inhibitors of iron-dependent lipid peroxidation, the latter being an important component of ischemia-reperfusion tissue injury. It is hypothesized that reperfusion injury accompanies renal ischemia, and postischemic administration of one of these steroids, U74006F, will reduce renal damage in a rodent model, as assessed by renal function (plasma creatinine), histologic evidence of renal injury, and animal survival during a 72-hour interval.Fifty-one rats subjected to 45 minutes of renal ischemia were treated on clamp release with 3 or 10 mg/kg U74006F intravenously (n = 5 and 19, respectively), an inactive vehicle (n = 23), or sham operation (n = 4).Both doses of U74006F improved morphologic outcome compared with vehicle-treated animals. Statistically significant improvement in renal function was observed with the 10 mg/kg dose of U74006F (p = 0.029, 0.014, and 0.065 at 24, 48, and 72 hours, respectively) but not with the 3 mg/kg dose. Only one (5.2%) of 19 rats receiving high-dose U74006F (10 mg/kg) died within 72 hours after ischemia, compared with five deaths (29.4%) in 17 rats receiving citrate vehicle alone (p = 0.060). All sham-operated animals survived 72 hours with normal morphology and plasma creatinine levels.These data suggest that iron-dependent lipid peroxidation is a component of reperfusion injury and indicate that U74006F may be useful in reducing this form of renal ischemic damage.

Intravenous leiomyomatosis is a rare uterine neoplasm characterized by nodular or wormlike masses of histologically benign smooth muscle growing within myometrial veins and extending variable distances into the veins of contiguous organs and major pelvic veins. In some cases, there has been extension into the gonadal or iliac veins to the vena cava and right atrium, causing symptoms of congestive heart failure and an eventual fatal outcome. We present a report of the first case in which high-output cardiac failure was caused by the development of arteriovenous shunting within the intravenous component of the tumor that involved the pelvic organs and retroperitoneal and gonadal veins but not the vena cava. Treatment by total abdominal hysterectomy, bilateral oopherectomy, and tumor mass excision from the retroperitoneum was successful.

Little information has been published regarding appendiceal changes in ulcerative colitis of any extent. An early study has shown the appendix to be involved in over 50% of all cases of ulcerative colitis for which a proctocolectomy was performed, but the extent of the colitis was not always defined. While some investigators have found appendiceal involvement only in continuity with adjacent involved cecum, others believed it may occur as a skip lesion. In this study, the colons and nonobliterated appendices of 87 patients who underwent total proctocolectomy for ulcerative pancolitis were examined to determine the frequency of appendiceal involvement and to determine the frequency with which such involvement truly occurs as a skip lesion. All 87 cases had ulcerative pancolitis, and 66 (62%) had colitic changes in the appendix. In the remaining 21 cases, there was no appendiceal inflammation. In all cases in which the appendix was involved, the cecum was also involved. Cecal activity or lack of activity correlated with appendiceal activity in 52 of the 87 cases (60%). Of the 35 cases in which there was some discrepancy in disease activity between the appendix and cecum, nine had more active disease in the appendix, and 26 had greater activity in the cecum, but in none of the cases where the cecum was normal or near normal was the appendix more severely involved. These data suggest that appendiceal involvement in resected ulcerative pancolitis always occurs in continuity with adjacent involved cecum, although there may be differences in disease activity between the two sites.

Current experimental models of heart transplantation include a period of ischemia after donor harvest, resulting in rhythm disturbances, myocardial distention, and reperfusion injury on implantation. A model of cervical heterotopic heart transplantation that avoids ischemia by using retrograde perfusion was developed. More than 100 consecutive successful transplantations have been performed both as control protocols and as a part of experimental protocols. The advantages of this technique include: avoidance of ischemia and reperfusion injury, prevention of myocardial damage caused by overdistention, and potential evaluation of pretreatment regimens for transplanted hearts.