Clinical implications of acellular mucin pools in resected rectal cancer with pathological complete response to neoadjuvant chemoradiation.

AIM: Approximately 20% of rectal cancers treated with neoadjuvant chemoradiation achieve a pathological complete response (pCR), which is associated with an improved oncological outcome. However, in a proportion of patients with a pCR, acellular pools of mucin are present in the surgical specimen. The aim of this study was to evaluate the clinical implications of acellular mucin pools in patients with rectal adenocarcinoma achieving a pCR after neoadjuvant chemoradiation followed by proctectomy. METHOD: A single-centre colorectal cancer database was searched for patients with clinical Stage II and Stage III rectal adenocarcinoma who achieved a pCR (i.e. ypT0N0M0) after neoadjuvant chemoradiation followed by proctectomy between 1997 and 2007. Patients were categorized according to the presence or absence of acellular mucin pools in the resected specimen, and groups were compared. Patient demographics, tumour and treatment characteristics, and oncological outcomes were recorded. Primary outcomes were 3-year local and distant recurrences, and disease-free and overall survivals. RESULTS: Two hundred and fifty-eight patients with clinical Stage II or Stage III rectal adenocarcinoma were treated by neoadjuvant chemoradiation. Fifty-eight of these patients had a 58 pCR. Eleven of the 58 patients with a pCR had acellular mucin pools in the surgical specimen. The median follow up was 40 months. The groups were statistically similar with respect to demographics, chemoradiation regimens, distance of tumour from the anal verge, clinical stage and surgical procedure. No patient had local recurrence. Patients with acellular mucin pools had increased distant recurrence (21%vs 5%), decreased disease-free survival (79%vs 95%) and decreased overall survival (83%vs 95%) rates, although none of these differences was statistically significant. CONCLUSION: The presence of acellular mucin pools in a proctectomy specimen with a pCR does not affect local recurrence, but may suggest a more aggressive tumour biology.

Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer.

BACKGROUND: A molecular classification of colorectal cancer has been proposed based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in the KRAS and BRAF oncogenes. This study examined the prevalence of these molecular classes, and differences in clinical presentation and outcome. METHODS: Demographics, tumour characteristics and survival were recorded for 391 subjects with colorectal cancer. Tumour DNA was analysed for MSI (high (MSI-H) or microsatellite stable (MSS)), CIMP (high (CIMP-H) or no (CIMP-neg)) and BRAF and KRAS mutations. Clinical differences between four phenotypes were examined. RESULTS: Most tumours were MSS/CIMP-neg (69.8 per cent), with a nearly equal distribution of MSI-H/CIMP-H, MSI-H/CIMP-neg and MSS/CIMP-H types. MSS/CIMP-neg tumours were less likely to be poorly differentiated (P = 0.009). CIMP-H tumours were more common in older patients (P < 0.001). MSI-H/CIMP-H tumours had a high frequency of BRAF mutation and a low rate of KRAS mutation; the opposite was true for MSS/CIMP-neg tumours (P < 0.001). The four molecular phenotypes tended towards divergent survival (P = 0.067 for stages 1-III). MSI-H cancers were associated with better disease-free survival (hazard ratio 2.00 (95 per cent confidence interval 1.03 to 3.91); P = 0.040). CONCLUSION: Colorectal cancers are molecularly and clinically heterogeneous. These different molecular phenotypes may reflect variable prognosis.

The utility of cytokeratin 5/6 in the recognition of cutaneous spindle cell squamous cell carcinoma.

BACKGROUND: 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. METHODS: 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%). RESULTS: 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. CONCLUSIONS: 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.

Laparoscopic renal autotransplantation.

BACKGROUND AND PURPOSE: Renal autotransplantation is an extensive open surgical operation consisting of two distinct procedures, live-donor nephrectomy and autotransplantation, and requiring two large skin incisions. Herein, we analyze the feasibility of performing the entire procedure laparoscopically. MATERIALS AND METHODS: Renal autotransplantation was performed entirely laparoscopically in six female farm pigs. Following a left donor nephrectomy, intracorporeal renal hypothermia was achieved by intra-arterial perfusion of ice-cold solution through a 4F balloon catheter. During autotransplantation, the renal vessels were anastomosed intracorporeally to the previously prepared ipsilateral common iliac vessels in an end-to-side fashion. Laparoscopic freehand suturing (5-0 Prolene) and knot-tying techniques were employed exclusively. A staged contralateral native nephrectomy was performed in five animals. Postoperative follow-up included serial creatinine measurements, intravenous urography, aortography, and renal histologic examination. RESULTS: The mean operating time was 6.2 hours (range 5.3-7.9 hours), the venous anastomosis time was 33 minutes (range 22-46 minutes), the arterial anastomosis time was 31 minutes (range 27-35 minutes), and the total iliac clamping time was 77 minutes (range 62-88 minutes). The total renal ischemia time was 68.7 minutes: warm ischemia 5.1 minutes, cold ischemia 33 minutes and rewarming 31 minutes. Serum creatinine concentrations remained stable: baseline 1.3 mg/dL, after autotransplantation 1.1 mg/dL, and after contralateral nephrectomy 1.6 mg/dL. Intravenous urography and aortography prior to euthanasia (N = 5) demonstrated prompt contrast uptake and excretion by the autotransplanted kidneys and patent arterial anastomoses, respectively. Histopathologic examination of the autograft demonstrated normal renal architecture. CONCLUSIONS: Renal autotransplantation can be performed utilizing laparoscopic techniques exclusively. This study may form the basis for performance of complex urologic vascular procedures laparoscopically.

Laparoscopic orthotopic ileal neobladder.

BACKGROUND AND PURPOSE: Orthotopic ileal neobladder is currently the preferred continent urinary diversion in suitable patients undergoing radical cystectomy for muscle-invasive bladder cancer. To our knowledge, presented herein is the initial report of laparoscopic orthotopic ileal neobladder following cystectomy that was performed completely intracorporeally in a porcine model. MATERIALS AND METHODS: The laparoscopic technique was developed in seven pigs. Subsequently, a long-term survival study was performed in 12 consecutive animals. Laparoscopic cystectomy was performed, preserving the urethral sphincter. An ileal segment of 35 cm (first three animals), 45 cm (next four), or 55 cm (final five animals) with adequate mesentery was isolated; and ileal continuity was restored intracorporeally by a stapled anastomosis. Ileal detubularization for construction of an ileal neobladder, urethroileal anastomosis, and bilateral stented ileoureteral anastomoses to a tubular Studer limb extension were all created completely intracorporeally using only laparoscopic free-hand suturing and knot-tying. Biochemical data (preoperative and serial postoperative hemoglobin, renal panel, blood gases), radiologic studies (intravenous urogram, retrograde pouchgram), functional measures (neobladder urodynamics, Whitaker pressure-flow study of both ureters), and microscopic evaluation of the neobladder and ureteroileal and urethroileal anastomotic sites were obtained to evaluate the long-term functional and anatomic outcome. RESULTS: Completely intracorporeal laparoscopic construction of an ileal orthotopic neobladder was successful in all 12 animals without intraoperative or early postoperative complications or open conversion. The mean operating time was 5.4 hours (range 4.5-6.5 hours), and the blood loss was minimal. All study pigs survived their predetermined follow-up period, ranging from 1 to 3 months. Late complications occurred in three animals: one port-site abscess and two cases of E. coli pyelonephritis and azotemia, leading to one death at 2 months. The mean serum creatinine concentrations were 1.33 mg/dL, 1.61 mg/dL, and 1.55 mg/dL at 1, 2, and 3 months, respectively. The mean neobladder capacity was 420 mL (range 250-700 mL) with pressures < or = 20 cm H2O (range 17-20 cm H2O). Pre-euthanasia Whitaker testing confirmed excellent drainage in all 24 ureters. No ileoureteral or ileourethral anastomotic strictures or leaks were noted on intravenous urography, retrograde pouchgram, or postmortem physical calibration of the anastomotic sites. Histologic examination confirmed excellent healing without obvious fibrosis. CONCLUSION: Laparoscopic construction of an orthotopic neobladder is feasible. The anatomic and functional outcome is excellent and comparable to that of open surgery. Clinical application is imminent.

Validation of a multicolor interphase fluorescence in situ hybridization assay for detection of transitional cell carcinoma on fresh and archival thin-layer, liquid-based cytology slides.

OBJECTIVE: To evaluate the feasibility of performing multicolor interphase fluorescence in situ hybridization (FISH) on ThinPrep slides of transitional cell carcinoma (TCC). STUDY DESIGN: Slides from 20 voided urine specimens were prepared by the ThinPrep technique (Cytyc, Boxborough, Massachusetts, U.S.A.), pretreated using a pretreatment kit and subjected to hybridization with the multicolor FISH probe UroVysion (Vysis, Downers Grove, Illinois, U.S.A.). Archival slides were placed in xylene, destained in alcohol and washed prior to pretreatment. Urines from patients with cytology-positive, biopsy-proven grade 1 (n = 5), 2 (n = 7) and 3 (n = 5) TCC and negative cytology and biopsy (n = 3) were selected. Freshly prepared (n = 10) and archival (n = 10) slides were used. RESULTS: All carcinoma cases were FISH positive (> 5 cells with complex abnormalities of > or = 2 studied chromosomes per slide). None of the normal samples were aneusomic. Gain of chromosomes 3, 7 and 17 constituted the majority of positive cases. Proper destaining and slight decrease in stringency wash conditions enabled reliable detection of signals in archival cases. CONCLUSION: Routine ThinPrep slides can be used for multicolor interphase FISH analysis of urine cytology specimens. Archival slides provide the opportunity to analyze by FISH the nature of atypical cells identified by cytology. This revised method allows FISH technology more accessibility for routine use in cytology laboratories.

Aneusomy of chromosomes 7, 8, and 17 and amplification of HER-2/neu and epidermal growth factor receptor in Gleason score 7 prostate carcinoma: a differential fluorescent in situ hybridization study of Gleason pattern 3 and 4 using tissue microarray.

Recent evidence shows that the proportion of poorly differentiated prostate carcinoma (Gleason pattern [GP] 4/5) is a surrogate factor for biochemical failure after radical prostatectomy (RP). However, little is known about specific molecular and cytogenetic changes in this aggressive component of localized prostate cancer. We constructed a tissue microarray containing areas of GP 3 and 4 from formalin-fixed radical prostatectomy specimens of 39 patients with Gleason score 7 carcinoma (>or=50% GP 4), known pathologic staging parameters (stage < T3b), and biochemical failure data (mean follow-up, 30 months; range, 5 to 74 months). Interphase fluorescent in situ hybridization (FISH) was performed on 5-microm microarray sections using pericentromeric probes to chromosomes 7, 8, and 17 and probes for the HER-2/neu and epidermal growth factor receptor (EGFR) genes. Low-level amplification of HER-2/neu was found in 26% of cases (3 to 5 signals per nucleus, corrected for chromosome 17 aneusomy). Aneusomy of chromosomes 7, 8, and 17 was identified in 21%, 15%, and 5% of cases, respectively. All aberrations occurred almost exclusively in GP 4 carcinoma (8 of 8 aneusomies 7, 2 of 2 trisomies 17, 9 of 10 HER-2/neu amplifications, and 5 of 6 aneusomies 8; P < .001). The presence of HER-2/neu amplification was associated with high tumor volume (>2.0 cm(3), P = 0.004). Among patients with negative surgical margins, gain of chromosome 7 was associated with biochemical failure after RP (P =.004, log-rank). Amplification of the EGFR gene occurred in only 1 case (3%). Significant differences in HER-2/neu amplification and gain of chromosomes 7, 8, and 17 were detected between GP 4 prostate carcinoma and GP 3. The frequency of aberrations increased with tumor volume. Chromosome 7 abnormalities may play an important role in cancer progression in margin-negative patients. EGFR amplification was rare, suggesting that this oncogene is not altered at the gene copy number level.

[Susacs syndrome: case report]. / Síndrome de Susac: relato de caso.

We present the case of a 34-year-old woman with clinical picture suggestive of Susacs syndrome, or retinocochlear vasculopathy. This syndrome, which was described for the first time in 1979, is characterized by a clinical triad of encephalopathy, neurosensorial deafness and visual deficit. Its pathogenesis and treatment are still disputed. We have called special attention to differential diagnosis, since this entity has not yet been described in Brazil, and is probably underdiagnosed.

The diagnosis of leprosy among patients with symptoms of peripheral neuropathy without cutaneous lesions: a follow-up study.

Forty-four patients with neuritic leprosy were individually followed for periods ranging from 4 months to almost 4 years for the purpose of ascertaining the presence and/ or absence of leprosy. The neural symptoms presented were sensory impairment (41), parasthesia (28), nerve enlargement (22), nerve tenderness (20), paresia (20), amyotrophy (8). Leprosy was diagnosed in ten out of the total number of patients studied. Leprosy was confirmed by the appearance of reactional neuritis (4), reversal reaction (2), biopsy of the hypoesthesic area (3) and the appearance of non-reactional cutaneous lesion. We reported an experience in the diagnosis of neuritic leprosy and its most frequent clinical presentation with which clinicians have to be acquainted. We can also state that the clinical follow-up was an effective strategy for the diagnosis of the disease when diagnostic facilities are not available or have not confirmed the diagnosis.

Immunohistochemistry in the differential diagnosis of acinar and endocrine pancreatic neoplasms.

Histologic differential diagnosis of acinar cell carcinoma (ACC), mixed acinar-endocrine cell carcinoma (MAEC), and pancreatic endocrine tumors (PET) can be difficult but is important because of differences in their clinical behavior. This study investigates the utility of immunohistochemistry (IHC) in this differential diagnosis using immunohistochemical stains that are available in most laboratories. IHC was performed on paraffin-embedded tissue in ACC (n = 6), MAEC (n = 2), and PET (n = 13), using synaptophysin (SYN), chromogranin (CHR), chymotrypsin (CHY), and alpha-1-antitrypsin (AAT). Electron microscopy (EM) was performed in all cases to confirm the diagnosis. Long-term follow-up and death of disease (DOD) was known in all patients. The ACCs stained as follows: CHY (4/6), AAT (3/6), SYN (4/6); CHR was negative in all cases. Both cases of MAEC stained with CHY, AAT, and SYN (2/2); CHR was negative. PET stained as follows: SYN (13/13), CHR (8/13), CHY (4/13), AAT (5/13). In the ACC/ MAEC group, six of eight patients were DOD at mean follow-up of 11 months. Among the PET, two of 16 patients were DOD at mean follow-up of 37 months. Considerable immunophenotypic overlap exists between ACC, MAEC, and PET. Consequently, one can neither confirm nor rule out a diagnosis of ACC or MAEC using generally available immunohistochemical stains alone. These findings support a role for EM in the evaluation of exocrine and endocrine pancreatic neoplasms.

A reassessment of primary thyroid lymphoma: high-grade MALT-type lymphoma as a distinct subtype of diffuse large B-cell lymphoma.

AIMS: Primary lymphoma of the thyroid gland (PTL) is a relatively rare disease. During an 18-year period, 53 cases of primary non-Hodgkin's lymphoma involving this extranodal site were seen at our institutions. The aims of this study were to evaluate the spectrum of PTLs using current lymphoma classification concepts and immunocytochemical markers, determine whether features of MALT-type lymphoma were evident in PTL, and if there was any clinical significance of such a finding. METHODS AND RESULTS: The cases were retrospectively studied clinically, histologically and immunohistochemically. The tumours were classified according to the Revised European-American Lymphoma Classification of lymphoid malignancies (REAL classification). Thirty-eight patients were females, 15 were males and mean age at diagnosis was 66.3 years (range 38-90). Three cases were low-grade marginal zone lymphomas (low-grade MALT-type lymphomas). There were 45 diffuse large B-cell lymphomas (DLBCL) of which there were 27 DLBCL-NOS and 18 high-grade MALT-type lymphomas. Within the diffuse large B-cell lymphoma (DLBCL) category, cases were subdivided into those without (DLBCL-NOS) and those with features of 'high-grade' MALT-type lymphoma based on presence of a low-grade component or large cell lymphoepithelial lesions (HG MALT-type lymphoma). In addition there were three follicle centre lymphomas, one anaplastic large cell lymphoma and one peripheral T-cell lymphoma. Twenty cases were stage IE, 18 stage IIE, and four stage IV. All patients with low-grade MALT-type lymphoma are alive without disease. The 5-year survivals for DLBCL-NOS and HG MALT-type lymphoma were 75% and 25%, respectively. Univariate analysis (log rank) among the DLBCLs showed stage (P < 0.001) and subtype (P = 0.005) were associated with survival. Stage was associated with type of DLBCL, 65% of DLBCL-NOS being stage IE compared to 20% of HG MALT-type lymphomas. CONCLUSIONS: We conclude that primary thyroid lymphomas occur most commonly in elderly women and are frequently present in clinical stage IE and IIE. Low-grade MALT-type lymphomas are relatively uncommon but appear to have a favourable prognosis. DLBCL is the most common lymphoma and features of MALT can be seen in over one-third of cases. As a group, HG MALT-type lymphomas had a worse outcome than DLBCL-NOS, primarily due to higher clinical stage at diagnosis. These two subtypes of DLBCL appear to be distinct clinical and histological entities.

The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression.

OBJECTIVE: The reported risk of progression from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or carcinoma (CA) in Barrett's esophagus varies. However, the validity of a diagnosis of LGD may be questioned because of interobserver variability. METHODS: A search of the Cleveland Clinic Foundation surgical pathology files between 1986 and 1997 yielded biopsy specimens from 43 patients with Barrett's esophagus diagnosed and coded as LGD. Patients with concurrent or prior diagnoses of HGD or carcinoma were excluded. The LGD cases were randomized and blindly reviewed by three gastrointestinal (GI) pathologists along with cases originally diagnosed as Barrett's esophagus without dysplasia (ND; n = 28), indefinite for dysplasia (IND; n = 14), or HGD (n = 15). Each pathologist classified every biopsy specimen as ND, IND, LGD, or HGD, and interobserver agreements were determined by kappa statistics (K). Follow-up data were available on 25 patients originally diagnosed with LGD. Progression was defined as a subsequent diagnosis of HGD or CA on esophageal biopsy or resection specimens. RESULTS: Agreement between two GI pathologists for a diagnosis of LGD was fair (K = 0.28) and poor (K = 0.21 and -0.04). Individual GI pathologists agreed with the original diagnosis of LGD in 70%, 56%, and 16% of cases. The 25 patients with follow-up included 21 men and four women (mean age, 67 yr) with a mean follow-up of 26 months (range: 2-84 months). Seven patients (28%) with follow-up developed HGD (five patients) or CA (two patients), 2-43 months (median: 11 months) after a diagnosis of LGD. The individual GI pathologists' diagnosis did not correlate with progression. However, when at least two GI pathologists agreed on LGD, there was a significant association with progression (seven of 17 patients, 41%, p = 0.04). When all three GI pathologists agreed on a diagnosis of LGD, four of five patients progressed (p = 0.012). In contrast, of the eight patients with follow-up and no agreement among GI pathologists for a diagnosis of LGD, none progressed. CONCLUSIONS: A high degree of interobserver variability is seen in the histological diagnosis of Barrett's esophagus-related LGD. Although the number of observations is low, a consensus diagnosis of LGD among GI pathologists suggests an increased risk of progression from LGD to HGD or carcinoma.

A case report of intraspinal paracoccidioidomycosis.

The authors report a case of paraplegia caused by a lumbar intraspinal paracoccidioidomycosis (PCM) granuloma. Clinical neurological diagnosis of a compressive spinal cord lesion was confirmed by spinal magnetic resonance imaging (MRI). Patient was submitted to surgery with total excision of the lesion. Histopathological analysis confirmed the diagnosis of PCM. Patient is on sulfamethoxazole/trimethoprim combined with fluconazole and is experiencing positive neurological recovery.

[Sporadic amyotrophic lateral sclerosis. Diagnostic criteria]. / Esclerose lateral amiotrófica esporádica. Critérios diagnósticos.

The authors report two cases of amyotrophic lateral sclerosis (ALS) misdiagnosis (a craniocervical junction disorder, and a cervical spinal cord ependymoma). They review some causes of ALS-like syndrome and propose a protocol to be adopted for the study of all patients who present clinical abnormalities suggesting ALS.

Esclerose lateral amiotrófica esporádica / Sporadic amyotrophic lateral sclerosis

The authors report two cases of amyotrophic lateral sclerosis (ALS) misdiagnosis (a craniocervical junction disorder, and a cervical spinal cord ependymoma). They review some causes of ALS-like syndrome and propose a protocol to be adopted for the study of all patients who present clinical abnormalities suggesting ALS.

[Iatrogeny. The importance of clinical diagnosis. Myopathies induced by clofibrate]. / Iatrogenia. A importância do diagnóstico clínico. Miopatia induzida por clofibrate.

The authors describe the neurological manifestations of a female patient with hypercholesterolemia who developed myopathy in the course of her treatment with clofibrate. After the drug was tapered off, the neurological signs and symptoms disappeared. Therefore, attention is called for the importance of the differential diagnosis of iatrogenic myopathies with polymyositis.

[Motor neuron disease: metabolic evaluation]. / Doença do neurônio motor. Avaliação metabólica.

The authors studied serum and urinary calcium and phosphorus levels, as well as abnormalities on the spine of 30 patients with motor neuron disease. The authors believe in multifactorial aspects in the pathogenesis of motor neuron disease, calling special attention to toxic and metabolic factors.

Doença do neurônio motor: avaliaçäo metabólica / Motor neuron disease: metabolic evaluation

Com base nos escassos dados da literatura médica internacional, os autores estudam os níveis séricos e urinários de cálcio e fósforo, bem como a existência de possíveis anormalidades na coluna vertebral de 30 enfermos com o diagnóstico de doença do neurônio motor. Os autores postulam a participaçäo de múltiplos fatores na etiopatogenia da doença, fazendo mençäo aos aspectos tóxicos e metabólicos

Iatrogenia: a importância do diagnóstico clínico; miopatia induzida por clofibrate / Iatrogeny: the importance of clinical diagnosis; myopathies induced by clofibrate

Os autores descrevem o caso de uma enferma que apresentou síndrome polimiosite símile durante tratamento de hipercolesterolemia com clofibrate. Com a suspensäo da medicaçäo, os sinais e sintomas de acometimento muscular desapareceram por completo. Os autores chamam a atençäo para a importância das miopatias iatrogênicas no diagnóstico diferencial de pacientes com doenças do sistema neuromuscular