Atypical Mycobacteria Masquerading in the CNS

12 04 2010

Below is a case report I was invloved with in which the patient was found to have a Mycobacterium haemophilum brain abscess.  Interesting case!

Atypical Mycobacteria Masquerading in the CNS

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Overexpression of Cyclooxygenase-2 (COX-2) Correlates with Grade, Stage and Lymph Node Status in Colorectal Adenocarcinoma (CRC)

2 12 2009

KA Robstad, JD Choate, JS Ross, CE Sheehan and DM Jones, Department of Pathology, Albany Medical College, Albany, NY

Background: COX-2 is an inducible enzyme involved in prostaglandins metabolism that has been associated with cellular resistance to apoptosis both in normal and malignant epithelial cells.  Over-expression of COX-2 has been identified in various epithelial malignancies including colorectal CRC, but large scale studies of its prognostic significance for the disease have not been previously performed.

Design: Formalin-fixed, paraffin-embedded sections from 155 CRC were immunostained by an automated method (Ventana Medical Systems; Tucson, AZ) using mouse monoclonal COX-2 (clone CX-294, DAKO, Carpinteria, CA).  Cytoplasmic immunoreactivity was semi quantitatively evaluated based on both intensity (weak, moderate and intense) and distribution (focal <10%, regional 10 to 50% and diffuse >50%) and results were correlated with histologic and prognostic variables.

Result: Intense diffuse over-expression of COX2 was observed in 71/155 (46%) of CRC and correlated with increasing tumor grade [16% of grade 1 vs 51% of grade 2 vs 48% of grade 3, p=0.018); advanced AJCC stage (38% of stage I/II vs 53% of stage III/IV; p=0.048); and lymph node status (35% node negative vs 53% node positive, p=0.024).  COX2 over-expression did not correlate with disease recurrence or overall survival. On multivariate analysis, pathologic stage at diagnosis independently predicted patient survival.

Conclusion: Over-expression of COX-2 is associated with high tumor grade, advanced pathologic stage and positive lymph node status in CRC. Further study of COX-2 expression in CRC, particularly with reference to its clinical prognostic implications, appears warranted.





Bmi-1 Nuclear Overexpression Correlates with Low Tumor Grade and Lengthened Overall Survival in Colorectal Adenocarcinoma (CRC)

10 11 2009

JD Choate, KA Robstad, CE Sheehan, JS Ross and DM Jones
Department of Pathology, Albany Medical College, Albany, NY

BMI 20x

Bmi-1 Staining at 20x

Background: Bmi-1 protein expression plays a vital role in cell cycle regulation and senescence, and has been implicated in lymphangiogenesis and carcinogenesis.  Bmi-1 oncogene overexpression has been previously identified in several human malignancies including hematologic malignancies, as well as carcinomas including CRC; however, clinicopathologic and prognostic significance of Bmi-1 expression has not been fully elucidated.

Design: Formalin-fixed, paraffin-embedded sections from 153 colorectal adenocarcinomas (CRCs) were immunostained by an automated method (Ventana Medical Systems; Tucson, AZ) using mouse monoclonal Bmi-1 (clone F6; Millipore, Burlington, MA).  Nuclear and cytoplasmic immunoreactivity were semi quantitatively evaluated based on both intensity (weak, moderate and intense) and distribution (focal <10%, regional 10 to 50% and diffuse >50%) and results were correlated with clinic-pathologic variables.

Result: Bmi-1 nuclear immunoreactivity was over-expressed in 100/153 (65%) of CRC, while cytoplasmic over-expression was observed in 62/153 (41%). Nuclear overexpression correlated with low tumor grade (77% grade 1 vs 72% grade 2 vs 49% grade 3, p=0.016) and lengthened overall survival (80% alive vs 59% expired, p=0.008). There were no other significant correlations.  On multivariate analysis, only pathologic stage at diagnosis independently predicted patient survival.

Conclusion: Bmi-1 overexpression is associated with lower grade CRC’s and significantly correlates with increased overall survival. These findings indicate that Bmi-1 over-expression may be a significant prognostic biomarker that could play a role in the planning of therapy in CRC. Further study of Bmi-1 expression in CRC appears warranted.





Prognostic Implications of Cytoplasmic and Nuclear Overexpression of Lipocalin-2/NGAL in Colorectal Adenocarcinoma (CRC)

9 11 2009

KA Robstad, JD Choate, CE Sheehan, JS Ross and DM Jones
Department of Pathology, Albany Medical College, Albany, NY

Lipo 20x

Lipocalin-2 Stain at 20x

Background:  The lipocalin family is a diverse group of secreted soluble proteins that bind hydrophobic ligands and act as small molecule transporters.  Lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), is an inflammatory cytokine upregulated in acute inflammatory conditions which has been found to be over-expressed in various human malignancies including carcinomas of the breast, ovary, pancreas and colon.  The prognostic significance of Lipocalin-2 expression in CRC has not been previously investigated.

Design: Formalin-fixed, paraffin-embedded sections from 156 colorectal adenocarcinomas (CRCs) were immunostained by an automated method (Ventana Medical Systems; Tucson, AZ) using rat monoclonal lipocalin-2/NGAL (R&D Systems, Minneapolis, MN).  Cytoplasmic and nuclear immunoreactivity was semi quantitatively evaluated based on both intensity (weak, moderate and intense) and distribution (focal <10%, regional 10 to 50% and diffuse >50%) and results were correlated with clinicopathologic variables.

Result: Lipocalin-2 immunoreactivity was predominately cytoplasmic, however, significant nuclear immunoreactivity was noted in a subset of cases.  Intense diffuse cytoplasmic overexpression of lipocalin-2 was observed in 30/156 (19%) of CRC and correlated with early AJCC stage (28% of stage I/II vs 11% of stage III/IV; p=0.007) and presence of concomitant Crohn’s disease (100% with Crohn’s vs 0% without Crohn’s).  Nuclear lipocalin-2 immunoreactivity was noted in 6 cases, all 6 of which (100%) were lymph node negative (p=0.005), early stage (p=0.015), and moderately differentiated/grade 2 (p=0.102) tumors.  Lipocalin-2 over-expression did not correlate with disease recurrence or overall survival. On multivariate analysis, pathologic stage at diagnosis independently predicted patient survival.

Conclusion: Cytoplasmic lipocalin-2 over-expression is associated with both early AJCC tumor stage as well as the presence of pre-existing Crohn’s disease potentially reflecting its role as an inflammatory cytokine.  Nuclear expression, only identified in a small subset of CR, was found to correlate significantly with low-stage, moderately differentiated, lymph node-negative tumors. Further studies of both nuclear and cytoplasmic lipocalin-2 expression in CRC appear warranted.





Abstract: Overexpression of Notch-1 Correlates with Grade, Stage and Overall Survival in Colorectal Adenocarcinoma (CRC)

31 03 2009

KA Robstad, JD Choate, MN Donovan, MA DiMaio, CE Sheehan and JS Ross
Department of Pathology, Albany Medical College, Albany, NY

Background: Notch signaling is believed to play a crucial role in cell differentiation, proliferation and survival. Dysregulation of Notch signaling has been reported in a wide variety of human malignancies including breast, cervical, CNS, lung, and pancreatic cancer as well as melanoma and certain leukemias. There is recent evidence that Notch signaling contributes to the natural progression of CRC. However, the prognostic significance of Notch-1 expression in CRC has not been previously investigated.

Design: Formalin-fixed, paraffin-embedded sections from 125 colorectal adenocarcinomas (CRCs) were immunostained by an automated method (Ventana Medical Systems; Tucson, AZ) using polyclonal Notch-1 antibody (sc-6014; Santa Cruz Biotechnology, Santa Cruz, CA). Cytoplasmic immunoreactivity was semiquantitatively evaluated based on both intensity and distribution and results were correlated with histologic and prognostic variables.

Result: Intense, diffuse overexpression of Notch-1 was observed in 45% (57/125) of CRC cases and correlated significantly with increasing AJCC stage (24% of stage I, 58% of stage II, 35% of stage III, and 66% of stage IV; p=0.041); histologic grade (11% of grade 1; 52% of grade 2, and 50% of grade 3; p=0.006), and overall survival (27% in those alive, 53% in those expired; p=0.011). On multivariate analysis, only pathologic stage was an independent predictor of overall survival.

Conclusion: Notch-1 overexpression is associated with tumor aggressiveness in CRC and significantly correlates with increasing tumor grade, pathologic stage and overall survival. Notch 1 overexpression may be a valuable prognostic indicator that can be used to plan therapy in CRC. Further study of Notch-1 expression in CRC management and targeted therapy development appears warranted.

 

Poster View:

Official 2009 USCAP Poster Submission - K. Robstad

Official 2009 USCAP Poster Submission - K. Robstad





Abstract: Evaluation of Sentinel Lymph Node Intraoperative Frozen Section Diagnoses In Breast Cancer Patients

31 03 2009

Robstad, K. Department of Pathology. Albany Medical Center. Albany, NY

Objective: To evaluate the effectiveness of intraoperative frozen section diagnosis at appropriately staging patients undergoing breast cancer surgery at Albany Medical Center, and to compare these data to existing published reports.

Background: It has been established that selective axillary dissection guided by lymph node scintillography can reduce the morbidity associated with a full axillary lymph node dissection. The safety of this approach, however, is contingent upon accurate staging of the patient intraoperatively. False negative reporting may cause morbidity for the patient including additional surgery or disease recurrence.

Methods: A database search of pathology reports from 2003 to 2008 containing the keywords, “breast” and “sentinel node” was conducted using the SoftPath software suite. Diagnosis at the time of frozen section was compared to the final reported diagnosis. From this information, accuracies, sensitivities, and negative predictive values were calculated overall and by year for both cases as a whole and by total number of recovered sentinel lymph nodes. This data was then compared with figures reported in current literature.

Results: Between 2003 and 2008, there were 581 surgical cases in which intraoperative consultation was obtained regarding sentinel lymph node involvement by breast cancer; in these cases, a total of 1,647 lymph nodes were evaluated. The overall diagnostic accuracy at time of frozen was 96.28%. The overall sensitivity of detecting macrometastases was 80.34%. The negative predictive value was 95.62%. Data by year is reported in figures one through three.

Discussion: The data from the researched reports compares favorably with previously-published figures. Langer et al (2008) and Van de Vrande et al (2008) both report an accuracy of 90% compared with 96% at Albany Medical Center (AMC). Van de Vrande also documented a sensitivity of 84% in identifying macrometastases which compared to AMC’s 80% value. AlSahaf et al (2008) and Ali et al (2008) both report a negative predictive value of 97% which compares to AMC’s 95.6% value. Micrometastases were excluded from analysis because they have been found to have no impact on a patient’s prognosis; there were, however, 66 instances in which a case was reported as negative for tumor on frozen section that was  later designated to have involvement by either a focus of cancer measuring less than 0.2mm or isolated tumor cells (resulting in a N0i+ designation); only 23 cases were reported at AMC in which permanent sectioning revealed sentinel node involvement greater than 0.2mm which was not seen on frozen sections.

It is of note, that most published data compares frozen section diagnosis to the outcome of subsequent total lymph node dissection and not subsequent permanent fixation of the same specimen evaluated using frozen sectioning. Also, most existing publications fail to delineate the difference and micro- and macrometastases, making interpretation of existing data a complicated process. Finally, it is noteworthy that 12% of AMC case reports do not explicitly include a measurement of carcinoma involvement in the lymph node when not observed during intraoperative consultation.

 

 

CASES

2003

2004

2005

2006

2007

2008

Accuracy

95.24%

98.20%

98.91%

96.97%

94.31%

94.12%

Sensitivity

77.78%

90.00%

90.91%

82.61%

75.00%

73.08%

NPV

94.29%

97.85%

98.78%

96.46%

93.14%

93.00%

 

 

 

 

 

 

 

NODES

2003

2004

2005

2006

2007

2008

Accuracy

96.97%

99.28%

99.65%

98.41%

97.09%

97.31%

Sensitivity

70.00%

93.10%

92.86%

81.48%

75.76%

77.42%

NPV

96.74%

99.20%

99.64%

98.29%

96.80%

97.03%

 

Table 1. Accuracies, sensitivities and negative predictive values for overall cases and for individual nodes from 2003 to 2008.

 

References:

1.       Ali R, Hanly AM, Naughton P, Castineira CF, Landers R, Cahill RA, Watson RG. Intraoperative frozen section assessment of sentinel lymph nodes in the operative management of women with symptomatic breast cancer.  World J Surg Oncol. 2008 Jun 26;6:69.

2.       AlSahaf M, AlShaban B, Mulsow J, Power C, Leen E, Walsh TN. Intra-operative examination of the sentinel node in breast cancer.  Ir Med J. 2008 Apr;101(4):120-2.

3.      Davit FE, Gatmaitan P, Garguilo G. Sentinel node mapping for breast cancer: the operative experience of a breast surgeon in a rural community.

4.       Holwitt DM, Gillanders WE, Aft RL, Eberlein TJ, Margenthaler JA. Sentinel lymph node biopsy in patients with multicentric/multifocal breast cancer: low false-negative rate and lack of axillary recurrence.  Am J Surg. 2008 Oct;196(4):562-5. Epub 2008 Aug 29.

5.       Langer I, Guller U, Berclaz G, Koechli OR, Moch H, Schaer G, Fehr MK, Hess T, Oertli D, Bronz L, Schnarwyler B, Wight E, Uehlinger U, Infanger E, Burger D, Zuber M. Accuracy of frozen section of sentinel lymph nodes: a prospective analysis of 659 breast cancer patients of the Swiss multicenter study.  Breast Cancer Res Treat. 2009 Jan;113(1):129-36. Epub 2008 Feb 23.

6.       Van de Vrande S, Meijer J, Rijnders A, Klinkenbijl JH. The value of intraoperative frozen section examination of sentinel lymph nodes in breast cancer. Eur J Surg Oncol. 2008 Sep 9.

7.       Van Wely BJ, Smidt ML, de Kievit IM, Wauters CA, Strobbe LJ. False-negative sentinel lymph node biopsy. Br J Surg. 2008 Nov;95(11):1352-5.

8.     Varga Z, Rageth C, Saurenmann E, Honegger C, von Orelli S, Fehr M, Fink D, Seifert B, Moch H, Caduff R. Loss of metastatic deposits in breast sentinel lymph nodes during intra-operative frozen section analysis.  Verh Dtsch Ges Pathol. 2007;91:221-4.








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