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March 2004
Anatomic pathology abstracts editors: Michael Cibull, MD, professor of
pathology and laboratory medicine and director of surgical pathology, University
of Kentucky Medical Center, Lexington, Subodh Lele, MD, assistant professor
of pathology and laboratory medicine, University of Kentucky Medical Center,
and Melissa Kesler, MD, hematopathology fellow, University of Texas Southwestern
Medical Center at Dallas.
Relevance of occult axillary micrometastasis in ductal carcinoma
in situ
Ductal carcinoma in situ represents 20 percent of newly diagnosed breast carcinoma
cases. The incidence of axillary metastasis in DCIS historically has been small
(one to two percent), and its significance has been debated. It is widely known
that serial sections of lymph nodes coupled with keratin immunohistochemistry
increase the identification of micrometastasis. The advent of sentinel lymph
node evaluation underscores the need to re-evaluate the significance of occult
micrometastases in DCIS. Patients with DCIS and negative axillary lymph nodes
from 1974 to 1992 were selected from the Saint Barnabas Medical Center Tumor
Registry for a study. All diagnoses were confirmed, and paraffin blocks were
retrieved after subjects were accepted into the study. Seven serial sections
were obtained from each block and evaluated with two cytokeratin immunohistochemistry
stains. Clinical followup ranged from 10 to 28 years. The study was conducted
with 102 patients. Micrometastases were identified in 13 patients (13 percent),
mostly on one level and composed of microscopic clusters in the subcapsular
sinus. Seven of these lymph node-positive patients (58 percent) had high-grade
comedo DCIS, four (33 percent) had intermediate grades of various types of DCIS,
and one had a low-grade micropapillary DCIS. The overall disease recurrence
rate was 12 percent, but micrometastasis was not detected in any of the patients
who developed disease recurrence. The authors concluded that serial immunohistochemistry
evaluation of lymph nodes dramatically increases the identification of occult
micrometastasis. Micrometastasis detected by immunohistochemistry, however,
has no apparent clinical significance in DCIS based on the current long-term
clinicopathologic study. The authors, therefore, question the significance of
occult micrometastasis, identified by immunohistochemistry, in DCIS of any type
and extent. Further evaluation and followup of lymph node micrometastases in
patients with invasive tumors of various sizes are needed. The current findings
would not support altering the stage of patients with DCIS and micrometastasis
detected by immunohistochemistry alone.
Lara JF, Young SM, Velilla, RE, et al. The relevance of occult axillary micrometastasis
in ductal carcinoma in situ: a clinicopathologic study with long-term follow-up.
Cancer. 2003;98:2105–2113.
Reprints: Dr. Jonathan F. Lara, Dept. of Pathology, St. Barnabas Medical Center,
94 Old Short Hills Rd., Livingston, NJ 07039; jlara@sbhcs.com
A new classification scheme for the prognostic stratification
of meningioma
Meningiomas are usually considered benign tumors, yet relapses, including histopathologically
aggressive and benign tumors, occur in 10 to 20 percent of patients. The authors
explored the value of numerical abnormalities for chromosomes 1, 9, 10, 11,
14, 15, 17, 22, X, and Y in meningiomas from 70 patients for predicting relapse-free
survival. The presence of numerical abnormalities for one or more chromosomes
was found in 77 percent of the patients. Chromosome 22 in the whole series and
chromosome Y in males were the most frequently altered, followed by chromosomes
1, 14, and X in females. Abnormalities of chromosomes 1, 9, 10, 11, 14, 15,
17, the sex chromosomes, and gains of chromosome 22 were associated with adverse
prognostic features, more frequent relapses, and shorter relapse-free survival
rates. Multivariate analysis showed that tumor grade together with chromosome
14 status and age were the best combination of independent variables for predicting
relapse-free survival rates. According to these variables, all patients with
a score of two or who had more than two adverse prognostic factors had experienced
relapse at five years, whereas none of those with a score of zero had experienced
relapse 10 years after surgery. The authors concluded that in addition to age
and histologic grade, abnormalities of chromosome 14 contribute to a better
prognostic stratification of meningioma patients at diagnosis. Additional prospective
studies in larger series of patients, including larger numbers of patients who
experienced relapse, are necessary to confirm the utility of the proposed predictive
model.
Maillo A, Orfao A, Sayagues JM, et al. New classification scheme for the prognostic
stratification of meningioma on the basis of chromosome 14 abnormalities, patient
age, and tumor histopathology. J Clin Oncol. 2003;21:3285–3295.
Reprints: Dr. Angel Maillo, Servicio de Neurocirugia, Hospital Universitario
de Salamanca, Paseo de San Vicente 58, 37007 Salamanca, Spain; a_maillo@yahoo.es
Confirming molecular classification of DLBCL by immunohistochemistry
using a tissue microarray
Diffuse large B-cell lymphoma (DLBCL) can be divided on the basis of gene expression
profiling, using a cDNA microarray, into three prognostically important subgroups:
germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3.
The GCB group has significantly better survival than the other two groups, and
therefore identification of subgroups is of great clinical interest. Gene expression
technology, however, is not widely available for routine clinical use. Furthermore,
it is expensive and requires fresh or frozen tissue. The authors evaluated the
use of immunohistochemistry to predict subgroups in DLBCL, correlating their
results with results of cDNA microarray gene-expression data. They created tissue
microarray blocks from 152 cases of DLBCL, 142 of which had been previously
evaluated by cDNA microarray. Sections were stained with antibodies to CD10,
bcl-6, MUM1, FOXP1, cyclin D2, and bcl-2. The authors then subclassified cases
based on expression of CD10, bcl-6, and MUM1 into GCB and non-GCB subgroups.
Forty-two percent of the cases were considered GCB, and 58 percent were considered
non-GCB. The five-year overall survival rate for the GCB group was 76 percent,
while that for the non-GCB group was only 34 percent (P<.001), similar
to data on overall survival reported using the cDNA microarray. Furthermore,
the tissue microarray immunostain panel reproduced the cDNA microarray classification—GCB
versus non-GCB—in approximately 80 percent of cases. In cases with discrepant
classification, the overall survival rate was predicted better using the tissue
microarray. In multivariate analysis, a high International Prognostic Index
score of three to five and the non-GCB phenotype were independent adverse predictors
(P<.0001) of survival. These results suggest that a relatively limited
immunostaining panel can be used to determine the GCB and non-GCB subgroups
of DLBCL and to predict survival similar to the cDNA microarray.
Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular
classification of diffuse large B-cell lymphoma by immunohistochemistry using
a tissue microarray. Blood. 2004;103:275–282.
Reprints: Dennis D. Weisenburger, Dept. of Pathology and Microbiology, 983135
Nebraska Medical Center, Omaha, NE 68198; dweisenb@unmc.edu
Ability to assess the histopathologic prognostic
variables in primary cutaneous melanoma
The prognosis for patients with localized primary cutaneous melanoma depends
principally on tumor thickness and to a lesser extent on ulcerative state and
Clark level. The authors recently found in an analysis of 3,661 patients that
tumor mitotic rate is also an important prognostic parameter, ranking second
to tumor thickness. However, few studies have assessed the accuracy and reproducibility
with which these features of a melanoma are recorded by histopathologists. The
authors of the present study assessed the interobserver reproducibility of major
pathologic prognostic parameters in cutaneous melanoma. Single hematoxylin and
eosin-stained slides of 69 dermally invasive primary cutaneous melanomas were
circulated among six pathologists who had different experiences in assessing
melanocytic tumors. The observers independently determined the tumor thickness,
Clark level of invasion, ulcerative state, and tumor mitotic rate for each lesion.
They calculated intraclass correlation coefficients and kappa scores for multiple
ratings per subject. The intraclass correlation coefficients were 0.96 for tumor
thickness and 0.76 for tumor mitotic rate. The kappa scores were 0.83 for ulcerative
state and 0.60 for Clark level. These results indicated excellent agreement
among the pathologists for measuring tumor thickness, ulcerative state, and
tumor mitotic rate and fair to good agreement for Clark level. The authors concluded
that appropriately trained and experienced histopathologists can assess prognostically
important features of melanomas accurately and reproducibly. Given recent findings
of the significance of tumor mitotic rate in determining prognosis, it is important
that this feature be assessed by a standardized method and documented for all
primary cutaneous melanomas.
Scolyer RA, Shaw HM, Thompson JF, et al. Interobserver reproducibility of histopathologic
prognostic variables in primary cutaneous melanomas. Am J Surg Pathol.
2003; 27:1571–1576.
Reprints: Richard A. Scolyer, Dept. of Anatomical Pathology, Royal Prince Alfred
Hospital, Missenden Rd., Camperdown, NSW 2050 Australia; richard.
scolyer@ email.cs.nsw.gov.au
Tumor size predicts survival within stage IA non-small cell lung cancer
It has been demonstrated that patients with stage I lung cancer have improved
five-year survival rates. This observation has stimulated interest in lung cancer
screening programs in an effort to detect smaller and potentially more curable
tumors. The authors conducted a study in which they retrospectively analyzed
patients with pathologically confirmed stage IA non-small cell lung cancer resected
at their institution between 1991 and 2001. Kaplan-Meier survival analysis was
performed to estimate the five-year overall and disease-specific survival probability
stratified by tumor size. The effects of age, gender, histology, and tumor size
on survival were also analyzed using a Cox proportional hazards regression model.
The authors identified 244 patients (median followup, 2.6 years). Of these,
229 received lobectomy, eight segmentectomy, and seven wedge resection. Histologic
diagnoses included adenocarcinoma (59.4 percent), squamous cell carcinoma (18.9
percent), bronchioloalveolar (15.2 percent), large cell (4.5 percent), and poorly
differentiated (2.0 percent). The five-year survival probability for all patients
was 71.1 percent. For patients with tumors of 2 cm or less, the five-year probability
of survival was 77.2 percent, compared with 60.3 percent for patients with tumors
larger than 2 cm. The overall five-year disease-specific survival was 74.9 percent.
For patients with tumors of 2 cm or less, it was 81.4 percent, compared with
63.4 percent for patients with tumors larger than 2 cm. The authors concluded
that, even within the confines of stage IA cancer, there appear to be differences
in survival rates based on tumor size. They suggest that further substaging
be considered.
Port JL, Kent MS, Korst RJ, et al. Tumor size predicts survival within stage
IA non-small cell lung cancer. Chest. 2003;124:1828–1833.
Correspondence: Dr. Nasser Altorki, Dept. of CT Surgery, Ste. M404, Weill Medical
College of Cornell University, 525 E. 68th St., New York, NY, 10021
Histopathological parameters as predictors for
the course of Crohn’s disease
Recent classification systems discriminate penetrating Crohn’s disease
from stricturing and nonstricturing/nonpenetrating CD, however, no easily detectable
marker has yet been identified that can predict the course of CD. Individual,
clinical course-specific new treatment schemes would be highly desirable for
different potentially divergent pathophysiological pathways—for example,
fistula versus stenosis. The authors retrospectively studied intestinal tissue
biopsies from 63 CD patients with disease followup of up to seven years. In
the biopsy specimens, 34 histopathological features present prior to the onset
of strictures or fistulas were evaluated and compared with biopsies from patients
with nonstricturing/ nonpenetrating disease. Five histomorphological parameters
demonstrated significant associations to different disease courses when applying
univariate analysis. In a multivariate logistic regression model, the best predictors
of an uncomplicated disease course were severe lymphocytic infiltration of the
lamina propria, presence of crypt atrophy, and absence of lymphocytic infiltration
of the epithelium. The combination of these parameters has a sensitivity of
67 percent and a specificity of 83 percent for predicting nonstricturing/nonpenetrating
disease (positive predictive value, 0.75). The authors concluded that histopathological
parameters may help to predict complications of CD prior to its onset, but the
results of this study have to be confirmed prospectively.
Bataille F, Klebl F, Rümmele P, et al. Histopathological parameters as
predictors for the course of Crohn’s disease. Virchows Arch.
2003;443:501–507.
Reprints: F. Bataille, Dept. of Pathology, University of Regensburg, 93042
Regensburg, Germany; frauke.bataille@
klinik.uni-regensburg.de
Causes of hepatic granulomas
Epithelioid granulomas have been reported in two to 15 percent of unselected
liver biopsies, and numerous underlying etiologies have been described. However,
all United Kingdom series were reported before hepatitis C virus was identified.
The authors evaluated the current etiologies of hepatic granulomas and assessed
the prognosis for the “idiopathic” group, in which all investigations
for a recognized cause were negative or normal. The authors conducted a retrospective
review of patient case notes between 1991 and 2001. All patients who had a liver
biopsy at Glasgow Royal Infirmary that revealed epithelioid granulomas had their
case notes and liver biopsies reviewed and a standard proforma completed. Of
the 1,662 liver biopsies performed during the study period, hepatic granulomas
were found in 63 patients, 47 of whom were female and a mean age of 42 years
(range, 17 to 81 years). The underlying etiologies were primary biliary cirrhosis
(PBC; 23.8 percent), sarcoidosis (11.1 percent), idiopathic (11.1 percent),
drug induced (9.5 percent), HCV (9.5 percent), PBC/autoimmune hepatitis (AIH)
overlap (6.3 percent), Hodgkin lymphoma (6.3 percent), AIH (4.8 percent), tuberculosis
(4.8 percent), resolving biliary obstruction (3.2 percent), and other single
miscellaneous causes (9.5 percent). Of the seven patients with idiopathic hepatic
granulomas, one was lost to followup, one died of stroke, and the remaining
five were well with no liver-related morbidity at a mean followup of 6.2 years.
The authors noted that the etiology of hepatic granulomas is broad, and HCV
is an important cause in this population. Despite extensive investigations,
10 to 15 percent of patients still had idiopathic hepatic granulomas. The prognosis
for this group, however, appears to be excellent.
Gaya DR, Thorburn D, Oien KA, et al. Hepatic granulomas: a 10-year single centre
experience. J Clin Pathol. 2003;56:850–853.
Reprints: Dr. D. Gaya, 15 Julian Ave., Kelvinside, Glasgow, G12 ORB, United
Kingdom; danielgaya@aol.com
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