The traditional criteria ever used to evaluate laboratory tests has
been the predictive 'accuracy' of the test.
None of the available laboratory tests used in the selection of
treatments for cancer patients have ever been tested for 'efficacy'. This
includes estrogen receptor, progesterone receptor, Her2/neu,
immunohistochemical staining for tumor classification, bacterial culture
and sensi...
The traditional criteria ever used to evaluate laboratory tests has
been the predictive 'accuracy' of the test.
None of the available laboratory tests used in the selection of
treatments for cancer patients have ever been tested for 'efficacy'. This
includes estrogen receptor, progesterone receptor, Her2/neu,
immunohistochemical staining for tumor classification, bacterial culture
and sensitivity testing, CT, MRI and FDG Pet Scans to measure tumor
response to treatment.
There is no literature establishing clinical 'efficacy' of these
laboratory tests, because the costs of such clinical trials are
prohibitive, granting agency support is non-existent, and no other
analogous tests have been or will likely ever be subjected to such an
unreasonably high bar criterion for clinical use.
The only data supporting any of them relate to test 'accuracy', and
there is a total lack of information regarding test 'efficacy'.
(randomized trials with outcome measurements for diagnostic tests)
Also, no one is seriously proposing that any of the molecular tests
now available (Oncotype DX, EGFR amplification/mutation) should have to be
proven 'efficacious', as opposed to merely 'accurate', before they are
used in clinical decisions regarding treatment selection.
The American Society of Clinical Oncology (ASCO) reviews of cell
culture assay tests for establishing clinical 'efficacy' specifically
excluded all studies reporting the predictive 'accuracy' of the tests. In
other words, they excluded reports that only reported correlations between
assay results and clinical outcomes.
Instead, ASCO reviews included old, previously-reviewed studies
comparing outcomes of patients who had treatment based on assay results
versus patients with empirically chosen therapy. The criteria of
laboratory assay 'efficacy', as opposed to laboratory assay 'accuracy'
sound reasonable, but it is unprecendented with regard to any other
laboratory test ever evaluated.
Cell culture assay tests have been well proven to have predictive
'accuracy' with that of estrogen receptor, progesterone receptor, Her2/neu
and the newer molecular tests. In light of the precious little in the way
of guidance from clinical trials with respect to best empiric therapy
(where the only thing that has been proven to correlate with treatment
decisions is reimbursement to the prescribing oncologist) and the
importance of basing cancer treatment at least in part on patient
preferences, it is entirely reasonable to support judicious application of
laboratory tests which have been well characterized with respect to test
'accuracy'. These are diagnostic tests and should be held to that
criteria, and not to that of therapy.
These laboratory tests are a tool for the oncologist. The oncologist
should take advantage of all the tools available to him/her to treat a
patient. And since studies show that only 25-30% of patients do respond to
chemotherapy that is available to them, there should be due consideration
to looking at the advantage of human tissue assay tests to the resistance
that has been found to chemotherapy drugs.
Cell culture drug resistance testing is for preventing use of known
anti-cancer drugs that are not likely effective in the specific tumor.
Cell culture drug sensitivity testing tries to determine specific drug and
dose effectiveness. The distinction between sensitivity and resistance is
more semantic than substantive.
In virtually all forms of cancer, clinical trials have failed to
identify best drug regimens for use in all individuals with a given form
of cancer.
Oncologists have been documented to use reimbursement (payment to the
oncologist) as the most important criterion for selecting between the
large array of otherwise equally acceptable regimens. (Jacobson,
M.,O'Malley, A.J., Earle, C.C., et al. Health Affairs 25(2):437-443, 2006)
& (Patterns of Care: 2005,Vol 2,Issue 1)
The established criterion on which to judge all laboratory tests used
to help in the selection of cancer treatment is test 'accuracy' and not
test 'efficacy'.
Cell culture assay tests with cell-death endpoints have been
exceedingly and reproducibly well established to be usefully 'accurate' in
correlation with and predicting for clinical outcomes, including tumor
response and patient survival.
There should an expansion of Medicare and private insurance
reimbursement to promote even greater utilization and development of
laboratory-based mechanisms, like cell culture assays, for improving the
match between tumors and an ever-increasing number of partially effective
and very expensive drug therapies.
We read with great interest the original article by Bernardi et al.
[1] in the December 2005 issue of the Journal.
According to literature previously published, the authors believe that
necroscopy is the standard method to determine the cause of death when
investigating clinicopathological discrepancies and the epidemiology of
disease. They reviewed the provisional and final reports of necropsies
per...
We read with great interest the original article by Bernardi et al.
[1] in the December 2005 issue of the Journal.
According to literature previously published, the authors believe that
necroscopy is the standard method to determine the cause of death when
investigating clinicopathological discrepancies and the epidemiology of
disease. They reviewed the provisional and final reports of necropsies
performed at their Institution in 2001 to check diagnostic changes between
initial gross diagnosis and subsequent histological analysis in several
organs. They found that microscopic examination has a major impact on
macroscopic diagnosis, altering and refining previous diagnoses,
especially in the lungs, liver and kidneys. Moreover Bernardi et al. [1]
raise the question that, in routine necropsies, histological sampling
increases costs and turnaround times, and consequently some pathologists
believe that histology may not always be necessary.
We found their discussion of literature and interpretation of the data
very pertinent and we wish to share with the authors and the readers our
experience.
We would like to stress out even further the necessity for the pathologist
to realize the usefulness of histological analysis. Due to a misbelief
that post mortem events alter morphology in such a way to prevent a
correct diagnosis, some pathologists decide not to take samples for
histology. Grellner and coll. [2] have systematically shown however that
histological analysis is feasible and useful even when the exam is made of
exhumed bodies months after burial.
At the autopsy, the pathologist should first describe the macroscopic
aspect of each organ and take samples of each visible lesion. A
provisional diagnosis may be given while histology is pending but the
diagnosis should be confirmed by histological analysis. It should be noted
that a correct sampling by the pathologist must be performed to avoid
forensic consequences from misdiagnosis.
Moreover pathologists should keep in mind that the classical pathological
patterns are changing due to the effects of novel and more prompt
interventions. In some cases alterations are identifiable only at a
microscopic level.
We would like to point out that the histological analysis of the heart
sometimes is fundamental to determine the cause of death and date the
event. This is especially important in such diseases as non-
atherosclerotic coronary pathology [3-5]. In our own small experience an
accurate histological examination allowed us to specify the chain of
events which brought on unexpected sudden death [6,7].
In conclusion we are grateful to the authors for addressing such a
relevant issue. Although it may appear time consuming and costly at first,
a more complete assessment would reveal that the risk of misdiagnosis
using macroscopic only analyses is relatively high, and an accurate
assessment of the scenario using histological analysis assures the
reliability of the findings, which is of particular relevance in forensic
medicine. Moreover, the detailed analysis under the microscope is the
access pathway to a different dimension where the pathologist sees not
only the end event but he has insight of the pathophysiologic cascade of
cellular and molecular events leading to the disease.
References
1. Bernardi FD, Saldiva PH, Mauad T. Histological examination has a major
impact on macroscopic necropsy diagnoses. J Clin Pathol 2005;58:1261-4.
2. Grellner W, Glenewinkel F. Exhumations: synopsis of morphological and
toxicological findings in relation to the postmortem interval. Survey on a
20-year period and review of the literature. Forensic Sci Int 1997;90:139-
59.
3. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with
apparently normal heart. Cardiovasc Res 2001;50:399-408.
4. De Giorgio F, Abbate A, Vetrugno G, et al. Non-atherosclerotic coronary
pathology causing sudden death. J Clin Pathol in press.
5. De Giorgio F, Abbate A, Capelli A, et al. Spontaneous rupture of
coronary artery in HIV+ patient treated with HAART. Am J Forensic Med
Pathol 2005;26:197.
6. De Giorgio F, Abbate A, Biondi-Zoccai GG, et al. Fatal choking due to
amyloid infiltration of the laryngeal plexus. Virchows Arch. 2005;447:115-
7. De Giorgio F, Abbate A, Biondi-Zoccai GG, et al. An unusual cause of
fatal pulmonary embolism. Int J Cardiol. in press.
I recently read the article, "Basal-like breast carcinomas; clinical
outcome and response to chemotherapy" by Banerjee et al. (corresponding
author, Prof. Smith), published online in Journal of Clinical Pathology on
23.03.06. I would like to point out that the authors incorrectly make
reference to a paper of mine (reference 3), published in Journal of
Clinical Oncology in 1995, in connection with
g...
I recently read the article, "Basal-like breast carcinomas; clinical
outcome and response to chemotherapy" by Banerjee et al. (corresponding
author, Prof. Smith), published online in Journal of Clinical Pathology on
23.03.06. I would like to point out that the authors incorrectly make
reference to a paper of mine (reference 3), published in Journal of
Clinical Oncology in 1995, in connection with
grade determination. I have never been involved in this particular field,
indeed I have serious doubts as to its reproducibility, and my article
cited does not deal with grading but with cell proliferation determined as
Thymidine Labelling Index.
Nakhleh R E (1) has excelled in giving us a brilliant account on
the
quality assuarance and improvement plan in surgical pathological
reporting
in a nutshell. An accurate, comprehensive, brief and timely surgical
pathology report would always facilitate the optimum management of the
patient and it would also satisfy the needs of the customer, in this
case
the clinician.Undoubtably all the clinicians...
Nakhleh R E (1) has excelled in giving us a brilliant account on
the
quality assuarance and improvement plan in surgical pathological
reporting
in a nutshell. An accurate, comprehensive, brief and timely surgical
pathology report would always facilitate the optimum management of the
patient and it would also satisfy the needs of the customer, in this
case
the clinician.Undoubtably all the clinicians would value and admire a
well
focused, informative and well directed surgical pathology report.
The final product of complete surgical pathology report is
multifactorial and it necessitates a multidisciplinary approach. Request
forms have to be well written with a short and a well directed clinical
history. It should elaborate the crux of the matter and be stressed to
all clinicians should be stressed the importance of it regardless of the
place
in the hierarchical structure. Specimen collection, analyzing, labeling,
transporting to the labouratory, reporting, report correction,
verification and report delivery should occur in a sequential well
directed flow.
The reporting has to be performed in a well formatted structured
manner and this kind of standardized proforma leads to better quality
surgical pathology reports(2). Most institutions have their own
proforma in
reporting histopathological specimens. But unfortunately people find it
difficult to adhere to a system (3) and some of the forms are found to
be
incomplete. This highlights the importance of training and motivating
the
work force.
There seems to be wide variation in interpretation of phrases used
in
histopathology reports between pathologists and clinicians
(4). Interdisciplinary meetings have to be conducted frequently and
they
would summarize the clinical findings, biochemical findings and finally
the histological findings and they would culminate to facilitate the
management plan of the patient concerned. They should be considered as
essential ingredients in the formula for a better patient care.
Moreover there should always be a better way of communication
between
the clinician and the pathologist when summating to an optimal
management
plan. So it would have been better if the review by Nakhleh R E had
included few words on the importance of communication between the
clinician and the pathologist, the importance of adhering to proforma
when
reporting, and interdisciplinary meetings.
References
(1) Nakhleh R E .What is quality in surgical pathology? Journal of
clinical
pathology 2006; 59:669-72.
(2) Beattie G C.Improvement in quality colorectal cancer pathology
reporting with a standardized proforma-a comparative study. Colorectal
Disease November 2003; Vol 5:558.
(3) Nagetaal I D.Pathology data in the central databases of
multicenter randomized trials needs to be based on pathology reports and
controlled by trained quality managers. Journal of Clinical Oncology,
Vol 18, Issue 8, (April), 2000:1771-1779.
(4) Hewavisenthi SJ De S, Fernando P.Use and interpretation of
phrases in histopathology reports. Ceylon Medical Journal 2005; 1:37-38.
Smellie et al, in their article Best Practice in Primary Care Pathology: Review 3(1) cite our article published in the BMJ in 1994.(2)
Unfortunately they state that this was a study of “people referred from primary care to a hospital lipid clinic” and it wasn’t. Our study was, on the contrary, a review of computerised medical records of a group
of patients with hyperlipidaemia in one general prac...
Smellie et al, in their article Best Practice in Primary Care Pathology: Review 3(1) cite our article published in the BMJ in 1994.(2)
Unfortunately they state that this was a study of “people referred from primary care to a hospital lipid clinic” and it wasn’t. Our study was, on the contrary, a review of computerised medical records of a group
of patients with hyperlipidaemia in one general practice which alone had the 1542 tests described.
The vast majority of people with raised lipids in the United Kingdom are not referred to hospital lipid clinics and the key clinical issue is how they should be best managed and treated in general practice.
Yours faithfully
Philip Evans, Denis Pereira Gray
References
(1) Smellie WSA, Forth J, Bareford D, Twomey P, Galloway MJ, Logan ECM et al. Best practice in primary care pathology: review 3. J Clin
Pathol 2006; 59(8):781-789.
(2) Evans P, Pereira Gray DJ. Value of screening for secondary causes of hyperlipidaemia in general practice. British Medical Journal 1994; 309:509-510.
I read with interest the article by Zhang et al published in the September 2006 issue of the Journal of Clinical Pathology (J Clin Pathol 2006;59:958–964.). The authors wrote on fascin, an actin-binding protein,
as a potential biomarker for early-stage oesophageal squamous cell carcinoma. There are a number of methodological issues with the research and paper that potentially weakens their findings and int...
I read with interest the article by Zhang et al published in the September 2006 issue of the Journal of Clinical Pathology (J Clin Pathol 2006;59:958–964.). The authors wrote on fascin, an actin-binding protein,
as a potential biomarker for early-stage oesophageal squamous cell carcinoma. There are a number of methodological issues with the research and paper that potentially weakens their findings and interpretation.
Firstly, the design of the study is suboptimal. The authors used two different patient groups for different aspects of the work. 102 archival materials from 2001 to 2003 were used for the immunohistochemical staining
and specimens from 49 patients with oesophageal cancer operated upon in 2003 and 2004 were used for the western blot and real-time RT-PCR analyses. However, the results from the two different groups were presented and compared as if from the same study population. Methodologically, it would have been better to use the 2003/2004 patient
cohorts for the whole research.
Immunohistochemical positivity was defined as cells showing >5% cytoplasmic staining in the methodology section. Later in the result section, the authors said they graded positivity as mild, moderate and severe but the readers are not told on what basis this grading was based.
For the RT-PCR analysis, they used beta-actin as the internal control (i.e. house-keeping gene). Given that fascin is an actin binding protein, surely the potential for interaction between the target gene and internal
control gene therefore exists.
Lastly, whilst the authors gave a good description of the statistical analysis carried out, I think they have employed wrong tests to analyse the data. Chi-squared test was used to analyse proportions but given that some of the data items were very small (<10) as presented in Table 2,
Fischer’s exact test would have been more appropriate in those situations. Also, for the continuous data presented in Tables 3 and 4 they used student’s t-test to analyse the data, thereby assuming normality. However, looking more closely at the data, there is a strong suggestion that the
data presented are not normally distributed with standard deviations as high (even higher) than the mean concentrations/levels of fascin (1). This is actually not a surprise, as it is generally known in statistics that
data obtained from ratios or concentrations are usually not normally distributed. Therefore, the authors should either have log transformed (2) their data before using student’s t-test or use a non-parametric test such as Mann-Whitney test for the statistical analysis.
The above methodological and statistical issues call into question the interpretation of the data generated and presented and therefore, weakens the conclusions reached. It would be interesting to hear the authors’ responses to the above points.
Yours truly
Dr Olorunda Rotimi MRCPath, PGDip Health Research
References
1. Altman DG, Bland JM. Detecting skewness from summary information. BMJ 1996;313:1200
2. Bland JM, Altman DG. Transforming data. BMJ 1996;312:770
We read with interest the paper entitled “Rectal adenocarcinoma with oncocytic features: possible relationship with pre-operative chemoradiotherapy” published in the October issue of this journal (1). In this paper 5 cases of rectal carcinomas mainly composed of oncocytic cells are reported. All the five cases underwent radio and chemotherapy before surgery. The Authors suggest t...
We read with interest the paper entitled “Rectal adenocarcinoma with oncocytic features: possible relationship with pre-operative chemoradiotherapy” published in the October issue of this journal (1). In this paper 5 cases of rectal carcinomas mainly composed of oncocytic cells are reported. All the five cases underwent radio and chemotherapy before surgery. The Authors suggest that radio and chemotherapy might be responsible for the oncocytic features observed. In a recent previous study (2) based on 28 cases of advanced rectal carcinomas treated pre-operatively with radio and chemotherapy, according to a protocol similar to that applied in the paper by Rouzbahman et al. (1) we had almost the same results. Oncocytic changes were searched on haematoxylin and eosin and with an immunohistochemical method using an anti-mitochondrial antibody, both on the endoscopic biopsy performed before treatment and on the surgical specimen (after treatment). Oncocytic changes were difficult to find on haematoxylin-eosin stained slides, in pre-treatment biopsies, while immunohistochemistry revealed that
neoplastic cells were rich in mitochondria. Oncocytic changes were very evident on haematoxylin-eosin stained slides in post-treatment specimens. In addition ultrastructural examination performed in two cases confirmed
the oncocytic modifications. Our conclusions were that rectal carcinomas are “mitochondrion rich” tumours that acquire a definite oncocytic phenotype after radio-
chemotherapy. It has been demonstrated that damage to mitochondrial DNA may be responsible for drug resistance (3,4). In addition thyroid carcinomas with oncocytic features are less responsive to radioactive iodine (5).
Recently, a case of oncocytic meningioma with rapid progression after radiosurgery was observed at our Institution (6). All these data support the concept that mitchondrion enrichment might be responsible for resistance to radio and chemotherapy.
Maria P.Foschini, Andrea Ambrosini-Spaltro, Christine M. Betts°.
Section of Pathology, University of Bologna, at Ospedale Bellaria
Bologna (Italy).
°Dept. of Experimental Pathology, University of Bologna, Bologna (Italy).
References:
1. Rouzbahman M, Serra S, Chetty R. Rectal adenocarcinoma with
oncocytic features: possible relationship with pre-operative
chemoradiotherapy. J Clin Pathol 2006;59:1039-1043.
2. Ambrosini-Spaltro A, Salvi F, Betts CM, et al. Oncocytic modifications
in rectal adenocarcinomas after radio and chemotherapy. Virchows Archiv
2006; 448:442-448.
3. Lièvre A, Chaupsot C, Bouvier Am, et al. Clinical value of
mitochondrial mutations in colorectal cencer. J Clin Oncol 2005; 23:3517-
3525.
4. Xu R, Pelicano H, Zhou Y, et al. Inhibition of glycolysis in cancer
cells: a novel strategy to overcome drug resistance associated with
mitochondrial respiratory defect and hypoxia. Cancer Res 2005;665:613-621.
5. Màximo V, Sobrinho-Simoes M. Hurtle cell tumours of thyroid. A review
with emphasis on mitochondrial abnormalities with clinical relevance.
Virchiws Archiv 2000; 437:107-115.
6. Marucci G, Betts CM, Frank G, et al. Oncocytic mengingioma: Description
of a case with progression after radiosurgery. Int J Surg Pathol 2007; in
press.
In the article by Weiss et al. 'No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis' the authors conclude that the absence and/or random distribution of select pathogens (i.e. H pylori and M pneumoniae)
precludes their direct role in the development of atherosclerosis. Given the rather small sample size of this study (36 patients), and the larg...
In the article by Weiss et al. 'No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis' the authors conclude that the absence and/or random distribution of select pathogens (i.e. H pylori and M pneumoniae)
precludes their direct role in the development of atherosclerosis. Given the rather small sample size of this study (36 patients), and the larger collection of data which supports a role for microbial pathogens in atherogenesis this conclusion may be premature. Numerous studies have
isolated H. pylori DNA from atherosclerotic lesions providing an association of this bacterium in atherogenesis (1,2). Furthermore, treatment of H pylori infections has shown to reduce coronary restenosis
in patients after percutanerous transluminal coronary angioplasty (3) suggesting a causal relationship between H. pylori and atherogenesis. Through technological advancement and modification of current PCR methods,
solutions for optimizing sensitivity while maintaining specificity may further our understanding of the relationship of pathogens like H pylori and the development of atherosclerosis (4). Thus, the call for larger
patient group studies adjusting for confounding factors such as age, race, family history of coronary artery disease, cigarette smoking and hypertension are necessary to study the causality relationships that may exist between microbial pathogens and atherogenesis (5).
References
1. Franceschi F, Leo D, Fini L, Santoliquido A, Flore R, Tondi P,
Roccarina D, Nista EC, Cazzato AI, Lupascu A, Pola P, Silveri NG,
Gasbarrini G, Gasbarrini A. Helicobacter pylori infection and ischaemic
heart disease: an overview of the general literature. Dig Liver Dis. 2005:
37(5):301-8.
2. Kowalski M, Pawlik M, Konturek JW, Konturek SJ. Helicobacter
pylori infection in coronary artery disease. J Physiol Pharmacol. 2006; 57
Suppl 3:101-11.
3. Kowalski M. Helicobacter pylori (H. pylori) infection in coronary
artery disease: influence of H. pylori eradication on coronary artery
lumen after percutaneous transluminal coronary angioplasty. The detection
of H. pylori specific DNA in human coronary atherosclerotic plaque. J
Physiol Pharmacol 2001; 52 (Suppl. 1): 3-31.
4. Arias E, Martinetto H, Schultz M, Ameriso S, Rivera S, Lossetti O,
Sevlever G. Seminested polymerase chain reaction (PCR) for detecting
Helicobacter pylori DNA in carotid atheromas. Diagn Mol Pathol. 2006;
15(3):174-9.
5. Gois J, Higuchi M, Reis M, Diament J, Sousa J, Ramires J, Oliveira
S. Infectious Agents, Inflammation, and Growth Factors: How Do They
Interact in the Progression or Stabilization of Mild Human Atherosclerotic
Lesions? Ann Vasc Surg. 2006 Sep 17, published online.
We read with interest the section in this review of duodenal pathology describing AIDS enteropathy. However, the histological description of the lesion by Serra and Jani 1 does not accurately reflect the majority of literature on the subject and the comments regarding pathogenesis are confused.
We read with interest the section in this review of duodenal pathology describing AIDS enteropathy. However, the histological description of the lesion by Serra and Jani 1 does not accurately reflect the majority of literature on the subject and the comments regarding pathogenesis are confused.
The pathogenesis of villous atrophy in the small intestinal mucosa of many patients infected with HIV (HIV enteropathy), and the significance of reduced mucosal absorptive surface area in the aetiology of diarrhoea,
remain controversial in spite of two decades of investigation.2 The bowel is one system which merits further study in AIDS.3 The paper of Serra and Jani describes villous atrophy with crypt hypoproliferation, and yet also details a hyper-regenerative crypt response to villous atrophy mediated by cytokine effects.
Villous atrophy in the small intestine of patients infected with HIV has indeed been associated with both hyperproliferative4-8 and hypoproliferative9-11 activity in crypts. There is also some evidence based on studies of primates infected with Simian Immunodeficiency Virus that a hyperproliferative enteropathy may evolve into a hypoproliferative state later in the course of the disease.12 Furthermore, there is confusion regarding whether changes in crypt cell kinetics are a regenerative response to enterocyte shedding and villous collapse, or whether they cause villous shortening.13 The changes in mucosal structure observed in HIV enteropathy bear some similarities to the lesion of coeliac disease, although severe villous atrophy is seen rarely in HIV-infected patients. Coeliac disease is mediated by a T cell response in the intestinal lamina propria mounted against antigenic gluten peptides.14 A response to damage and loss of villous enterocytes, increased proliferation of crypt epithelial cells induced by local growth factors, mucosal response to luminal nutrients, and increased degradation of the extracellular matrix support of the villous structure all may contribute to the mucosal changes observed in an enteropathy.13 14 It is not clear whether these phenomena are causally linked, and if so, which are primary or secondary events. There is evidence from fetal explant experiments, however, that crypt cell hyperplasia induced by mucosal T cell activation is the primary mucosal response and that this precedes villous atrophy.15 16 More recently we have shown that hyperplasia affects both transit and stem cells of the crypt epithelium in patients infected with HIV.17
A close correlation is present in the small bowel mucosa of patients infected with HIV between crypt hypertrophy and reduced villous surface area. 4 5 This structural relationship in the crypt/villus unit indicates either that crypt elongation encroaches on villous height, or that villous collapse stimulates crypt hyperplasia. Crypt hypertrophy is the mucosal response of human fetal explants to HIV infection, indicating that accelerated crypt kinetics is the driving force in the pathogenesis of
villous atrophy in the intestine of AIDS patients.18 Crypt cell hyperplasia is the primary mucosal lesion in this enteropathy, driving immature enterocytes onto the sides of villi and reducing absorptive villous surface area by shifting the crypt/villus junction in a luminal direction.
The contribution of this pathology to the malabsorption and weight loss these patients suffer is as yet unclear. There is a strong correlation between fat malabsorption and jejunal villous atrophy in HIV positive patients in the absence of enteropathogens. Whilst this tructural-functional relationship in the crypt/villus unit accounts for
diarrhoea and weight loss in some of the patients, it is important to recognise that factors other than enteropathy may be responsible for these symptoms in others, such as exocrine pancreatic insufficiency,19 gut autonomic neuropathy 20 and drug therapy.
References
1. Serra S, Jani P A. An approach to duodenal biopsies. J Clin
Pathol 2006; 59: 1133-1150.
2. Kotler D P, Gaetz H P, Lange M, Klein E B, Holt P R. Enteropathy
associated with the Acquired Immunodeficiency Syndrome. Ann Intern Med
1984; 101: 421 - 428.
3. Levy J A. HIV and the Pathogenesis of AIDS; 2nd Edition, Preface.
1998. ASM Press.
4. Batman P A, Miller A R O, Forster S M, Harris J R W, Pinching A J,
Griffin G E. Jejunal enteropathy associated with human immunodeficiency
virus infection: quantitative histology. Journal of Clinical Pathology
1989; 42: 275 - 281.
5. Batman P A, Kapembwa M S, Miller A R O, et al. HIV Enteropathy:
Comparative Morphometry of the Jejunal Mucosa of HIV infected patients
resident in the United Kingdom and Uganda. Gut 1998; 43: 350 – 355.
6. Kotler D P, Francisco A, Clayton F, Scholes J V, Orenstein J M. Small
intestinal injury and parasitic diseases in AIDS. Ann Intern Med 1990;
113: 444 - 449.
7. Greenson J K, Belitsos P C, Yardley J H, Bartlett J G. AIDS
enteropathy: occult enteric infections and duodenal mucosal alterations in
chronic diarrhoea. Ann Intern Med 1991; 114: 366 - 372.
8. Heise C, Dandekar S, Kumar P, Duplantier R, Donovan R M, Halsted C H.
Human immunodeficiency virus infection of enterocytes and mononuclear
cells in human jejunal mucosa. Gastroenterology 1991; 100: 1521 - 1527.
9. Ullrich R, Zeitz M, Heise W, L'age M, Höffken G, Riecken E O. Small
intestinal structure and function in patients infected with Human
Immunodeficiency Virus (HIV): Evidence for HIV-induced enteropathy. Ann
Intern Med 1989; 111: 15 - 21.
10. Anonymous. HIV-Associated Enteropathy. Lancet 1989; 2: 777 – 778.
11. Ullrich R, Riecken E O, Zeitz M. HIV-Induced Enteropathy. Immunol Res
1991; 10: 456 – 464.
12. Zeitz M, Ullrich R, Schneider T, Kewenig S, Hohloch K, Riecken E O.
HIV/SIV Enteropathy. Ann NY Acad Sci 1998; 859: 139 – 148.
13. Wong W M, Wright N A. Cell Proliferation in Gastrointestinal Mucosa. J
Clin Pathol 1999; 52: 321 – 333.
14. Sollid L M. Molecular Basis of Coeliac Disease. Annu Rev Immunol 2000;
18: 53 – 81.
15. MacDonald T T, Spencer J. Evidence that activated mucosal T cells play
a role in the pathogenesis of enteropathy in human small intestine. J Exp
Med 1988; 167: 1341 - 1349.
16. Ferreira R da C, Forsyth L E, Richman P I, Wells C, Spencer J,
MacDonald T T. Changes in the rate of crypt epithelial cell proliferation
and mucosal morphology induced by a T-cell-mediated response in human
small intestine. Gastroenterology 1990; 98: 1255 - 1263.
17. Batman P A, Kotler D P, Kapembwa M S, Booth D, Potten C S, Orenstein J
M, Scally A J, Griffin G E.
HIV Enteropathy: Crypt stem and transit cell hyperproliferation induces
villous atrophy in HIV/Microsporidia-infected jejunal mucosa. AIDS; in
press.
18. Batman P A, Fleming S C, Sedgwick P M, MacDonald T T, Griffin G E. HIV
infection of human foetal intestinal explant cultures induces epithelial
cell proliferation. AIDS 1994; 8: 161 – 167.
19 Kapembwa M.S, Fleming S.C, Griffin G.E, Caun K, Pinching A.J, Harris
J.R.W.
Fat absorption and exocrine pancreatic function in human
immunodeficiency virus infection. Quarterly Journal of Medicine 1990; 273:
49 – 56.
20 Batman P A, Miller A.R.O, Sedgwick M.P, Griffin G.E.G. Autonomic
denervation in jejunal mucosa of homosexual men infected with HIV. AIDS
1991; 5:1247 – 1252.
P A Batman, MD FRCPath, Consultant Histopathologist, Bradford
Teaching Hospitals Foundation Trust, UK
M S Kapembwa, PhD FRCP, Consultant Physician, Northwick Park Hospital, UK
This interesting paper raises important points regarding the staging of renal carcinomas using the TNM classification of malignant tumours (2). In particular, one of the take-home messages was the need for further
clarification of the type of vessel that must be invaded for tumours to be staged as pT3b. In fact, clarifications regarding the staging system for renal tumours had been sought from the TNM com...
This interesting paper raises important points regarding the staging of renal carcinomas using the TNM classification of malignant tumours (2). In particular, one of the take-home messages was the need for further
clarification of the type of vessel that must be invaded for tumours to be staged as pT3b. In fact, clarifications regarding the staging system for renal tumours had been sought from the TNM committee (personal communications, LH Sobin) during the revision of the Royal College of
Pathologists Dataset for Reporting Adult Renal Parenchymal Tumours, and are worth re-emphasising here.
As far as TNM staging is concerned, renal vein invasion only upstages the tumour to pT3b if it is seen macroscopically. The 6th edition (2) is more explicit in the definition of the renal vein(s) by making reference
to the inclusion of the larger calibre tributaries. The statement that the walls of these tributaries contain smooth muscle, an observation that is largely microscopic, further defines the relevant vessels but does not imply that microscopic identification is sufficient. The need for a
careful macroscopic examination is inherent to the TNM system and this requirement for staging purposes has recently been stressed (3). Drs Soilleux and Roberts (1) highlight the fact that, with experience and diligence, most of the cases of renal sinus vein invasion in their series
were visible macroscopically. In that case, the 47.7% increase in the percentage of tumours staged as pT3b is probably real. However, they state that, as per protocol, further blocks were taken if the initial sections of the renal sinus failed to reveal vascular invasion. This is
not necessary for staging purposes as microvascular invasion identified by random sampling does not upstage a tumour, although it may be of prognostic significance (4). Elsewhere (3), it has been suggested that microvascular invasion in perinephric tissues could upstage a tumour to pT3a. However, such upstaging only occurs in the TNM system if there is direct invasion of perinephric tissues. The reference to renal sinus fat as perinephric tissue in the 6th edition (2) was not a change in the definition of perinephric tissues but a clarification of what these
include. Histological identification of invasion of vessels in perinephric tissues or elsewhere can be recorded using the optional TNM categories for lymphatic or vascular invasion (2).
As the authors mention, whether it makes biological sense to insist on macroscopic renal vein invasion for staging purposes is unclear, although, intuitively, the presence of grossly visible tumour thrombus
would suggest a more aggressive tumour. The problem is that the TNM system does not have an evidence base that can be examined and either disputed or confirmed. It has historically been the result of consensus, rather than systematic evidence review, and modifications, including a
literature watch, were only introduced after the last edition, with the aim of continuously improving the system (5). This will hopefully result in more transparency and better prognostication.
References:
1. Soilleux EJ, Roberts IS. Assessment of the Cardiff nephrectomy cut-up protocol with total blocking of the renal sinus: effect on tumour staging and practical issues. J Clin Pathol 2006;59:1209-11.
2. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours., 6th edition. New York: Wiley-Liss, 2002.
3. Fleming S, Griffiths DF. Best Practice No 180. Nephrectomy for renal tumour; dissection guide and dataset. J Clin Pathol 2005;58:7-14.
4. Sorbellini M, Kattan MW, Snyder ME, et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol 2005;173:48-51.
5. Gospodarowicz MK, Miller D, Groome PA, et al. The process for continuous improvement of the TNM classification. Cancer 2004;100:1-5.
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This interesting paper raises important points regarding the staging of renal carcinomas using the TNM classification of malignant tumours (2). In particular, one of the take-home messages was the need for further clarification of the type of vessel that must be invaded for tumours to be staged as pT3b. In fact, clarifications regarding the staging system for renal tumours had been sought from the TNM com...
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