To the Editor:
Without doubt the hospital-based autopsy is an effective quality assurance
and learning tool. The study by Kuijpers et al. supports this.[1] However,
autopsy is a time-consuming and expensive procedure which may sometimes
cause distress to the deceased patient's family and be associated with
complex consent issues. It is therefore important to ask how far reaching,
beyond the pathologist and the referring cli...
To the Editor:
Without doubt the hospital-based autopsy is an effective quality assurance
and learning tool. The study by Kuijpers et al. supports this.[1] However,
autopsy is a time-consuming and expensive procedure which may sometimes
cause distress to the deceased patient's family and be associated with
complex consent issues. It is therefore important to ask how far reaching,
beyond the pathologist and the referring clinician, is the learning impact
of each individual autopsy?
The clinician requesting the autopsy is interested in the bullet-
point preliminary summary (based on the macroscopic findings) that is
signed out immediately. But how often is the final detailed multi-page
report followed up? Autopsies and the associated laboratory tissue-
processing usually do not take priority in a busy diagnostic department.
Final reports may not be verified for some time after the procedure,
decreasing their learning impact.
Frequency of minor diagnostic errors, as measured by the autopsy gold
standard, is increasing over time.[1] Improper use of imaging
investigations is contributing significantly to incorrect pre-mortem
diagnosis.[1] Could it be that the main problem is that there has been a
huge increase in the number of diagnostic investigations that can be
requested during life? More investigations at our fingertips do not
necessarily make things better for the doctor, or for the patient.[1] How
do we learn how to optimally use these investigations to avoid
misdiagnosis or alternatively to optimally learn from the inappropriate
use of past investigations, so that errors are not repeated?
Some of the current issues with use of diagnostic investigations are
as follows:
1. Understanding the tests:
a. Wrong test selected for the situation - whether it be imaging or
diagnostic pathology. This results in false positives or false negatives;
b. Sensitivity, specificity and positive/negative predictive value - these
parameters of a particular imaging modality or pathology test may not be
appreciated. Acting on the false result whether it is negative or positive
may have significant detrimental clinical impact;
c. With complex histopathology or imaging investigations, are the nuances
in the body of the report skipped or overlooked by the treating clinician?
2. Communication:
a. With immensely busy clinical loads, how often is the suitability of the
investigation or the unexpected final result discussed with the
radiologist or pathologist? In other words, how often do we practice in a
vacuum because of time constraints?
3. Clinico-pathological and radio-pathological correlation:
a. Were the radiologist or pathologist given any clinical information, and
if not did they seek such information before reporting?
Obviously selection and interpretation of diagnostic tests is often
not clear-cut in the real world. Furthermore, with increasing numbers and
complexity of diagnostic tests come increasing workloads for pathologists
and radiologists. There is increased expectation from both patients and
referring clinicians. Faced sometimes with extraordinary numbers of cases
to report each day, the pathologist may fail to look for or may miss a
vital component of the history that was provided to them by the
radiologist or clinician. This is easy to do in an electronic era where
most reports and referrals are scanned and it takes time to search. There
will also always be cases where only a proportion of slides or images were
viewed before issuing a report. Errors are part of the human condition.
The key is to learn from errors and to not repeat them.
In summary, autopsy has always been an excellent tool for quality
assessment in diagnostic accuracy. But is it a teaching and quality
assurance procedure that is time and cost-effective, with results that are
easy to disseminate with maximum learning benefit? Focus on development
and delivery of high impact and time-efficient continuing education
modules (particularly online) regarding quality assurance errors and
diagnostic and investigative medicine has already been demonstrated to be
of value,[2] so such modules may represent an alternative solution to
these issues.
References
1. Kuijpers C.C.H.J., Fronczek J., van de Goot F.R.W., et al. J Clin
Pathol 2014;67:512-519 doi:10.1136/jclinpath-2013-202122
2. Ritchie A., Jureidini E. and Kumar R.K. Educating Junior Doctors to
Reduce Requests for Laboratory Investigations: Opportunities and
Challenges. Med.Sci.Educ. 2014;24:161-163 DOI 10.1007/s40670-014-0041-2
We read with interest the report on postulated atorvastatin
induced lactic acidosis [1]. In our view, the arguments outlined by its
authors do not support this hypothesis at all, for the reasons outlined
below:
a) The patient clearly had a mixed acid-base disturbance (combined
respiratory alkalosis and metabolic acidosis, as evidenced by the normal
pH of 7.39 coupled with severe hypocapnia)....
We read with interest the report on postulated atorvastatin
induced lactic acidosis [1]. In our view, the arguments outlined by its
authors do not support this hypothesis at all, for the reasons outlined
below:
a) The patient clearly had a mixed acid-base disturbance (combined
respiratory alkalosis and metabolic acidosis, as evidenced by the normal
pH of 7.39 coupled with severe hypocapnia).
b) Both the delta anion gap (24.2 –16= 8 mEq/L) and the decrease in
standard base excess (which we use in preference to whole blood base
excess and calculate to be -17.9 mEq/L) are much larger than the delta
lactate, which is only approximately 1.5 mmol/L. This clearly indicates
that the metabolic acidosis is multifactorial, and that another
pathological process rather than hyperlactaemia is the major contributor
to the raised anion gap. This should lead to a search for other causes of
a raised anion gap. For example, one would need to measure serum
salicylates, the osmolar gap and plasma beta-hydroxybutyrate. With
concerns of statin myopathy, a serum CK would be useful. With a history of
paracetamol ingestion, pyroglutamic acidosis is a likely possibility and
could be diagnosed using a urinary organic acid screen [2].
c) The authors’ discussion of potential causes of an elevated plasma
lactate concentration is incomplete. For example, they have failed to
discuss the possible contribution of salbutamol to the hyperlactaemia.
Furthermore, covert tissue hypoxia is a possibility despite normal
arterial oxygenation, which can lead to hyperlactaemia.
d) If it were to be a mitochondrial paralysis from statin therapy, it
is hard to imagine an immediate clinical improvement upon cessation of the
medication.
Other significant and fundamental errors in the report detract from
its validity. They include the following:
a) The [HCO3-] is said to be 13.8 mmol/L, whereas at the quoted pH (7.39)
and PCO2 (1.2 kPa) it would be much lower at 5.3 mmol/L.
b) The quoted PO2 of 19.3 kPa on room air implies a negative A-a gradient
of nearly 1 kPa. This is clearly impossible in any patient, let alone an
82 year old woman. Presumably supplemental oxygen was being administered.
c) The mention of unmeasured cations instead of anions in the abstract when
discussing a raised anion gap is a cause for confusion.
We recognise that simvastatin has been reported to induce lactic
acidosis through mitochondrial failure [3]. However, this report describes
a mixed acid-base disorder not primarily due to lactate. Hence, the
authors cannot claim that it adds to the body of evidence supporting the
link between statin therapy and lactic acidosis.
(2) Dempsey GA, Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamic acidemia:
a cause of high anion gap metabolic acidosis. Crit Care Med
2000;28(6):1803-7.
(3) Goli AK, Goli SA, Byrd RP, Jr., Roy TM. Simvastatin-induced lactic
acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002;72(4):461-4.
Accurate histological grading of invasive carcinoma of the breast in
needle core biopsies is important for patient management, for example for
selecting patients for neoadjuvant chemotherapy. The grade in the core
biopsy tends to underestimate the grade in the excision specimen,
particularly due to underestimation of the mitotic count. We recently
proposed a reduction in the threshold for the mitotic count which we found...
Accurate histological grading of invasive carcinoma of the breast in
needle core biopsies is important for patient management, for example for
selecting patients for neoadjuvant chemotherapy. The grade in the core
biopsy tends to underestimate the grade in the excision specimen,
particularly due to underestimation of the mitotic count. We recently
proposed a reduction in the threshold for the mitotic count which we found
of particular value in tumours scored as T3, P3, M1 (less than 10%
tubules, marked nuclear pleomorphism and few mitoses) and therefore grade
2 on the core biopsy.(1,2)
Dhaliwal et al tested this approach in a 359 core biopsies in
Edinburgh and found it to be of no value either in the whole series or in
the T3, P3, M1 subset.(3) The two series of tumours show important
differences. The histological grade of the Edinburgh carcinomas was on
average lower: 27% of carcinomas were grade 3 in the surgical specimen
compared with 40% in our series from Nottingham. Potential explanations
for this difference include the high number of Edinburgh patients excluded
because they received neoadjuvant chemotherapy (22% in Edinburgh compared
with 4% in the older Nottingham series). Such patients often have grade 3
tumours. In addition the majority of Edinburgh cancers (58%) were detected
by screening (such tumours tend to be of lower grade than symptomatic
cancers as shown in tables 2 and 3 of the Edinburgh paper). Breast cancer
resections in Nottingham are received fresh in the laboratory and incised
immediately to ensure good fixation, which is important for accurate
assessment of grade. Poorly fixed specimens tend to have lower grade
including lower mitotic count. Were the specimens immediately incised in
Edinburgh? Finally it is not clear why only tumours that were excised with
breast conserving surgery were included.
Dhaliwal achieved 79% agreement between grade in the core biopsy and
the surgical specimen. As they state this is at the upper end of the range
reported in the literature. The mitotic counts were assessed by two
observers retrospectively and if there was a discordance with the original
report the biopsy was reassessed. In the Nottingham study the core grade
was assessed prospectively and independently by 5 different observers.
Double reporting as performed in Edinburgh may improve the assessment of
grade. The lower proportion of grade 3 tumours in Edinburgh reduces the
potential impact of undergrading on the core biopsy.
The Edinburgh study does not disprove the potential value of reducing
the mitotic threshold as their series is selective with a low proportion
of grade 3 tumours. Further studies including a good proportion of grade 3
tumours are needed to test whether reducing the mitotic threshold in the
core biopsy is of value in assessing histological grade.
1. O'Shea AM, Rakha EA, Hodi Z, Ellis IO, Lee AHS. Histological grade
of invasive carcinoma of the breast assessed on needle core biopsy -
modifications to mitotic count assessment to improve agreement with
surgical specimen. Histopathology 2011;59:543-548
2. Lee AHS, Rakha EA, Hodi Z, Ellis IO. Re-audit of revised method for
assessing the mitotic component of histological grade in needle core
biopsies of invasive carcinoma of the breast. (Letter) Histopathology
2012;60:1166-1167
3. Dhaliwal CA, Graham C, Loane J. Grade of breast cancer in needle core
biopsy: does a reduction in mitotic count threshold improve agreement with
grade on excised specimens? J Clin Pathol 2014;67:1106-1108
When a patient has an infection, doctors often send a
sample of infected blood or tissue to a lab where
they can grow the bacteria and see which antibiotics
are most effective (called Bacterial Culture and
Sensitivity Testing). Chemosensitivity testing is an
attempt to do something similar for cancer; fresh
samples of the patient's tumor from surgery or a
biopsy are grown in test tubes and tested wit...
When a patient has an infection, doctors often send a
sample of infected blood or tissue to a lab where
they can grow the bacteria and see which antibiotics
are most effective (called Bacterial Culture and
Sensitivity Testing). Chemosensitivity testing is an
attempt to do something similar for cancer; fresh
samples of the patient's tumor from surgery or a
biopsy are grown in test tubes and tested with
various drugs. Drugs that are most effective in
killing the cultured cells are recommended for
treatment. It is highly desirable to know what drugs
are effective against your particular cancer cells
before highly-toxic agents are systemically
administered to your body.
One approach to individualizing patient therapy is
chemosensitivity testing. Chemosensitivity assay is a
laboratory test that determines how effective
specific chemotherapy agents are against an
individual patient's cancer cells. Often, results are
obtained before the patient begins treatment. This
kind of testing can assist in individualizing cancer
therapy by providing information about the likely
response of an individual patient's tumor to proposed
therapy. Chemosensitivity testing may have utility at
the time of initial therapy, and in instances of
severe drug hypersensitivity, failed therapy,
recurrent disease, and metastatic disease, by
providing assistance in selecting optimal
chemotherapy regimens.
All available chemosensitivity assays are able to
report drug "resistance" information. Resistance
implies that when a patient's cancer cells are
exposed to a particular chemotherapy agent in the
laboratory, the cancer cells will continue to live
and grow. Some chemosensitivity assays also are able
to report drug "sensitivity" information. Sensitivity
implies that when a patient's cancer cells are
treated with a particular chemotherapy agent in the
laboratory, that agent will kill the cancer cells or
inhibit their proliferation.
The goal of all chemosensitivity tests is to
determine the response of a patient's cancer cells to
proposed chemotherapy agents. Knowing which
chemotherapy agents the patient's cancer cells are
resistant to is important. Then, these options can be
eliminated, thereby avoiding the toxicity of
ineffective agents. In addition, some
chemosensitivity assays predict tumor cell
sensitivity, or which agent would be most effective.
Choosing the most effective agent can help patients
to avoid the physical, emotional, and financial costs
of failed therapy and experience an increased quality
of life.
Fresh samples of the patient's tumor from surgery or
a biopsy are grown in test tubes and tested with
various drugs. Drugs that are most effective in
killing the cultured cells are recommended for
treatment. Chemosensitivity testing does have
predictive value, especially in predicting
what "won't" work. Patients who have been through
several chemotherapy regimens and are running out of
options might want to consider chemosensitivity
testing. It might help you find the best option or
save you from fruitless additional treatment. Today,
chemosensitivity testing has progressed to the point
where it is 85% - 90% effective.
Chemosensitivity testing might help you find the best
option, or save you from fruitless additional
treatment. Another situation where chemosensitivity
testing might make particularly good sense is in rare
cancers where there may not be enough experience or
previous ideas of which drugs might be most
effective.
Finally, there has been a veritable deluge of new
approvals of cytotoxic drugs in recent years as the
tortuous FDA process has been speeded and
liberalized. In many cases a new drug has been
approved on the basis of a single very very narrow
indication. But these drugs may have many useful
applications - and it's going to take years to find
out. Chemosensitivity testing offers a way of seeing
if any of these new drugs might apply to your
specific cancer.
We are happy to address the points raised by Lee et al in their
commentary on our paper [1] and thank them for their interest in it.
Lee et al correctly note that our re-assessment was of the mitotic
count in these specimens. To clarify, these were carried out by either of
two observers (CAD, JL) blinded to the original core and excision grading.
The other elements of the tumour grade...
We are happy to address the points raised by Lee et al in their
commentary on our paper [1] and thank them for their interest in it.
Lee et al correctly note that our re-assessment was of the mitotic
count in these specimens. To clarify, these were carried out by either of
two observers (CAD, JL) blinded to the original core and excision grading.
The other elements of the tumour grade (tubule formation and nuclear
score) were not re-assessed, but were as per the original report, that is
to say, as reported prospectively by the original reporting pathologist.
Similar to Nottingham, in Edinburgh five pathologists with a specialist or
subspecialist interest in breast pathology were involved in reporting
these cases. The mitotic counts of cases in which our count on review
would have assigned the case to a different mitotic score (M) category
were reviewed jointly by both authors and a consensus count agreed. These
represented just 7% of our cases. It is thus very unlikely that this had
any significant effect on the assessment of grade between core and
excision.
Edinburgh is one of the largest breast cancer centres in the UK. We
follow the NHSBSP guidelines in our handling of specimens and are aware of
the potential difficulties of poor fixation. We do not however have this
problem, as evidenced by the grade distribution of tumours in our
department which is comparable to other centres on national audit.[2]
Lee's main concerns however appear to be that our series is selective
(presumably relating to our inclusion of breast conserving surgery tumours
only) and the low proportion of grade 3 tumours (on excision) in our
series, suggesting it would lower the potential impact of undergrading on
core biopsy.
We did not include tumours treated by mastectomy principally because
the majority of these (117/170) would have been excluded on the basis of
multifocal disease (56), having received neoadjuvant chemotherapy /
systemic therapy (31), having a past history of breast cancer (20) or
having had their core biopsy performed in another hospital and not
available for review (10). Had the remaining 53 cases been included they
would not have made a material difference to the outcome or conclusions of
our study and they would only have increased our proportion of grade 3
cancers to 29% (120/412).
More importantly in relation to the potential impact of the
proportion of grade 3 tumours in our series Lee at al fail to note that of
our symptomatic cases 48% (72/150) were grade 3 on excision. Neither the
whole symptomatic group nor the subset of 41 cases scored as (T3, N3, M1)
within it showed benefit from application of the modification of the
mitotic scores. Of the (T3, N3, M1) subset 14 would have been
reclassified as grade 3* on core biopsy, only 6 of which were grade 3 on
excision. As for all other subsets, in our experience there is a marginal
increase in the sensitivity counterbalanced by a larger reduction in the
specificity of cases designated as grade 3 on core biopsy using the
modified scores.
Finally, we do not seek to disprove the findings of Lee's group.
They have shown their utility in their own population.[3] We demonstrate
that they do not work in ours. Our conclusion remains that the current
recommended mitotic count thresholds are appropriate and should be
maintained. We agree that further studies could contribute to the debate,
but note that the treatment of the breast cancer population is changing to
include more cases receiving neoadjuvant therapy which may make repetition
more difficult.
References:
1. Dhaliwal CA, Graham, C, Loane J. Grading of breast cancer on
needle core biopsy; does a reduction in mitotic count threshold improve
agreement with grade on excised specimens? J Clin Pathol 2014; 67:1106-8
2. NHS breast screening programme and Association of Breast Surgery:
An audit of screen detected cancers for the year of screening April 2012
to March 2013; Public Health England, May 2014.
3. Lee A, Rakha E, Hodi Z et al. Re-audit of revised method for
assessing the mitotic component of the histological grade in needle core
biopsies of invasive carcinoma of the breast. Histopathology 2012; 60:
1166-7
We read with interest the recent article by Alikhan et al , in which
they reviewed necropsy reports to find out the number of deaths due to
fatal pulmonary embolism in hospitalised patients.[1] There seem to be a
number of confusions in this paper.
1. Acute infection was the most common medical illness found in
patients who had died from pulmonary embolism, in particular respiratory
in...
We read with interest the recent article by Alikhan et al , in which
they reviewed necropsy reports to find out the number of deaths due to
fatal pulmonary embolism in hospitalised patients.[1] There seem to be a
number of confusions in this paper.
1. Acute infection was the most common medical illness found in
patients who had died from pulmonary embolism, in particular respiratory
infections. The authors state that the pathophysiology of venous
thromboembolism in the presence of acute infection remains to be fully
defined and then quote recent evidence that respiratory viruses are
capable of infecting endothelial cells and causing a shift from anti-
coagulant to pro-coagulant activity.[2] Such a proposed mechanism would
presumably increase the likelihood of pulmonary thrombosis, not
thromboembolism from deep venous thromboses.
2. The authors recognise that without denominator numbers for the
surgical and medical patient groups, no interpretation is possible
regarding the actual incidence of fatal pulmonary embolism. However, they
themselves then go on to make a number of comparisons between surgical and
“non-surgical” groups.
3. Pulmonary emboli were recorded as the cause of death when the
necropsy report stated that embolism was the main or contributing cause of
death. Many things get written down as contributing towards death, as any
pathologist knows. The authors also state that it is difficult to
distinguish between fatal, contributory, and incidental emboli when the
definitions and interpretations are based on pathologists’ opinions over a
long time period. One obvious way to address this difficulty would be for
the authors to ask a pathologist to help them interpret the necropsy
reports.
References
1. Alikhan R, Peters F, Wilmott R, et al. Fatal pulmonary emboli
in hospitalised patients: a necropsy review. J Clin Pathol 2004;57:1254-7.
2. Visseren FL, Bouwman JJ, Bouter KP, et al. Procoagulant
activity of endothelial cells after infection with respiratory viruses.
Thromb Haemost 2000;84:319-24.
I read this article with interest. I totally agree with the authors'
statement that many requests for HFE mutation analysis are frequently
ordered in the community without measuring serum iron and transferrin
saturation (T-sat) first. While this report is intriguing, I am very much
interested to know if the samples for serum iron and T-sat in this study
were fasting samples or postprandial samples. The diet rich in iron...
I read this article with interest. I totally agree with the authors'
statement that many requests for HFE mutation analysis are frequently
ordered in the community without measuring serum iron and transferrin
saturation (T-sat) first. While this report is intriguing, I am very much
interested to know if the samples for serum iron and T-sat in this study
were fasting samples or postprandial samples. The diet rich in iron can
obviously increase the T-sat. Medications such as vitamin C, dietary
supplement containing iron, multivitamins with iron and oral contraceptive
pills (OCPs) and can increase the T-sat [1,2]. Another point to consider
is that about half of the adults in the western countries take vitamins
and other dietary supplements regularly and about three to three quarter
million women in Britain take OCPs [3,4]. This means the results of the
serum iron and T-sat obtained in the daily clinical practice can highly be
influenced by the iron-rich diet, vitamins, dietary supplements and OCPs.
I wonder how many patients in this current study are on those medications
and how many samples were drawn postprandially. Provided those patients
were excluded from this study, the actual number of the patients with T-
sat > 50% would be decreased. This translates to further saving of
money from unnecessary testing of HFE mutation analysis. Referring
physicians should submit fasting blood samples for serum iron and T-sat.
Patients who are on above-mentioned medications should avoid their
medications for at least 24 hours prior to the fasting blood draw [2].
Thein H. Oo, MD
References:
1. Transferrin saturation test.
http://www.cdc.gov/ncbddd/hemochromatosis/training/diagnostic_testing/testing_protocol.html
Accessed May 8, 2015
2. Transferrin saturation.
http://emedicine.medscape.com/article/2087960-overview Accessed May 8,
2015
3. Vitamins: How many Americans use them?
http://www.huffingtonpost.com/2011/04/13/vitamin-use_n_848777.html
Accessed May 8, 2015.
4. Contraception: patterns of use fact use.
http://www.fpa.org.uk/factsheets/contraception-patterns-use Accessed May
8, 2015
The paper by Turnbull and colleagues (1) on the decline of the adult
hospital autopsy rate in UK prompted me to review and extend the Norwich
data that they kindly quoted (2). I calculated the adult hospital autopsy
rate since our publication (including that relating to the first five
months of this year) using the method that we both employed. The modest
improvement that we reported in the adult hospital autopsy rate i...
The paper by Turnbull and colleagues (1) on the decline of the adult
hospital autopsy rate in UK prompted me to review and extend the Norwich
data that they kindly quoted (2). I calculated the adult hospital autopsy
rate since our publication (including that relating to the first five
months of this year) using the method that we both employed. The modest
improvement that we reported in the adult hospital autopsy rate in Norwich
between 2003 and 2005 was not subsequently sustained and the overall trend
continued downward. During the period since 1 January 2006, the mean
adult hospital autopsy rate in Norwich was 1.1% (range 0.1%-1.7%). The
rate in 2013 was 0.6%, in line with the data presented by Turnbull et al.
(1).
During 2006-2014, there has been a rising trend here in the annual
number of autopsies undertaken for HM Coroner (mean 1191; range 1037-
1355). Most such cases represented deaths in the community or in the A&E
Department, but some were patients who died in the wards after admission.
In such cases the attending clinicians were unable to complete a
certificate of the cause of death. While some such cases followed trauma
or other unnatural events, many were natural deaths in which the clinical
course was difficult to understand, sometimes despite detailed examination
and testing; no confident diagnostic label was attached before death.
Such Coroner's cases arising from within the hospital patient population
represent medicolegal quasi-hospital autopsies and provide a partial means
of alleviating the decline in consented adult hospital autopsies. It is
my experience that many such cases provide valuable opportunities to study
disease and the efficacy of diagnosis and treatment in the hospital
setting.
The continuing decline of the adult hospital autopsy is of great
concern. It is likely to multifactorial and to be influenced by the
attitudes of clinicians, pathologists and bereaved families (3,4). It
does have important implications for clinical audit, diagnostics and
medical education (3). While such matters can, at least in part, be
addressed by the coronial autopsies that are undertaken on certain
hospital deaths, such cases are relatively few and do not necessarily
reflect the normal population of patients who die in hospital; they are
likely to provide a skewed experience. We know little about the numbers
of such cases or what stimulates a clinician to discuss a seemingly
natural death with the Coroner, rather than to use clinical judgement and
suggest the most likely cause of death and complete a death certificate.
It may be that clinicians wish to have a greater degree of certainty than
such an approach allows.
While medicolegal quasi-hospital autopsies are an imperfect
substitute for properly conducted hospital autopsies, they are better than
nothing and should, perhaps, be considered when assessing adult hospital
autopsy rates. The whole matter clearly requires further research.
Autopsy practice in general is threatened by the decline in the numbers of
histopathologists who are prepared to undertake any such examinations.
That itself is a matter of concern and requires deeper understanding and
rectification. It chimes with Byard's view that the decline in the autopsy
is, at least in part, the responsibility of histopathologists (4).
References
1. Turnbull A, Osborn M, Nicholas N. Hospital autopsy: Endangered or
extinct? J Clin Pathol Published Online First: [15 06 2015]
doi:10.1136/jclinpath-2014-202700
2. Limacher E, Carr U, Bowker L, et al. Reversing the slow death of
the clinical necropsy: developing the post of the Pathology Liaison Nurse.
J Clin Pathol 2007; 60:1129-34.
3. Carr U, Bowker L, Ball RY. The slow death of the clinical post-
mortem examination: implications for clinical audit, diagnostics and
medical education. Clin Med 2004; 4:417-23.
4. Byard RW. Who's killing the autopsy? A new tool for assessing the
causes of falling autopsy rates. Med J Aust 2005; 183:654-5.
In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.
As described, dyspnoea had been present and worsening for 6 weeks. The blood gas results cited were from 5 days after the date of hospital admission but were not significantly different from gases taken on 2 earlier occasions during the admission. The results cited were the ones tha...
In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.
As described, dyspnoea had been present and worsening for 6 weeks. The blood gas results cited were from 5 days after the date of hospital admission but were not significantly different from gases taken on 2 earlier occasions during the admission. The results cited were the ones that lead to consideration of the possibility that the statin was the culprit. We regarded the mixed acid-base disturbance as a metabolic acidosis compensated by respiratory alkalosis.
We would agree that there were other unmeasured components in the acidosis but can exclude the suggested salicylate and paracetamol on the basis of the six weeks preceding medical history and the five days known medication intake, by virtue of the in-patient stay. Beta-hydroxy-butyrate assay was not available but we agree this may have contributed. CK on admission was 99 U/L (ref range 0-160 U/L).
The patient was receiving nebulised salbutamol 5mg qds. This was continued after discontinuation of the statin, at which time the acidosis resolved. Salbutamol may of course have been a third element contributing to the acidosis.
Immediate is a relative term. Symptomatic relief began on the day after the first missed dose. However, Atorvastatin has a long half life and a blood gas taken 6 days after statin cessation was pH 7.44, pCO2 3.9kPa, pO2 10.8 kPa, HCO3 22.3 mmol/L, base excess –3.9 mmol/L; indicating near complete normalisation of results.
The blood gas analyser output for the sample indicates that HCO3(s) was 13.8 mmol/L as correctly stated in the report; tCO2 however was 5.7 mmol/L, which is consistent with Dr Kruger's estimate.
The inspired pO2 recorded for the blood gas sample reported is 21%. However, this is also the default in the event of a non-entry so we concur that supplemental oxygen was probably in use at the time of sampling.
Finally, we would like to point out that we did not specifically suggest that we were adding to the body of evidence linking statins to lactic acidosis; we suggested that the combination of statin with thiamine deficiency may be important; i.e. the proximate cause of the acidosis was the thiamine deficiency but the symptomatic presentation was precipitated by the statin. On this point, it is significant that after some months of thiamine therapy (and after publication of the report), the patient was restarted on Atorvastatin because of new ischaemic vascular symptoms with no recurrence of acidosis. We therefore conclude that the combination of the two factors was critical.
Rewriting "Little Red Riding Hood" story may be dangerous
Maria Cecilia Mengoli,1 Giuseppe Bogina,2 Alberto Cavazza, 3 Giulio
Rossi 1
1Section of Pathology, Azienda Ospedaliero-Universitaria Policlinico,
Modena, Italy
2Section of Pathologic Anatomy, Hospital "Don Calabria", Negrar, Verona,
Italy
3Department of Oncology and Advanced Technologies, Operative Unit of
Oncology, Arcispedale S. Maria Nuova /...
Rewriting "Little Red Riding Hood" story may be dangerous
Maria Cecilia Mengoli,1 Giuseppe Bogina,2 Alberto Cavazza, 3 Giulio
Rossi 1
1Section of Pathology, Azienda Ospedaliero-Universitaria Policlinico,
Modena, Italy
2Section of Pathologic Anatomy, Hospital "Don Calabria", Negrar, Verona,
Italy
3Department of Oncology and Advanced Technologies, Operative Unit of
Oncology, Arcispedale S. Maria Nuova / I.R.C.C.S., Reggio Emilia, Italy
Corresponding author:
Giulio Rossi, MD
Section of Pathology, Azienda Ospedaliero-Universitaria Policlinico
Via del Pozzo, 71 - 41124 Modena (Italy)
Telephone: +39.059.4223890; Fax: +39.059.4224998;
Email: giurossi68@gmail.com
To the Editor:
We greatly appreciated the work by Klebe et al1 on the different
results of TTF-1 expression in lung and pleural neoplasms using different
clones, namely 8G7G3/1 and SP141. The authors reported TTF1 expression
with clone SP141 in normal bronchial mucosa, in about half of squamous
cell carcinomas and in 42% of sarcomatoid pleural mesotheliomas. By
contrast, no expression was noted with 8G7G3/1 in the same tissues.
We recently shared the same experience when clone SP141 momentarily
substituted 8G7G3/1 in our Lab. In addition, several colleagues sent us in
consultation cases of morphologically-overt squamous cell carcinomas
expressing p63 or p40 as well as strong TTF-1 positivity, TTF-1 positive
mesotheliomas and metastatic carcinomas from breast and gastrointestinal
tract cancers. The last TTF-1 positive case with clone SP141was a minute
mucous gland adenoma (Fig. 1A-B) incidentally discovered at bronchoscopy
in a 75 year-old man with a previous history of papillary carcinoma of the
thyroid. The positive staining with SP141 (Fig. 1C) raised the possibility
of a metastasis from thyroid cancer, but clinical and imaging findings,
and morphology strongly favoured a benign lesion from bronchus-associated
salivary glands. Indeed, TTF-1 staining with clone 8G7G3/1 was restricted
to entrapped pneumocytes (Fig. 1D).
Figure 1. Bronchoscopy showing an endobronchial millimetric lesion
with smooth, glistening surface (A) histologically appearing as well-
defined, submucosal proliferation of mucous-filled enlarged bland-looking
glands consistent with a mucous gland adenoma (B). Bronchial mucosa and
mucous glands expressing TTF-1 clone SP141 (C), while TTF-1 clone 8G7G3/1
stained only few entrapped pneumocytes (D).
When pathologists begun to use TTF-1 immunostaining in pulmonary
tissue in discriminating primary lung tumours from metastatic malignancies
or to distinguish some benign or malignant entities among a large spectrum
of pulmonary lesions, 8G7G3/1 was the only commercially available clone.
Then, we learned a huge amount of information from several studies
robustly indicating the diagnostic value of TTF-1 positivity and
negativity in different thoracic conditions (Table 1).
Table 1. A brief summary of positive and negative thoracic tumours
with TTF-1 clone 8G7G3/1
?, positivity is mainly restricted to peripheral-type carcinoids; *,
some variants of adenocarcinoma (e.g., mucinous, colloid, enteric types)
may be entirely negative
TTF-1 powerfully entered in all labs of surgical pathology and
promptly appeared as one of the most reliable antibody in the routine
practice.
By the way, controversial issues with TTF-1 clone 8G7G3/1 expression
occurred in neuroendocrine tumours (staining in peripheral rather than
central carcinoids or positivity in high-grade extrapulmonary
neuroendocrine carcinomas)2,3 or in a subset of metastatic tumors to the
lungs (e.g., gynaecological tumours).4
Although it is unclear the significance of the higher sensitivity/affinity
for TTF-1 protein of clone SP141 (or SPT24) when compared with clone
8G7G3/1, in our hands a weak nuclear signal from clone G8G7G3/1 does
appear more sincere than a strong signal from clone SP141.
TTF1 clone 8G7G3/1 is far from being perfect, but the higher specificity
of this clone in subtyping non-small cell lung cancer (NSCLC) and in
discriminating lung adenocarcinoma from mesothelioma or metastatic cancers
is not renounceable.5,6
Keeping in mind that the majority of thoracic tumours may be likely
diagnosed on morphology alone and immunohistochemistry is an ancilla of
the haematoxylin-eosin stain, the lessons learned from the story of TTF-1
immunostaining clearly indicate that the clone SP141 does represent the
"wolf in grandma", while clone 8G7G3/1 is the "good grandmother".
References
1. Klebe S, Swalling A, Jonavicius L, Henderson DW. An
Immunohistochemical comparison of two TTF-1 monoclonal antibodies in
atypical squamous lesions and sarcomatoid carcinoma of the lung, and
pleural malignant mesothelioma. J Clin Pathol 2015 doi
2. Du EZ, Goldstraw P, Zacharias J, et al. TTF-1 expression is specific
for lung primary in typical and atypical carcinoids: TTF-1 positive
carcinoids are predominantly in peripheral location. Hum Pathol
2004;35:825-831.
3. Agoff SN, Lamps LW, Philip AT, et al. Thyroid transcription factor-1 is
expressed in extrapulmonary small cell carcinomas but not in other
extrapulmonary neuroendocrine tumors. Mod Pathol 2000;13:238-242.
4. Siami K, McCluggage WG, Ordonez NG, et al. Thyroid transcription factor
-1 expression in endometrial and endocervical adenocarcinomas. Am J Surg
Pathol 2007;31:1759-1763.
5. Ordonez NG. Value of thyroid transcription factor-1 immunostaining in
tumor diagnosis: a review and update. Appl Immunohistochem Mol Morphol
2012;20:429-40.
6. Kadota K, Nitadori J, Rekhtman N, Jones DR, Adusumilli PS, Travis WD.
Reevaluation and reclassification of resected lung carcinomas originally
diagnosed as squamous cell carcinoma using Immunohistochemical analysis.
Am J Surg Pathol 2015;39:1170-80.
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Rewriting "Little Red Riding Hood" story may be dangerous
Maria Cecilia Mengoli,1 Giuseppe Bogina,2 Alberto Cavazza, 3 Giulio Rossi 1
1Section of Pathology, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy 2Section of Pathologic Anatomy, Hospital "Don Calabria", Negrar, Verona, Italy 3Department of Oncology and Advanced Technologies, Operative Unit of Oncology, Arcispedale S. Maria Nuova /...
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