'High risk medicolegal autopsies: is a full post-mortem examination
necessary?'
Comment on the article by Fryer et al, J Clin Pathol 2013, 66:1-7
The article by Fryer et al raises several critical issues - I do not
agree with them on all points - and leads to an important overall
conclusion for the future prosecution of autopsies in the UK.
The piecemeal introduction of cadaveric imaging for n...
'High risk medicolegal autopsies: is a full post-mortem examination
necessary?'
Comment on the article by Fryer et al, J Clin Pathol 2013, 66:1-7
The article by Fryer et al raises several critical issues - I do not
agree with them on all points - and leads to an important overall
conclusion for the future prosecution of autopsies in the UK.
The piecemeal introduction of cadaveric imaging for non-homicide
cases in (currently) a few centres in England is probably unstoppable, and
has the backing of government (although not the central funding). As
stated in their article, it is intended to avoid performing an open
autopsy examination in a proportion of cases where a coroner has commanded
a post-mortem examination. Interestingly whilst this article, and other
publications like it, discuss replacing open autopsy with imaging, in
public educational fora when presentations by pathologists and
radiologists are made, the emphasis is more on imaging as an adjunct than
a replacement for autopsy. What is not widely discussed anywhere is how
the useful contribution of cadaveric imaging is critically dependent on
clinical case-mix.
We would all agree that having imaging data prior to commencing a
standard autopsy, whether the imaging was done under hospital care prior
to death or done just prior to the autopsy as with deaths in the
community, is valuable. It focuses attention to relevant clinical
pathologies to be examined, and provides negative information for some
organs (such as the brain in ?intracranial haemorrhage). An unintended and
underused consequence of pre-autopsy imaging is enabling feedback to
radiologists, particularly in the in-hospital setting, of their diagnostic
performance. They necessarily receive plentiful such information in cancer
multi-disciplinary meetings, but do not regularly obtain information on
their diagnostic hits and misses when it comes to the moribund. Like all
diagnosticians they are fallible.
High risk cases
Fryer et al suggest that in cadavers of patients with suspected illicit
drug intake, and known 'high-risk infection' (specifically Hazard Group
category 3 infections, including HCV, HBV, HIV), an external examination
plus blood sample toxicology can remove the need for autopsy in more than
half the cases. The results, presented in % terms, are indeed persuasive.
Toxicology alone provided the cause of death in 78% of cases, and CT scan
alone in 25%. In the validation group (suspected drug abuse but no
infection), the toxicology provided the cause of death in 87%.
The arguments presented for avoiding open autopsy on high risk cases
include expense, disruption to busy mortuary work, and health risk to
staff. Interestingly, the authors state that some pathologists in their
centre are reluctant to perform autopsies on such cases. But these general
statements do not stand up to scrutiny. And crucially the data arise from
only a small numbers of cases examined.
In the 15 years covered by the study, only (my italics) 70 cases
happened, ie 4.6 a year. Most were HCV+ve, 3 HIV+ve and one HBV+ve; the
latter should really be excluded from the list of high risk infection in
practice, since all NHS exposure-prone staff have to be successfully
vaccinated against HBV and thus this poses no risk. I would contrast this
very low cadaver infection rate with what happens at St Thomas' Hospital
mortuary, where we see 1-2 HCV and/or HIV+ve cases a week, and have had no
problems in performing them safely. Joint compilation of protocols for all
eventualities by both anatomical pathology technologists (APTs) and
pathologists ensures smooth, safe and efficient practice. I would suggest
that the reported reluctance to perform such autopsies depends on
unfamiliarity.
With the implementation of universal precautions for all autopsies,
the true risks of high risk autopsy practice is minimal. When such
infections are common, they do not disrupt the work flows, since all
bodies are essentially treated the same, and they do not engender more
expense. Let us not forget that in the recent times of good safe working
practice, the likelihood of acquiring such an infection at work is vastly
less than the risk to life of travelling to and from the workplace.
What are the consequences of reducing open autopsy practice by such
minimal invasive techniques, and what are the opportunity costs? The focus
here is on persons suspected of drug abuse with HCV or HIV.
Refinement of causes of death
I am pleased that in Table 1, autopsies were indeed done to identify the
alcoholic ketoacidosis syndrome and co-morbid infections. These variants
of toxic pathology cannot be addressed without tissue samples, and
preferably open autopsy examination of the relevant organs. But how much
other important and/or interesting pathology might be missed by not doing
open examinations? Table 1 lists a good number of lesions that may not be
seen with CT: heart valve vegetations, tuberculosis (a public health
notifiable infection), asthma, and cirrhosis (a disease of public health
concern, and not reliably identified by imaging even in the living).
From my own observations I could add three generic scenarios:
* The complicated and often critical contribution of co-morbidities, eg
chronic lung and heart disease, to death from drug toxicity; it is much
easier to evaluate the concepts of borderline toxicity and drug tolerance
in individual cases when the whole pathology is known.
* The contribution of sepsis from the IV injection habit pe se, both
acutely with septic shock, and chronically through amyloidosis and renal
failure.
* The importance of considering the timing of a drug-related death, such
as with evidence of aspiration pneumonitis, and addressing the questions
of distressed relatives at inquest - for which there can be much evidence
from the autopsy pathology.
Pathology education (or lack of)
This is what disturbs me most about these trends towards imaging-only post
-mortem examinations. Where and how are we going to teach the next
generations of pathologists in the difficult arts of dissection and, even
more importantly, histological examination? The current human tissue
regulations already impact badly here, and removing yet more case work
(drug-related deaths are indeed interesting and have significant internal
pathologies that could become unfamiliar) takes away even more
opportunity. Whilst some would argue that much of this type of examination
is a waste of time, I hold that it provides practice in technique and
interpretation, so that when a truly difficult and nuanced case emerges,
it can be addressed with experience and reason.
Research opportunities
Coronial autopsies are not intended for research but, basically, to
determine whether a cause of death is natural, and an inquest may be
dispensed with, or actually or potentially unnatural and so needs more
investigations and inquiry. That said, because they provide >95% of
adult autopsy work in the UK, they inevitably have a surveillance and
potential research role. The epidemiology of diseases, including
infections, changes constantly, and the autopsy provides one mode of
monitoring and reporting on this.
The prime common example (I omit transmissible spongiform
encephalopathies deliberately) is HIV disease. Much of what we know of the
clinico-pathological cadence of HIV disease and results of new treatments
(beneficial and adverse) comes from autopsy work. And it is published as
such, although the commissioning coroners are probably not aware of that.
Coronial autopsies make a significant contribution to our
understanding of cardiovascular disease in HIV-infected persons. Those not
familiar with HIV may not realise the large clinical research, treatment
and pharma interest into whether HIV per se and/or its anti-retroviral
therapies do, or do not, activate endothelial cells and so augment
arteriosclerosis, affecting the heart and brain in particular.
HIV-infected suspected drug abusers thus contain within themselves at
least two interesting pathological aspects (what is HIV doing and what are
the drugs doing to that person), where a full autopsy can provide unique
and cumulative evidence, to the ultimate benefit of public health.
Requirement for minimal invasive post-mortem examinations
As Fryer et al state, the minimal invasive system requires two robust
processes in place. First rapid toxicology, and they indicate one week as
satisfactory. I would argue that this is not fast enough, since bodies do
decompose even whilst refrigerated and important histopathological
information is lost. More practically, in London, none of the laboratories
offering services performs even that fast. That should be remediable, if
the paymasters (the coroners) exercised their power to force the
laboratories to turn over tests within, say, 3 working days.
Secondly, available imaging, particularly CT scanning. This is in
practice impossible without proper funding; I pass over the availability
of interested pathologists. At present, such non-forensic imaging is
funded from now rather old government grants, or from individual
initiatives such as jewish or moslem communities, or even interested
radiologists with some surplus monies in their educational funds. But
these are not appropriate for a nation-wide roll-out of cadaveric imaging
- whether as replacement or (I would argue) as adjunct to open autopsy.
These post-mortem examinations are done at the behest of coroners, and
unfortunately they are not centrally but locally funded, with all that
implies for variation in service provision.
So is there a future plan? The NHS has recently issued a large post-
consultation document on cadaveric imaging {ref}, written by Prof Guy
Rutty in Leicester and colleagues, with input from many other relevant
specialities. I do encourage all autopsy-active pathologists (and
coroners) to read it.
It provides the first realistic estimates of the actual costs of
autopsies, with or without imaging costs, which alone make enlightening
and disturbing reading for those involved in the economics of autopsy
practice. But its main plank is the plan for future mortuary provision in
England. Essentially, it is proposed that all mortuaries have attached
dedicated CT scanners; that there need be only 30 such facilities in
England (only 3 in London, the rest outside). And that all bodies are
scanned prior to autopsy. The optimal funding for such an integrated
pathology-radiology service is central government, not local source.
Conclusion
There is much controversial material in this NHS document to discuss, but
I certainly endorse the significant reduction of active mortuaries, with
provision of imaging facilities on-site, and the resulting concentration
of expertise in such places. As well as cases I still perform myself, I
review many autopsies done by others and am frequently disturbed by their
suboptimal or frankly dreadful quality. It is inevitable that experience,
insight and - crucially - constant audit by, and consultation with, peers
does sharpen and maintain practice standards. And so with autopsies: we
should be doing them as a speciality interest practice, with similarly
interested colleagues, in centres that do a lot of them very well. Which
brings me back to the start of this Comment: in such facilities, 'high
risk infections' will pose no problems for practitioners, who will be very
familiar with them and their wrinkles. So isolating that category of cases
for a qualitatively different approach to post-mortem examination from all
the other cases will not be necessary.
Whether the NHS plan is rolled out as proposed, or through other
exigencies the number of active mortuaries declines, the end result of
fewer, but properly specialised facilities is appropriate. Pre-examination
imaging will find it right place and 'high risk' cases will be optimally
prosected.
Prof Sebastian Lucas
Dept of Histopathology
St Thomas' Hospital
London SE1, UK
Sebastian.lucas@kcl.ac.uk
28th Jan 2013
Reference
"Can Cross-Sectional Imaging as an Adjunct and/or Alternative to the
Invasive Autopsy be Implemented within the NHS?"
Report from the NHS Implementation Sub-Group of the Department of Health
Post Mortem, Forensic and Disaster Imaging Group (PMFDI). October 2012.
The document can be downloaded from the East Midlands Forensic Pathology
Unit. The full website address is:
http://www2.le.ac.uk/departments/emfpu/Can%20Cross-
Sectional%20Imaging%20as%20an%20Adjunct%20and-
or%20Alternative%20to%20the%20Invasive%20Autopsy%20be%20Implemented%20within%20the%20NHS%20
-%20FINAL.pdf
Dear Editor,
We read with interest the comprehensive review on IgG4-related disease
(IgG4-RD) by Drs Culver and Bateman [1], and wish to add on IgG4-RD in
synovial tissue. A previous report suggested that up to 10% of patients
with IgG4-RD have arthritis [2]. Two reports of arthropathy by Umekita K
et al and Shinoda K et al showed evidence of infiltration of IgG4-positive
plasma cells in the synovium [3, 4]. It is therefo...
Dear Editor,
We read with interest the comprehensive review on IgG4-related disease
(IgG4-RD) by Drs Culver and Bateman [1], and wish to add on IgG4-RD in
synovial tissue. A previous report suggested that up to 10% of patients
with IgG4-RD have arthritis [2]. Two reports of arthropathy by Umekita K
et al and Shinoda K et al showed evidence of infiltration of IgG4-positive
plasma cells in the synovium [3, 4]. It is therefore interesting to
speculate if specific biomarkers of tissue IgG4-RD exist either in the
plasma or clinically relevant tissue filtrate (i.e., CSF, synovial fluid
etc) that is similar to the authors' concept of examining clinically non-
involved tissues for IgG4-RD.
Synovial fibroblasts or fibroblast-like synoviocytes in rheumatoid
arthritis use B-cell activating factor (BAFF) and TLR3 to promote
immunoglobulin class switch [5], that is evidence of perpetuation of
autoimmunity in non-lymphoid tissue and possibly similar to what happens
in IgG4-RD. Ugo Fiocco and colleagues from Italy have tried to identify
candidate synovial biomakers in psoriatic arthritis, and showed that
synovial fluid interleukin-6 (SF- IL-6) and SF-IL-1b levels along with
synovial tissue (ST)-CD45+ and ST-CD31+ levels were altered significantly
as well as disease activity after anti-TNF therapy [6]. A new report now
suggests that basophil-TLR and basophil/B cell-BAFF interaction may lead
to the development of IgG4-RD [7]. It is certainly not the end of the road
for this intriguing disease.
Conflict of interests: None declared
Authors: Sujoy Khan, Consultant Allergy & Immunology, Apollo
Gleneagles Hospital, Kolkata, India; Ratnadeep Ganguly, Consultant
Histopathologist, Apollo Gleneagles Hospital, Kolkata, India
References:
1. Culver EL, Bateman AC. IgG4-related disease: can non-classical
histopathological features or the examination of clinically uninvolved
tissues be helpful in the diagnosis? J Clin Pathol. 2012;65:963-9.
2. Masaki Y, Dong L, Kurose N et al. Proposal for a new clinical
entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of
64 cases of IgG4-related disorders. Ann Rheum Dis 2009; 68; 1310-5.
3. Umekita K, Kaneko Y, Yorita K et al. Arthropathy with infiltrate
IgG4-positive plasma cells in synovium. Rheumatology (Oxford). 2012;51:580
-2.
4. Shinoda K, Matsui S, Taki H et al. Deforming arthropathy in a patient
with IgG4-related systemic disease: Comment on the article by Stone et al.
Arthritis Care Res 2011; 63: 172.
5. Alsaleh G, Fran?ois A, Knapp AM et al. Synovial fibroblasts
promote immunoglobulin class switching by a mechanism involving BAFF. Eur
J Immunol. 2011;41:2113-22.
6. Fiocco U, Oliviero F, Sfriso P et al. Synovial biomarkers in
psoriatic arthritis. J Rheumatol Suppl. 2012;89:61-4.
7. Watanabe T, Yamashita K, Sakurai T et al. Toll-like receptor
activation in basophils contributes to the development of IgG4-related
disease. J Gastroenterol. 2012 Jun 29. [Epub ahead of print]
I read with interest the recent original article entitled 'Mucosal
large cell neuroendocrine carcinoma of the head and neck regions in
Japanese patients: a distinct clinicopathological entity' by Kusafuka et
al.[1] The patient (Case 2) in this article had been previously
reported.[2] I note some discrepancies between these two papers. In this
original article, the patient (Case 2) was a 65-year-old...
I read with interest the recent original article entitled 'Mucosal
large cell neuroendocrine carcinoma of the head and neck regions in
Japanese patients: a distinct clinicopathological entity' by Kusafuka et
al.[1] The patient (Case 2) in this article had been previously
reported.[2] I note some discrepancies between these two papers. In this
original article, the patient (Case 2) was a 65-year-old man. The mitotic
rate of this tumor was not specified, but >15 per 10 high power fields.
Immunohistochemically, the tumor cells were focally positive for
chromogranin-A, but negative for synaptophysin. The Ki-67 labeling index
was 90.8%[1]. In the case report[2], this patient was a 79-year-old man.
The mitotic rate was 13 per 10 high-power fields. The tumor cells were
focally positive for synaptophysin (shown in Figure 3c), but negative for
chromogranin-A. The Ki-67 labeling index was 82%.
There are also some discrepancies between this original article and
their recent review article[3]. In the review[3], they mentioned that four
of their eight mucosal large cell neuroendocrine carcinomas arose in the
larynx (supraglottis). The follow up periods were 12-96 months, and only
one patient died of disease. The authors concluded that the Japanese cases
of mucosal large cell neuroendocrine carcinoma had a better prognosis than
that reported in the literature. Three cases were immunopositive for
thyroid transcription factor-1. But in this original article[1], four
tumors occurred at the larynx, with three at the supraglottis and one at
the infraglottis. Three patients died of disease, and one patient died of
another disease (shown in Table 2), which led to the conclusion that their
Japanese series of large cell neuroendocrine carcinoma also indicated a
relatively poor prognosis as that reported in the literature. The follow
up periods were 15-90 months (shown in Table 2). Only two cases were
immunopositive for thyroid transcription factor-1.
Discrepancies were also present in this original article[1]. In the
section of Results, the age of the eight patients ranged from 52 to 75
years (mean 64.6 years). In the section of Discussion, they stated all the
cases in the present series were aged >65 years and the follow up
periods of the patients that have been disease-free were 24-108 months.
But in Table 2, the age ranged from 52 to 74 years and four patients were
alive without disease (31 months, 18 months, 24 months and 90 months after
surgery, respectively).
In conclusion, there are many inconsistent data in these articles
concerning mucosal large cell neuroendocrine carcinoma by Kusafuka et
al.[1-3] They should verify the original data and make a correction.
Sincerely,
Shaodong Yang.
Department of Oral Histopathology,
Hainan Medical College,
3 Xueyuan Road, Longhua District, Haikou, China.
REFERENCES
1. Kusafuka K, Abe M, Iida Y, et al. Mucosal large cell neuroendocrine
carcinoma of the head and neck regions in Japanese patients: a distinct
clinicopathological entity. J Clin Pathol 2012;65:704-9.
2. Kusafuka K, Asano R, Kamijo T, et al. Large cell neuroendocrine
carcinoma of the tongue base: case report of an unusual location with
immunohistochemical analysis. Int J Oral Maxillofac Surg 2009;38:296-9.
3. Kusafuka K, Ferlito A, Lewis JS Jr, et al. Large cell neuroendocrine
carcinoma of the head and neck. Oral Oncol 2012;48:211-5.
Re: EGFR gene copy number increase in vulvar carcinomas is linked
with poor clinical outcome. Woelber et al. J Clin Pathol. 2012
Feb;65(2):133-9.
Dear editor,
A very novel issue was assessed by Woelber et al.[1] in their
recently published study. This subject has major importance since the
medical interest for vulvar carcinoma has increased in the last decade as
the recognition of the increasing inci...
Re: EGFR gene copy number increase in vulvar carcinomas is linked
with poor clinical outcome. Woelber et al. J Clin Pathol. 2012
Feb;65(2):133-9.
Dear editor,
A very novel issue was assessed by Woelber et al.[1] in their
recently published study. This subject has major importance since the
medical interest for vulvar carcinoma has increased in the last decade as
the recognition of the increasing incidence of the disease, especially
among young women. However, the fact that this carcinoma is an uncommon
neoplastic disease makes its relative rarity an obstacle in designing
studies to evaluate the effectiveness of the prognostic factors of
molecular markers for this type of tumor. Thus, all experience on this
type of tumor regarding the molecular aspects, becomes of paramount
importance and we would like to share our experience in this field.
Woelber et al.[1] studied a series of 183 formalin-fixed paraffin-embedded
(FFPE) vulvar squamous cell carcinomas (VSCC) arranged in two TMAs, in
which FISH analysis for EGFR, HER-2, CCND1 and MYC, IHQ for EGFR, HER-2
and CCND1, besides HPV detection by conventional PCR were performed. All
data were associated to clinicopathological features. As the main results,
EGFR copy number increase was found in 39.3% of the tumors and
amplification of the EGFR gene in 9%. By IHQ, 53.3% of the samples showed
3+ staining for EGFR, being EGFR protein expression significantly
correlated to EGFR copy number increase (p<0.05). Copy number gain of
the EGFR locus was associated with high-invasion depth (p=0.045), non-
basaloid phenotype (p=0.03), high-tumour stage (p<0.001), human
papillomavirus negativity (p=0.04) and the number of lymph node metastases
(p=0.02). Therefore, the authors showed that EGFR copy number gains were
significantly related to unfavorable patient outcome and suggest the
potential role of EGFR as a suitable therapeutic target in a subgroup of
vulvar carcinomas.
In a very similar fashion, our group studied 139 invasive VSCC arranged in
two TMAs in which IHQ and FISH were performed for EGFR. In our approach,
IHQ was held on automated Benchmark? Platform (Ventana Medical Systems)
using the Zymed 31G7 mouse monoclonal antibody diluted 1:20, being this
dilution previously standardized on whole slides of vulvar carcinomas. The
absolute intensity of EGFR immunostaining was performed on a fourpoint
scale as suggested by several authors [2,3,4] in vulvar carcinomas:
(0=negative, 1=weakly positive, 2=positive, 3=strongly positive). In the
same way of the study of Woelber and colleagues[1], we used FISH probes
ZytoLight SPEC EGFR/CEN 7 Dual Color Probe (ZytoVision?) and the analysis
were also performed as Woelber et al[1]. In order to analyze the
relationship between the results obtained from IHC and FISH, associations
between these data and histopathological features from the classification
of the tumors (such as histological type, vascular and perineural invasion
among others) and clinical data (such as recurrence, death by cancer and
lymph node involvement), obtained from the clinical records of all the 139
patients were performed using the Chi-square test (X2) adopting p<0,05
as significant level.
Regarding the amplification of EGFR gene, our results showed a lower rate
of amplification (5 out of 78 cases - 6.4%) than those data raised by
Woelber et al.[1] - 9%; and Growdon et al. (2008)[4] - 11,7%. Similarly,
our IHQ analysis demonstrated only 3.9% of overexpression (3+) among our
cases, which is contradictory to previous findings that reported an
overexpression of 41-68% for this receptor [1,2,3]. Regarding the
correlation between protein expression and amplification, among our cases,
all tumors exhibiting amplification demonstrated an intense 3+
immunostaining by IHC, demonstrating a 100%correlation between FISH and
IHC. These results corroborate the findings of Growdon et al. (2008) [4]
to the observation that all tumors with intense 3+ expression of this
receptor exhibited EGFR amplification and contradicts Woelber et al. [1]
findings, regarding the occurrence of 20 vulvar carcinomas with EGFR copy
number increase (including tumors with high polysomy or amplification)
exhibiting low or intermediate levels of EGFR expression (scores 0, 1+ or
2+).
Moreover, contrary to Woelber et al[1] study , our results showed no
correlation between EGFR expression and the clinical and pathological
features evaluated. The only association observed was statistically
marginal and was related to FIGO staging, in which the most part of tumors
stained negative for EGFR on the membrane (scores 0 and 1+) were
classified as FIGO I or II, while the tumors EGFR positive (scores 2+ and
3+) were FIGO III or IV (p=0.08) which, as mentioned by Woelber et
al.(2012)[1], may underline the influence of EGFR on tumor progression.
Regarding the lack of association between EGFR expression and the clinical
and pathological features evaluated, we attribute this result to the great
heterogeneity of the intensity of immunostaining for EGFR observed in our
cases, also described by Brustmann (2007) [2]. This heterogeneity leads us
to believe that TMAs may not be useful for analyzing EGFR amplification in
vulvar carcinomas.
Anyway, it seems unanimous in the literature and among our results the
fact that EGFR is, on greater or lesser extent, amplified in vulvar
carcinomas and its overexpression could benefit a small group of patients
with the therapy against this tyrosine kinase receptor and that more
studies, regarding clinical trials, are required to elucidate this field.
References:
[1] Woelber L, Hess S, Bohlken H et al. EGFR gene copy number increase in
vulvar carcinomas is linked with poor clinical outcome. J Clin Pathol.
2012 Feb;65(2):133-9.
[2] Brustmann, H. Epidermal growth factor receptor is involved in the
development of an invasive phenotype in vulvar squamous lesions, but is
not related to MIB-1 immunoreactivity. Int J Gynecol Pathol.
2007;26(4):481-89.
[3] Oonk MH, de Bock GH, van der Veen DJ, Ten Hoor KA, de Hullu JA,
Hollema H et al. EGFR expression is associated with groin node metastases
in vulvar cancer, but does not improve their prediction. Gynecol Oncol
2007.104(1):109-13.
[4] Growdon WB, Boisvert SL, Akhavanfard S, Oliva E, Dias-Santagata
DC, Kojiro S et al. Decreased survival in EGFR gene amplified vulvar
carcinoma. Gynecol Oncol 2008.111(2):289-97.
We read this article with great interest and would like to share our
own similar experiences in support of this growing evidence base. Our
department has the added complexity of being one of the UK ST1 training
schools, with between ten and fifteen ST1 - ST5 trainees per year. We
have trained and developed a senior Biomedical Scientist (BMS) in all
specimen dissections who has gained the RCPath D...
We read this article with great interest and would like to share our
own similar experiences in support of this growing evidence base. Our
department has the added complexity of being one of the UK ST1 training
schools, with between ten and fifteen ST1 - ST5 trainees per year. We
have trained and developed a senior Biomedical Scientist (BMS) in all
specimen dissections who has gained the RCPath Diploma of Expert Practice
in Histological Dissection and been appointed as an Advanced Practitioner
(AP). This post covers all surgical specialties, and the AP currently
dissects the majority of specimens, both simple and complex, as and when
appropriate knowledge and experience has been gained. In terms of
colorectal specimens, all types are dissected by the AP, including
Extralevator Abdomino-Perineal Excision (ELAPE) specimens where the
levator ani and/or coccyx are also resected.
Macroscopy
In terms of macroscopic assessment we follow a similar defined
protocol to that of Sanders et al, with triage of each colorectal cancer
specimen before dissection. Included in this discussion is most
appropriate block selection. This process occurs for both the AP and the
trainees, with the AP following the same pathway as that of the trainees.
The AP and trainee take similar numbers of blocks, as appropriate to the
case, in keeping with the departmental protocol (at least four blocks
required). A macroscopic proforma is used to record data items during
dissection. This is used by all staff, regardless of grade, and is seen
as a method of ensuring that the minimum data items are recorded.
Evidence has shown there to be more chance of identifying extramural
vascular invasion (EVI) where additional tumour blocks are sampled [1].
In the study by Sanders et al it would be interesting to know how often
EVI was identified where additional tumour blocks were taken by the BMS,
as this may not be an appropriate criticism of practice.
Audit
We recently performed an audit to assess lymph node harvesting. This
showed the average lymph node harvest of the AP was twenty-five percent
higher that that of her histopathologist colleagues (consultant and
trainee) (20 vs 15). All staff groups achieve the RCPath requirement of a
harvest of twelve lymph nodes per case [2]. These findings were
statistically significant (p=<0.001) and were presented at a national
meeting [3]. The AP was less likely to perform resampling for additional
lymph nodes (8.1% vs 16.6%). This was attributed to the level of training
and experience of the AP in comparison to some trainee pathologists. In
Sanders et al study the mean numbers of lymph nodes harvested by medical
staff are similar to our own, but those harvested by the BMS are lower.
This may be related to the experience of the BMS, as a similar decrease is
seen with the least experienced trainees in our laboratory. Time spent on
dissection may be a factor as our AP takes on average forty-five to sixty
minutes per case.
Microscopy
As part of the Histopathology team our AP routinely reviews the
slides generated from her colorectal cancer dissections. Reports are
generated using a microscopic minimum dataset proforma and a paper copy of
this is initially completed by the AP for joint review with the consultant
before generation of the final report and authorisation by the consultant.
This pathway is identical to that of the trainees within our department.
Development of scientific staff
Our AP has a specific interest in gastrointestinal pathology and is
currently leading a research study around colorectal cancer diagnostics as
part of a Professional Doctorate in Biomedical Science. This follows the
Modernising Scientific Careers (MSC) programme which aims to provide the
most appropriate developmental opportunities to high achieving scientists
in their field [4]. Achieving the RCPath Specialist Diploma in lower
gastrointestinal histopathology is also a current aim for our AP. To
improve the knowledge base surrounding colorectal cancer management, she
also regularly attends the local colorectal cancer multidisciplinary team
meeting with one of the specialist consultants. This has the additional
benefits in that it publicises the role of the AP within the team, and
also provides an essential feedback mechanism on her performance. We feel
that the performance of the AP is similar to that of an experienced
registrar, and that she should be treated in the same way.
Benefits
The benefits to us are multiple. Consultant histopathologists
benefit from more time to perform other important duties and the ability
to delegate dissection training where appropriate. We would argue that in
many cases reporting is quicker with the AP than with a trainee, as
specimens are less likely to require resampling. Trainee
histopathologists benefit from the additional dissection training,
supervision and an additional source of advice. Due to the protocol
driven nature of the AP's practice, she is able to provide the trainees
with examples of agreed best practice within the department. APs benefit
from career development which was previously unavailable, with the
potential of eventual consultant healthcare scientist status when at
doctoral level and with appropriate experience [4]. Patients benefit from
the knowledge that dissection practice is standardised and that they are
receiving the correct treatment based on appropriate staging.
In conclusion, we feel that there is an important clinical role for
scientists within the histopathology team. Rather than simply working on
the laboratory based aspects of the service, high achievers within this
staff group should be utilised more appropriately. This may be in
specimen dissection and microscopy, but could equally be within
immunohistochemistry or molecular pathology. We agree that the evidence
base needs to be improved in order to support further development within
this area.
In defining underlying causes of pulmonary granulomatous inflammation
in their study population(s), Mukhopadhyay et al[1] correctly list
immunodeficiency disorders as one possible association. They define a
causal link between pathologist-observed granulomata and immune deficit
where the latter has been already been identified clinically in individual
patients. However, granulomatou...
In defining underlying causes of pulmonary granulomatous inflammation
in their study population(s), Mukhopadhyay et al[1] correctly list
immunodeficiency disorders as one possible association. They define a
causal link between pathologist-observed granulomata and immune deficit
where the latter has been already been identified clinically in individual
patients. However, granulomatous disease can be a presenting feature of
underlying, unsuspected immune deficiency, particularly in the context of
some primary antibody deficiency disorders. The relationship of
granulomatous inflammation in a biopsy and immunodeficiency needs to be
considered beyond the simple circumstance of a patient with a previously
defined immune deficit, in particular in the context of a) granulomatous
disease with an alternative diagnostic label (e.g. sarcoidosis) and b)
granulomatous disease of unknown aetiology. Awareness of the association
of granulomata and immune deficiency is important, whether in the context
of a geographically high incidence of sarcoidosis as a cause of pulmonary
granulomata or of a high rate of no underlying aetiological factor being
identified. Although relatively rare, primary immunodeficiency is an
important issue for clinicians caring for patients with granulomatous
disease to consider, identify, classify, risk assess and optimally manage.
Anecdotal local experience in the North of Scotland demonstrates that
occasional 'sarcoid' patients (not included in the population studied by
Mukhopadhyay et al) with pulmonary or extrapulmonary granulomatous
inflammation are ultimately shown to have a primary immunodeficiency
disorder (most frequently one of the common variable immune deficiency
group of diseases, CVID[2]) but only after significant diagnostic delay.
Such delay in these circumstances is relatively commonplace and is
frequently associated with either overt or insidious secondary disease
complications (usually pulmonary) which may be prevented or retarded by
early immunoglobulin replacement and/or immunomodulatory treatment. Subtle
histological differences have been described in the granulomata of sarcoid
and CVID[3]. Granulomatous disease (particularly with splenic
involvement), recurrent infections, cytopaenias and hypogammaglobulinaemia
(rather than the hypergammaglobulinaemia of sarcoid) are, collectively,
indicators of significant immune dysregulation and should prompt
consideration of CVID as a potentially unifying diagnosis. Clinicians
should consider routine measurement of serum immunoglobulins in
granulomatous disease of unknown aetiology and as part of the diagnostic
work-up in sarcoidosis. Similar recommendations, for similar reasons, have
recently been made in the context of non-cystic fibrosis
bronchiectasis[4]. Albeit relatively rarely, proactive detection of
underlying immune deficiency as a cause of granulomatous inflammation will
aid earlier diagnosis in conditions like CVID, allow more definitive and
accurate aetiological classification of some cases at the
clinician:pathologist interface and, not incidentally, will enhance
opportunities for improvements in morbidity, mortality and quality of life
for this group of complex patients.
REFERENCES
1. Mukhopadhyay S, Farver CF, Vaszar LT, et al. Causes of pulmonary
granulomas: a retrospective study of 500 cases from seven countries. J
Clin Pathol 2012; 65: 51-7
2. Morimoto Y, Routes JM. Granulomatous disease in common variable
immunodeficiency. Curr Allergy Asthma Rep 2005; 5: 370-5
3. Bates CA, Ellison MC, Lynch DA et al. Granulomatous-lymphocytic
lung disease shortens survival in common variable immunodeficiency. J
Allergy Clin Immunol 2004; 114: 415-21
4. Pasteur MC, Bilton D, Hill AT. British Thoracic Society guideline
for non-CF bronchiectasis. Thorax 2010; 65: i1-58
A very important issue was assessed by Yang et al in their
outstanding study recently published by this journal1. As pointed out by
the authors, distant metastasis is the most preoccupant complication of
differentiated thyroid carcinoma (DTC) and a very anguishing therapeutic
challenge for the attending physician. A series of studies have been
trying to establish a molecular pattern able to predic...
A very important issue was assessed by Yang et al in their
outstanding study recently published by this journal1. As pointed out by
the authors, distant metastasis is the most preoccupant complication of
differentiated thyroid carcinoma (DTC) and a very anguishing therapeutic
challenge for the attending physician. A series of studies have been
trying to establish a molecular pattern able to predict more aggressive
follicular cell behavior. One of the most promissory markers integrating
this molecular pattern is the expression of neural cell adhesion molecules
(NCAM).
Yang et al studied a series of 365 surgical cases of thyroid disease
- 214 DTC and 151 benign lesions. Immunohistochemistry showed that most
benign lesions presented NCAM expression, whereas a significant proportion
of DTC lost completely or showed a reduced NCAM expression, which confirms
previous results suggesting that NCAM could be a diagnostic marker of DTC
2. We also studied NCAM expression in a series of 527 surgical cases of
thyroid tissues - 395 DTC (343 papillary thyroid carcinomas and 52
follicular carcinomas) and 132 nonmalignant thyroid tissues (18 normal
thyroids, 58 goiters and 56 adenomas). One hundred fifty-three of our
patients presented metastasis at diagnostic and 58 developed distant
metastasis during a follow-up of 12-298 months (43.50?33.29 months), Mo=21
months. NCAM expression was evaluated by immunohistochemistry and the same
technique used by Yang et al, but with anti-NCAM monoclonal 123C3 clone
antibody (DAKO- Carpenteria, CA, USA). We also considered NCAM positive
those cases with NCAM expression in more than 30% of tumor cells. Fisher's
exact test showed total loss or reduction of NCAM expression in 74.65% of
DTC cases, while a significant portion (52.73%) of benign lesions were
positive for NCAM (p< 0.0001). However, NCAM expression was not able to
predict malignancy due to low sensibility (25.35%) and low specificity
(47.27%), suggesting that NCAM alone is not a useful diagnostic marker.
In addition, Yang et al found that persistent NCAM expression in DTC
is associated with a higher rate of metastasis. In our cohort, NCAM
expression was not correlated with the presence of metastasis at diagnosis
(p=0.4506), neither to tumor size (p=0.3814) nor to extrathyroid invasion
(p=0.9855), multifocality (p=0.2747) or pTNM stage (p=0.6928). A log-rank
test failed to show NCAM expression as a prognostic marker of relapse-free
survival (p=0.8846). Nevertheless, NCAM positivity was more frequent in
encapsulated tumors (37.78%) than in nonencapsulated tumors (20.62%;
p=0.0399), suggesting that the peritumoral fibrotic reaction is associated
with NCAM expression. In fact, 51.11% of our NCAM positive cases presented
concurrent chronic lymphocytic thyroiditis (CLT), while only 25.89% of
NCAM negative cases presented concurrent CLT (p=0.0045). We also evaluated
the presence of tumor infiltrating lymphocytes (TIL) in DTC specimens by a
routine HE staining. We found that NCAM expression was associated with the
presence of TIL (p=0.0427). In order to distinguish TIL subsets, we
performed immunohistochemical analysis using classical immune cell
markers. We observed that NCAM expression was associated with the presence
of CD4+ lymphocytes (p=0.0477), CD8+ lymphocytes (p=0.0015), CD20+
lymphocytes (p=0.0284) and FoxP3+ lymphocytes (p=0.0024). Interestingly,
most NCAM negative cases (80.10%) were also negative for sodium/iodine
symporter (NIS) protein immunohistochemical expression, whereas 71.43% of
NCAM positive cases were positive for NIS as well (p< 0.0001),
suggesting that NCAM could boost immunogenicity in DTC. These results
suggest that NCAM expression is engaged in the antitumor immune response.
However, the outcome of patients is not modified by NCAM expression,
perhaps because an appropriate management of DTC patient is the most
important and modifiable prognostic factor, impeding the natural course of
malignancy.
The differences between Yang results and our data could be related to
different population backgrounds, which are thought to affect antitumor
immunity in DTC 3. Since the tumorigenic process is a complex biological
system in which multiple molecular interactions may occur, minimum genetic
differences in populations might affect dramatically the obtained results.
An antitumor effect of NCAM may be expected in cases presenting genetic
background that facilitates antitumor immune defense 3-4. We also cannot
exclude that the different antibody used may lead to different results. In
addition, it is worthy noting that NCAM may be engaged in pleiotropic
functions in tumor progression, making the interpretation of NCAM
expression a difficult task. More studies are warranted to understand the
functional biologic role of NCAM expression in DTC tumors.
Unfortunately, our data do not support the conclusion of Yang et al that
NCAM expression in well differentiated thyroid carcinoma is an indicator
for a higher risk of distant metastasis.
Sincerely,
Lucas Leite Cunha1, Elaine Cristina Morari2, Suely Nonogaki3,
Fernando Augusto Soares4, Jose Vassallo5, and Laura Sterian Ward1.
1Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences
- University of Campinas (Unicamp). 126 Tessalia Vieira de Camargo Street,
Campinas, SP, Brazil.
2Department of biological sciences and health- State University of
Roraima. 231, Sete de Setembro Street, Boa Vista, Roraima, Brazil.
3. Adolfo Lutz Institute. 355, Doutor Arnaldo Avenue, S?o Paulo,
Brazil.
4Department of Pathology, A. C. Camargo Cancer Hospital. 211 Antonio
Prudente Street, S?o Paulo, SP, Brazil.
5Laboratory of Investigative and Molecular Pathology (Ciped), Faculty
of Medical Sciences - University of Campinas (Unicamp). 126, Tessalia
Vieira de Camargo Street, Campinas, SP, Brazil.
REFERENCES
1. Yang AH, Chen JY, Lee CH. Expression of NCAM and OCIAD1 in well-
differentiated thyroid carcinoma: correlation with the risk of distant
metastasis. J Clin Pathol 2011;
2. El Demellawy D, Nasr AL, Babay S, Alowami S. Diagnostic utility of
CD56 immunohistochemistry in papillary carcinoma of the thyroid. Pathol
Res Pract 2009;205:303-9.
3. Cunha LL, Tincani AJ, Assumpcao LV, Soares FA, Vassallo J, Ward
LS. Interleukin-10 but not interleukin-18 may be associated with the
immune response against well-differentiated thyroid cancer. Clinics (Sao
Paulo) 2011;66:1203-8.
4. Scarpino S, Di Napoli A, Melotti F, Talerico C, Cancrini A, Ruco
L. Papillary carcinoma of the thyroid: low expression of NCAM (CD56) is
associated with downregulation of VEGF-D production by tumour cells. J
Pathol 2007;212:411-9.
We noted with interest the study entitled "Breast cancer stem cell
markers CD44, CD24 and ALDH1: expression distribution within intrinsic
molecular subtype", published by Ricardo and colleagues [1]. Papers like
this one have major importance since retrospective studies analyzing the
proportion of cancer stem cells in breast tumor biopsies as prognosis
factors are still required. Ricardo et al. al...
We noted with interest the study entitled "Breast cancer stem cell
markers CD44, CD24 and ALDH1: expression distribution within intrinsic
molecular subtype", published by Ricardo and colleagues [1]. Papers like
this one have major importance since retrospective studies analyzing the
proportion of cancer stem cells in breast tumor biopsies as prognosis
factors are still required. Ricardo et al. also correlate the
identification of breast cancer stem phenotypical markers with the
molecular subtypes of breast cancer. Therefore, this report tries to
address important and relevant questions in breast cancer cell biology.
However, this study presents two major flaws. First, the authors performed
single CD44 or CD24 staining to identify cells with the CD44+/CD24- cancer
stem phenotype. Single immunohistochemistry is not the choice for
analyzing the combined expression of two different markers on the same
cell but, on the contrary, expression of both receptors needs to been
analyzed simultaneously. Double-staining immunohistochemistry for the
simultaneous detection of CD44 and CD24 in paraffin embedded sections from
breast cancer patients has been developed and validated first by Abraham
et al. [2] and subsequently by Mylona et al. [3]. In those reports, the
authors quantified the intensity of staining and then the proportion of
CD44+/CD24- tumor cells using software-based image analysis in order to
avoid bias derived from pathologist inspection. Ricardo and colleagues
quote both papers but they followed a different methodology. From our
perspective, the double immunofluorescence for CD44 and CD24 performed by
the authors in only 10% of the samples does not validate their methodology
since it still considered the percentage of cells expressing the receptors
rather than the intensity of labeling. On the other hand, they used flow
cytometry for the simultaneous analysis of CD44 and CD24 expression in
breast cancer cell lines. With this methodology, their results are
consistent with those from previous publications [4].
The second imperfection of this study is directly related to the first.
Ricardo and colleagues stratified their samples based on the percentage of
cells expressing one of the receptors rather than in the number of cells
with the CD44+/CD24- phenotype (as reported by Abraham et al. [2] and
Mylona et al. [3]). They defined as "CD44 positive" the samples containing
10-100% of tumor cells immunoreactive for CD44 and as "CD24 negative/low"
the samples with 0-25% of tumor cells expressing membranal CD24. With this
methodology, 411/463 samples (88.6%) were classified as CD24-/low. Thus,
nine out of ten samples fitted their description of CD24 "negativity",
leaving CD44 "positivity" as the characteristic that is mainly in charge
of their whole analysis. Accordingly, the correlation that they found
between CD44 expression (not the cancer stem cell phenotype) and the basal
subtype (where 94% of the samples were considered CD24-/low) has been
previously described in breast cancer cell lines by Charafe-Jauffret and
colleagues [5].
Given the clear methodological differences between the present studies
from Ricardo and colleagues and those from Abraham et al. [2] and Mylona
et al. [3], it is unclear how the authors classified their samples as
"CD44+/CD24- <10%" and "CD44+/CD24- >10%" for the further analysis
presented in tables 2-3, and figures 2-3. Therefore, we think that the
results of this very interesting paper need to be carefully reinterpreted.
References:
1. Ricardo S, Vieira AF, Gerhard R, et al. Breast cancer stem cell
markers CD44, CD24 and ALDH1: expression distribution within intrinsic
molecular subtype. J Clin Pathol. 2011; doi:10.1136/jcp.2011.090456
2. Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, and
Brauch H. Prevalence of CD44+/CD24-/low cells in breast cancer may not be
associated with clinical outcome but may favor distant metastasis. Clin
Cancer Res. 2005; 11(3):1154-9.
3. Mylona E, Giannopoulou I, Fasomytakis E, Nomikos A, Magkou C,
Bakarakos P, and Nakopoulou L. The clinicopathologic and prognostic
significance of CD44+/CD24(-/low) and CD44-/CD24+ tumor cells in invasive
breast carcinomas. Hum Pathol. 2008; 39(7):1096-102.
4. Fillmore CM, and Kuperwasser C. Human breast cancer cell lines contain
stem-like cells that self-renew, give rise to phenotypically diverse
progeny and survive chemotherapy. Breast Cancer Res. 2008; 10(2):R25.
5. Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adelaide J,
Cervera N, et al. Gene expression profiling of breast cell lines
identifies potential new basal markers. Oncogene. 2006; 25(15):2273-84.
Cancer Genetics Unit,
Hormones & Cancer Group, Kolling Institute of Medical Research,
University of Sydney, Sydney, Australia
RE: Differential expression of microRNA-675, microRNA-139-3p and
microRNA-335 in benign and malignant adrenocortical tumours. Schmitz et
al. 64:529-535 doi:10.1136/jcp.2010.085621
Cancer Genetics Unit,
Hormones & Cancer Group, Kolling Institute of Medical Research,
University of Sydney, Sydney, Australia
RE: Differential expression of microRNA-675, microRNA-139-3p and
microRNA-335 in benign and malignant adrenocortical tumours. Schmitz et
al. 64:529-535 doi:10.1136/jcp.2010.085621
To the Editor,
We noted with interest the study published by Schmitz and colleagues
1. The authors compared the microRNA (miRNA) expression profile of 4
adrenocortical carcinomas (ACCs) and 3 metastases to 9 adrenocortical
adenomas (ACAs) and 4 normal adrenal tissue using Taqman low density array
(TLDA). The results from the test cohort were confirmed on a validation
cohort of 11 ACAs, 4 ACCs and 1 lung metastasis.
Of 667 miRNAs analysed, the total number of differentially expressed
miRNAs in ACCs as compared to ACAs was 248 (159 up-regulated and 89 down-
regulated). This number is very high as compared to three previous
studies, where differential expression of 14, 23 and 23 miRNAs,
respectively, was found in ACCs compared to ACAs 2-4. Down-regulation of
three of the differentially expressed miRNAs, miR-675, miR-139-3p and miR-
335, was confirmed using quantitative RT-PCR. In the validation cohort,
however, only miR-139-3p was found to be down-regulated in ACCs as
compared to ACAs, whereas, the other two miRNAs, miR-675 and miR-335, were
up-regulated. miR-335 has been reported to be down-regulated in ACCs as
compared to ACAs in two other studies.2,5 The lack of consistency in the
results from the test cohort and the validation cohort in the present
study need to be resolved. This might be done by further confirming the
expression of these miRNAs in a larger sample size.
1. Schmitz KJ, Helwig J, Bertram S, et al. Differential expression of
microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant
adrenocortical tumours. J Clin Pathol 2011.
2. Soon PS, Tacon LJ, Gill AJ, et al. miR-195 and miR-483-5p Identified as
Predictors of Poor Prognosis in Adrenocortical Cancer. Clin Cancer Res
2009;15(24):7684-7692.
3. Tombol Z, Szabo PM, Molnar V, et al. Integrative molecular
bioinformatics study of human adrenocortical tumors: microRNA, tissue-
specific target prediction, and pathway analysis. Endocr Relat Cancer
2009;16(3):895-906.
4. Patterson EE, Holloway AK, Weng J, Fojo T, Kebebew E. MicroRNA
profiling of adrenocortical tumors reveals miR-483 as a marker of
malignancy. Cancer 2011;117(8):1630-9.
5. Cherradi, N., Chabre, O., Feige, J.J., 2011. Role of miRNA in ACC
[abstract]. Session: Molecular Pathogenesis of ACC-new insights from array
studies. International Adrenal Cancer Symposium; Feb 18-19, 2011;
Wurzburg, Germany.
I read with interest the report of Chakupurakal and colleagues on a
patient who developed peripheral neuropathy during imatinib treatment.(1)
Their report highlights the importance of vigilance for late, unexpected
adverse events in patients receiving potentially lifelong maintenance
chemotherapy.
The authors assert that neuropathy has not previously been reported
as a side effect of im...
I read with interest the report of Chakupurakal and colleagues on a
patient who developed peripheral neuropathy during imatinib treatment.(1)
Their report highlights the importance of vigilance for late, unexpected
adverse events in patients receiving potentially lifelong maintenance
chemotherapy.
The authors assert that neuropathy has not previously been reported
as a side effect of imatinib. I would like to draw the authors' attention
to a case of neuropathy during imatinib treatment, which I reported some
years ago.(2) In that case there was a temporal association between the
initiation of a concomitant medication (amlodipine) that may increase
imatinib exposure and the acute onset of neuropathic symptoms. A search of
Pubmed (accessed 28 April 2011) using the search terms 'imatinib' and
'neuropathy' identifies this paper, the paper of Chakupurakal and two less
relevant papers. Since the publication of my case report I have twice been
contacted by colleagues who had each observed a single case of neuropathy
during imatinib treatment with no other explanation identified. It is
difficult to know whether the frequency of neuropathy on imatinib is
greater than the frequency of idiopathic neuropathy in an age-matched
population.
The same caution applies to the interpretation of cases of left
ventricular dysfunction during imatinib treatment. The authors include
heart failure and left ventricular dysfunction in a list of 'commonly
reported side effects of imatinib'. However, the average age of patients
at diagnosis of chronic myeloid leukaemia coincides with the age at which
cardiac problems start to rise in incidence in the general population. The
experiments of Kerkela and colleagues (3) might lead us to predict many
more cases of left ventricular failure with dasatinib, which is 300 times
as potent as imatinib as an inhibitor of the ABL1 enzyme,(4) yet this is
not a major clinical problem in experience to date. Whilst the absence of
significant cardiac impairment in a prospective evaluation of imatinib-
treated patients (5) is somewhat reassuring, it remains possible that late
effects might emerge after many years of treatment, and ongoing
pharmacovigilance is required.
References
1. Chakupurakal, G., Etti, R.J. & Murray, J.A. Peripheral
neuropathy as an adverse effect of imatinib therapy. J Clin Pathol 2011;
64: 456.
2. Ross, D.M. Peripheral neuropathy on imatinib treatment for chronic
myeloid leukaemia: suspected adverse drug interaction with amlodipine.
Intern Med J 2009; 39: 708.
3. Kerkela, R., Grazette, L., Yacobi, R., Iliescu, C., Patten, R.,
Beahm, C., et al. Cardiotoxicity of the cancer therapeutic agent imatinib
mesylate. Nat Med 2006; 12: 908-916.
4. O'Hare, T., Walters, D.K., Stoffregen, E.P., Jia, T., Manley,
P.W., Mestan, J., et al. In vitro activity of Bcr-Abl inhibitors AMN107
and BMS-354825 against clinically relevant imatinib-resistant Abl kinase
domain mutants. Cancer Res 2005; 65: 4500-4505.
5. Estabragh, Z.R., Knight, K., Watmough, S.J., Lane, S., Vinjamuri,
S., Hart, G., et al. A prospective evaluation of cardiac function in
patients with chronic myeloid leukaemia treated with imatinib. Leuk Res
2011; 35: 49-51.
'High risk medicolegal autopsies: is a full post-mortem examination necessary?'
Comment on the article by Fryer et al, J Clin Pathol 2013, 66:1-7
The article by Fryer et al raises several critical issues - I do not agree with them on all points - and leads to an important overall conclusion for the future prosecution of autopsies in the UK.
The piecemeal introduction of cadaveric imaging for n...
Dear Editor, We read with interest the comprehensive review on IgG4-related disease (IgG4-RD) by Drs Culver and Bateman [1], and wish to add on IgG4-RD in synovial tissue. A previous report suggested that up to 10% of patients with IgG4-RD have arthritis [2]. Two reports of arthropathy by Umekita K et al and Shinoda K et al showed evidence of infiltration of IgG4-positive plasma cells in the synovium [3, 4]. It is therefo...
Dear Editor,
I read with interest the recent original article entitled 'Mucosal large cell neuroendocrine carcinoma of the head and neck regions in Japanese patients: a distinct clinicopathological entity' by Kusafuka et al.[1] The patient (Case 2) in this article had been previously reported.[2] I note some discrepancies between these two papers. In this original article, the patient (Case 2) was a 65-year-old...
Re: EGFR gene copy number increase in vulvar carcinomas is linked with poor clinical outcome. Woelber et al. J Clin Pathol. 2012 Feb;65(2):133-9.
Dear editor,
A very novel issue was assessed by Woelber et al.[1] in their recently published study. This subject has major importance since the medical interest for vulvar carcinoma has increased in the last decade as the recognition of the increasing inci...
Dear Editor,
We read this article with great interest and would like to share our own similar experiences in support of this growing evidence base. Our department has the added complexity of being one of the UK ST1 training schools, with between ten and fifteen ST1 - ST5 trainees per year. We have trained and developed a senior Biomedical Scientist (BMS) in all specimen dissections who has gained the RCPath D...
CAUSES OF PULMONARY GRANULOMAS
In defining underlying causes of pulmonary granulomatous inflammation in their study population(s), Mukhopadhyay et al[1] correctly list immunodeficiency disorders as one possible association. They define a causal link between pathologist-observed granulomata and immune deficit where the latter has been already been identified clinically in individual patients. However, granulomatou...
Dear Editor,
A very important issue was assessed by Yang et al in their outstanding study recently published by this journal1. As pointed out by the authors, distant metastasis is the most preoccupant complication of differentiated thyroid carcinoma (DTC) and a very anguishing therapeutic challenge for the attending physician. A series of studies have been trying to establish a molecular pattern able to predic...
To the Editor,
We noted with interest the study entitled "Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype", published by Ricardo and colleagues [1]. Papers like this one have major importance since retrospective studies analyzing the proportion of cancer stem cells in breast tumor biopsies as prognosis factors are still required. Ricardo et al. al...
Puneet Singh, Patsy S H Soon and Stan B Sidhu
Cancer Genetics Unit, Hormones & Cancer Group, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia
RE: Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours. Schmitz et al. 64:529-535 doi:10.1136/jcp.2010.085621
To the Editor,
We noted with i...
To the Editor,
I read with interest the report of Chakupurakal and colleagues on a patient who developed peripheral neuropathy during imatinib treatment.(1) Their report highlights the importance of vigilance for late, unexpected adverse events in patients receiving potentially lifelong maintenance chemotherapy.
The authors assert that neuropathy has not previously been reported as a side effect of im...
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