We read with interest the study reported by Palmieri et al in the January 10th issue of this journal.1 In their study, serum calcium, PTH and 25(OH)D levels were measured prospectively in 279 Caucasian women with breast cancer, 75 of whom had locally advanced or metastatic disease, but patients receiving bisphosphonates were excluded. Overall, the authors found that women with early-stage breast c...
We read with interest the study reported by Palmieri et al in the January 10th issue of this journal.1 In their study, serum calcium, PTH and 25(OH)D levels were measured prospectively in 279 Caucasian women with breast cancer, 75 of whom had locally advanced or metastatic disease, but patients receiving bisphosphonates were excluded. Overall, the authors found that women with early-stage breast cancer had significantly higher 25(OH)D and lower PTH than those with advanced disease, in keeping with experimental data indicating direct inhibition of parathyroid function by 25(OH)D itself.2 That the authors found no difference in serum calcium levels between the two groups is consistent with unaltered coupling of extracellular calcium concentrations to PTH secretion by the calcium-sensing receptor.3
We have prospectively assessed the same parameters in 45 patients with progressive bone metastases while on bisphosphonate therapy (pamidronate or clodronate) for a median interval of 20 months. We also found that 25(OH)D levels were low in many patients. However, we found that serum calcium levels were elevated compared to age-matched controls. Moreover, PTH levels did not show the same coupling to 25-hydroxyvitamin D, but were elevated among those with low normal calcium, irrespective of vitamin D status. When given to normocalcemic individuals, bisphosphonates are known to provoke a short-lived hyperparathyroid response to drug-induced hypocalcemia4, but the long-term effects of high-dose bisphosphonates are little studied. If there is a tendency toward chronic secondary hyperparathyroidism amongst metastatic breast cancer survivors on long-term bisphosphonates, even when serum calcium is within the normal range, then maintenance of a ‘normal’ 25OHD level is important. At first glance, this would appear to be a simple matter of recommending a daily supplement, but considerable controversy now surrounds the adequacy of current recommendations. Some authorities are now suggesting that 25OHD levels of 75 nmol/L be considered the minimum for optimal health outcomes, a value that may require more than 2000 IU/day to achieve.5
We are currently investigating further the role of Vitamin D in metastatic breast cancer patients with bone involvement to determine if it can act as an adjunct to bisphosphonate therapy in these patients and enhance the benefits of bisphosphonates as well as investigating its
potential cytostatic role in metastatic bone disease.6 This remains an interesting and challenging area of research in breast cancer patients with advanced metastatic bone disease.
References:
1 Palmieri C, MacGregor T, Girgis S, Vigushin D. Serum 25-hydroxyvitamin D levels in early and advanced breast cancer. J Clin Path.2006;59;1334-1336.
2 Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ. 25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion by bovine parathyroid cells. Kidney Int. 2006 Aug;70(4):654-9.
3 Chattopadhyay N, Brown EM. Role of calcium-sensing receptor in mineral ion metabolism and inherited disorders of calcium-sensing. Mol Genet Metab. 2006 Nov;89(3):189-202.
4 Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006 Jun;17(6):897-907.
5 Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006 Jul;84(1):18-28. Review
6 Wigington DP, Strugnell SA, Knutson JC. Pamidronate and 1,24(S)-dihydroxyvitamin D2 synergistically inhibit the growth of myeloma, breast and prostate cancer cells. Anticancer Res. 2005;25:1909-17.
We read with interest the case report of an adenocarcinoma arising in a gastrocystoplasty [1]. The authors also mention another report of a transitional cell carcinoma developing within a gastrocystoplasty [2] . We would like to point out however that a signet ring cell variant of adenocarcinoma within a gastrocystoplasty has also been described [3]. Briefly a 36-year-old man presented with renal failure...
We read with interest the case report of an adenocarcinoma arising in a gastrocystoplasty [1]. The authors also mention another report of a transitional cell carcinoma developing within a gastrocystoplasty [2] . We would like to point out however that a signet ring cell variant of adenocarcinoma within a gastrocystoplasty has also been described [3]. Briefly a 36-year-old man presented with renal failure having undergone a gastrocystoplasty for the treatment of a neuropathic bladder fourteen years earlier. He was subsequently found to have an anaplastic signet ring cell carcinoma which was invading the muscularis propria of both the gastric and vesical segments at the anastomosis and extended into the intramural segment of the wall of the left ureter. These observations would suggest that tumour formation is a late, but significant complication of gastrocystoplasty. Sixty cases of carcinoma formation within augmentation cystoplasties have now been described and there is evidence to suggest that the enterocystoplasties are genetically unstable and have an inherent potential for tumour formation [4-6]. Furthermore,
tumours arising within enterocystoplasties are often aggressive, have a high mortality and are not usually detected by routine follow up cystoscopy [7].
There is some evidence to indicate that histological changes characteristic of chronic inflammation, metaplasia, and dysplasia as well as benign and malignant neoplasms may be more common in gastrocystoplasties than in either colocystoplasties or ileocystoplasties [8,9]. We agree with the authors that patients with a gastrocystoplasty should be followed up long term but would suggest that such patients
should be informed of the potential risks of long term malignant transformation before undergoing the procedure. We would also suggest that it may be worthwhile to determine whether chromosomal abnormalities at the gastrovesical anastomosis may be useful in identifying those patients most at risk from malignant transformation.
References:
1. Balachandra B, Swanson PE, Upton MP, Yeh MM. Adenocarcinoma arising in a gastrocystoplasty. J Clin Pathol 2007; 60: 85-7.
2. Qiu H, Kordunskaya S, Yantiss RK. Transitional cell carcinoma arising in the gastric remnant following gastrocystoplasty: a case report and review of the literature. Intl J Surg Pathol 2003; 11: 143-7
3. Baydar DE, Allan RW, Castellan M, Labbie A, Epstein JI. Anaplastic signet ring cell carcinoma arising in gastrocystoplasty. Urology 2005; 65: 1226
4. Ivil KD, Jenkins GJ, Parry EM, Parry JM, Stephenson TP. Identification of early p53 mutations in clam ileocystoplasties using the restriction site mutation assay. J Urol 2003; 169 (Suppl 4): 139.
5. Ivil KD, Doak SH, Jenkins SA, Parry EM, Kynaston HG, Parry JM, Stephenson TP. Fluorescence in-situ hybridisation on biopsies from clam ileocystoplasties and on a clam cancer. Br J Cancer 2006; 94: 891-89.
6. Appanna TC, Doak SH, Jenkins SA, Kynaston HG, Stephenson TP, Parry JM. Comparative genomic hybridization (CGH) of augmentation cystoplasties. Int J Urol 2007. In Press.
7. Filmer RB, Spencer JR. Malignancies in bladder augmentations and intestinal conduits. J Urol 1990; 143: 671-8.
8. Buson H, Diaz DC, Manivel JC, Jessurun J, Dayanc M, Gonzalez R. The development of tumors in experimental gastroenterocystoplasty. J Urol 1993; 150: 730-3.
9. Little JS, Klee LW, Hoover DM, Rink RC. Long-term
histopathological changes observed in rats subjected to augmentation cystoplasty. J Urol 1994; 152: 720-4.
In the article by Wareham et al. (1) the authors discuss a case report of atypical endocarditis following innoculation of Capnocytophaga canimorsus from a dog bite, and briefly review the history and management of C. canimorsus infections. There are numerous reports describing the association between the normal flora, gram-negative rod, C. canimorsus and human cardiovascular pathology (2-6). A recent report...
In the article by Wareham et al. (1) the authors discuss a case report of atypical endocarditis following innoculation of Capnocytophaga canimorsus from a dog bite, and briefly review the history and management of C. canimorsus infections. There are numerous reports describing the association between the normal flora, gram-negative rod, C. canimorsus and human cardiovascular pathology (2-6). A recent report suggests that C. canimorsus may escape the immune system by interfering with TNF-alpha expression and NO induction resulting in an insufficent proinflammatory
response (7).
Yet infections aside, dog bites account for 12th leading cause of non -fatal injuries (all ages) in the United States (8). Thus, the human suffering alone (17 deaths, 6000 hospitalizations, > 330,000 emergency
department visits a year) and the associated economic impacts justify further efforts to prevent dog bites (9).
In conclusion, the first documented report of a C. canimorsus infection in a rabbit inflicted with a dog bite (10) further highlights the need for developing a comprehensive bite prevention program (11), and
better laboratory methods for accurate diagnosis (12).
References:
1. Wareham DW, Michael JS, Warwick S, Whitlock P, Wood A, Das SS. The
dangers of dog bites. J Clin Pathol. 2007 Mar;60(3):328-329.
3. Butler T, Weaver RE, Ramani TK, Uyeda CT, Bobo RA, Ryu JS, Kohler
RB. Unidentified gram-negative rod infection. A new disease of man. Ann
Intern Med. 1977 Jan;86(1):1-5.
4. Frigiola A, Badia T, Lovato R, Cogo A, Fugazzaro MP, Lovisetto R,
Di Donato M. Infective endocarditis due to Capnocytophaga canimorsus. Ital
Heart J. 2003 Oct;4(10):725-7.
5. Shankar PS, Scott JH, Anderson CL. Atypical endocarditis due to
gram-negative bacillus transmitted by dog bite. South Med J. 1980
Dec;73(12):1640-1.
6. Lion C, Escande F, Burdin JC. Capnocytophaga canimorsus infections
in human: review of the literature and cases report. Eur J Epidemiol. 1996
Oct;12(5):521-33. Review.
7. Shin H, Mally M, Kuhn M, Paroz C, Cornelis GR. Escape from immune
surveillance by Capnocytophaga canimorsus. J Infect Dis. 2007 Feb
1;195(3):375-86.
8. Sosin DM, Sacks JJ, Sattin RW. Causes of non-fatal injuries in the
United States, 1986. Accid. Anal. Prev. 1992; 24:685-687.
9. Quinlan KP, Sacks JJ. Hospitalizations for Dog Bite Injuries
[letter] JAMA 1999; 281:232-233.
10. van Duijkeren E, van Mourik C, Broekhuizen M, Leuven M, Gaastra W,
Houwers D. First documented Capnocytophaga canimorsus infection in a
species other than humans.
Vet Microbiol. 2006 Nov 26;118(1-2):148-50.
11. AVMA Task Force on Canine Aggression and Human-Canine
Interactions. A community approach to dog bite prevention. JAVMA 2001;
218: 1732-1749.
The histopathological assessment of prognostic factors in rectal cancer is important in guiding management. One of these factors is the circumferential resection margin (CRM). The involvement of CRM by tumour indicates a high risk of local recurrence, and is also an indicator of the quality of surgery performed1. Eid et al2 attempted to investigate the
effects of processing variability on the assessment of...
The histopathological assessment of prognostic factors in rectal cancer is important in guiding management. One of these factors is the circumferential resection margin (CRM). The involvement of CRM by tumour indicates a high risk of local recurrence, and is also an indicator of the quality of surgery performed1. Eid et al2 attempted to investigate the
effects of processing variability on the assessment of lateral (circumferential) resection margins in rectal cancer, however, there are several issues which raise concern.
The usefulness in measuring the longest perpendicular resection margin is dubious. Surely it is the nearest distance of tumour to the CRM, which holds the relevant prognostic information. It would have been more useful had the authors detailed whether the changes in the distance of the tumour to the CRM had made any difference to the pathological staging, and thus, were of clinical significance.
The selection of the duration of formalin fixation, in particular the longer period of 7 days, used to compare artefactual changes is a curiosity. Although there are no guidelines to indicate the optimum duration colorectal cancer specimens have to be immersed in formalin prior
to dissection, with increasing pressure to improve turnaround times and meet deadlines, it would be a surprise that they languish in formalin for up to 7 days before examination by a histopathologist. It is also best to
avoid over-fixation in formalin as this may cause irreversible alteration in protein structures, which may be resistant to antigen unmasking techniques, thus compromising immunohistochemical studies, when required.
It was not made clear why the authors chose to use fresh control specimens when their study specimens had at least 4 days of formalin fixation prior to dissection. Moreover, the authors failed to explain the rationale of sectioning the fresh control specimens into smaller pieces of 10mm lengths and why the duration of formalin fixation of these pieces was different to the study specimens. The authors also appear to investigate a different variable in their control and study specimens, longitudinal and transverse measurements, respectively. Thus, the comparison of control and study specimens is tenuous.
The paper’s title was misleading and alluded to processing variability, however, the only variable studied is the duration of formalin fixation. There are several steps involved in the preparation of a tissue sample for histological examination. Generally, it encompasses
fixation (usually by formalin), processing and embedding (the paraffin wax technique is the commonest) and sectioning. Contrary to the facts presented by the authors, formalin does not cause tissue shrinkage as a result of dehydration; it works by cross-linking proteins which results in firmness of the tissue. Tissue dehydration occurs during the processing stage whereby the tissue is subjected to progressive increased concentrations of ethanol. Furthermore, the authors gave no description of the processing technique used in their study and it is unclear where the rehydration stage, as described, takes place. It is therefore impossible to critically analyse their technique and accept their unexpected finding of tissue expansion.
Last but not least, it is a concern that the assessment of CRM may be suboptimal by the very economical application of yellow ink to the specimen illustrated in Figure 1. This appears to imply that tumour growth is restricted to a particular wall, when in actuality, many rectal cancers
are circumferential. It is certainly not possible to predict the location and depth of tumour invasion prior to sectioning. The practice illustrated by the authors is not in accordance with the Royal College of Pathologists minimum dataset for colorectal cancer, which recommends painting the
entire CRM with silver nitrate or India ink prior to dissection.
As there is a paucity of literature that examines the effects of formalin fixation on the histopathological assessment of CRM, the authors’ effort in attempting to address this is commendable, however, the study methodology and finding do not stand up to scrutiny.
References
1. National Minimum Dataset for Colorectal Cancer. The Royal College of Pathologists 1998.
2. Eid I, El-Muhtaseb MS, Mukherjee R, et al. Histological processing variability in the determination of lateral resection margins in rectal cancer. J Clin Pathol 2007; 60:593-595.
An interesting recent article by Sheehan et al. in your journal investigated whether the MIB-1 (Ki-67) labelling index in astrocytoma tissue cores – designed to replicate unrepresentative biopsies – could provide valuable information concerning tumor grade. The authors studied
134 cases of glioma and found that Ki-67 may be used to exclude low-grade astrocytoma, but cannot be used to distinguish between gli...
An interesting recent article by Sheehan et al. in your journal investigated whether the MIB-1 (Ki-67) labelling index in astrocytoma tissue cores – designed to replicate unrepresentative biopsies – could provide valuable information concerning tumor grade. The authors studied
134 cases of glioma and found that Ki-67 may be used to exclude low-grade astrocytoma, but cannot be used to distinguish between glioblastoma multiforme and anaplastic astrocytoma. They found that a MIB-1 staining count greater than 3.07% practically excludes low-grade astrocytoma,
although any MIB-1 count below that threshold cannot exclude anaplastic astrocytoma or glioblastoma multiforme.[1] This is of paramount importance since both anaplastic astrocytoma and glioblastoma multiforme require different therapeutic approach and carry diverse prognosis from low-grade
astrocytoma.
Our ongoing research deals with the usefulness of functional brain tumor imaging by single-photon emission computed tomography (SPECT). We currently investigate the imaging properties of technetium-99m-Tetrofosmin
(99mTc-TF), a lipophilic diphosphine routinely used for myocardial perfusion imaging that also displays tumor-seeking properties. We found that 99mTc-TF SPECT can reliably distinguish glioma recurrence from radiation necrosis and neoplastic from non-neoplastic intracranial
hemorrhage.[2,3] We also evaluated the relationship between glioma proliferation (as expressed by Ki-67) and the uptake of 99mTc-TF. We performed brain SPECT within a week prior to glioma surgical excision and then assessed the tumoral tracer uptake visually as well as semiquantitatively, by a method of lesion-to-normal uptake ratio calculation described elsewhere.[3,4] Statistical analysis verified that
the intensity of 99mTc-TF uptake displayed a linear strong positive correlation with Ki-67 expression.[4]
Since tumor immunostaining requires direct tissue sampling, a functional (metabolic) imaging technique to provide before surgery a non-invasive estimate of glioma proliferative potential, would be of particular clinical and prognostic value. In view of the unambiguously solid correlation between 99mTc-TF uptake and cellular proliferation in our series, we believe that 99mTc-TF brain SPECT could provide substantial additive information preoperatively to optimize patient management and
treatment. For example, it could guide tissue sampling biopsy towards the tumor region displaying maximal tracer uptake activity. We consider this initial evidence as strong enough to substantiate further research regarding the clinical utility of this imaging modality.
References 1. Sheehan KM, Burke M, Heffernan J, et al. Unrepresentative Astrocytoma biopsy sampling is partly overcome by assessment of the MIB-1 labeled growth fraction. J Clin Pathol. 2007;5: [Epub ahead of print].
2. Alexiou GA, Fotopoulos AD, Papadopoulos A, et al. Evaluation of brain tumor recurrence by 99mTc-Tetrofosmin SPECT – A prospective pilot study. Ann Nucl Med (in press; DOI: 10.1007/s12149-007-0027-x).
3. Alexiou GA, Bokharhii JA, Kyritsis AP, et al. Tc-99m Tetrofosmin SPECT for the differentiation of a cerebellar hemorrhage mimicking a brain metastasis from a renal cell carcinoma. J Neurooncol 2006;78:207-8.
4. Alexiou GA, Tsiouris S, Goussia A, et al. Evaluation of glioma proliferation by 99mTc-Tetrofosmin. Neurooncol (in press)
HPV (Human Papilloma Virus) is known to be related to cancers for a long time. However it was only recently that breakthrough has been made to introduce vaccines that can prevent HPV infection. The reason for this is that HPV infections are rarely, if ever, immediately ife-threatening.
Vaccination has always focused towards preventing causes of immediate death or disability.
HPV (Human Papilloma Virus) is known to be related to cancers for a long time. However it was only recently that breakthrough has been made to introduce vaccines that can prevent HPV infection. The reason for this is that HPV infections are rarely, if ever, immediately ife-threatening.
Vaccination has always focused towards preventing causes of immediate death or disability.
The importance of HPV vaccination has not been recognised either by healthcare providers or recipients as most of the HPV infections are silent but at least 50 percent(1) of sexually active men and women acquire genital HPV infection at some point in their lives. By age 50, at least 80
percent of women will have acquired genital HPV infection, manifest or otherwise.
The study conducted by Professor Margaret Stanley has dealt with HPV as aetiology, primarily of cervical cancer. However, HPV is also known to have a role in the causation of colorectal cancers, bladder cancers and head and neck cancers. In a study(2) conducted by National Cancer
Institute, NIH, Bethesda, Maryland, it was seen that more than 50% of patients with colorectal cancers were positive for HPV DNA, where as the controls were negative for the same. This implies that even though HPV cannot be designated as the causative factor in colorectal cancers, it does increase the risk of development of these cancers. Further, more than one-third of patients who were positive had the HPV 16 subgroup.
Though the protection provided by the vaccine is not 100%, the study has still proved a 70% efficacy of the vaccine. Vaccines that are part of the British National Vaccination Schedule vary in their efficacy. For example, the influenza vaccine(1) is only 50%- 60% effective in preventing influenza-related hospitalization or pneumonia in adults > 65 years, but it is still strongly advocated since it decreases a substantial amount of morbidity and burden of disease in the general population.
Cancer Prevention is a very important part of healthcare provided by the NHS (National Health Service) in the United Kingdom (UK). There are organised, active cancer screening programmes(3) for the prevention of colon cancer, cervical cancer and breast cancer. HPV vaccination along with screening programmes can effectively be part of a multi-modal approach to cancer prevention and treatment if introduced as a part of the British National Vaccination Schedule in the UK.
There is the question of cost-effectiveness in introducing HPV vaccination in the British National Vaccination schedule as its role is less important in males than in females. However, there have been studies which show that HPV has a role in causation of male genital warts,
carcinoma in situ and invasive carcinoma of the penis(4). In addition, as the study by Professor Margaret Stanley suggests, vaccination of young boys would help in establishing herd immunity, thus helping to prevent
cervical cancer. Hence, though the significance of HPV vaccination is lesser in males due to the lower incidence of penile cancer, vaccination is still important in males in preventing penile cancer and cervical cancer.
Since, at present there is no effective treatment for HPV infection except for removal of warts and excision of tissue damaged by the virus where possible, in my opinion HPV infections is better dealt with before it infects the body, than after.
References:
1. Centre for Disease Control and Prevention,Sexually Transmitted Diseases.
2. Clinical Cancer Research Vol. 11, 2862-2867, April 15, 2005
3. www.cancerscreening.nhs.uk
4. International Journal of Cancer, 2005 Sep 10;116(4):606-16.
Persistent enteroviral infection in gastric tissue is found in a high percentage of cfs-patients by Chia & Chia (Sept. 13, 2007) while histological changes are not specifically addressed in this paper. A comparison between cfs - and non-cfs enterovirus positive patients with
regard to local inflammatory reaction would be of interest, though, as the lack of a proper inflammatory response to infectious agents...
Persistent enteroviral infection in gastric tissue is found in a high percentage of cfs-patients by Chia & Chia (Sept. 13, 2007) while histological changes are not specifically addressed in this paper. A comparison between cfs - and non-cfs enterovirus positive patients with
regard to local inflammatory reaction would be of interest, though, as the lack of a proper inflammatory response to infectious agents is a common finding in postinfectious fatigue syndrome, and the symptoms are easily dismissed as psychosomatic.
Among the comparatively few that later develop cfs or myalgic encephalomyelitis (me) that see a doctor during the initial stages of a triggering infection, a lack of adequate inflammatory response is frequently seen not only with respect to fever and enlarged lymph nodes, but also to SR, CRP and white cell count, even in the presence of ongoing
infection verified otherwise. An exception to the rule are cases that present with low grade fever and enlarged lymph nodes, that may persist for months and years despite no other evidence of ongoing infection. Cfs/me is for instance rarely diagnosed following meningitis, whereas it may be triggered by what is perceived as a mild encephalitis - although these conditions almost invariably coexist.
During the Cumberland epidemic, white cell count was in the lower normal range (Wallis, 1957). During the Los Angeles epidemic in 1934 that ran parallel to a polio epidemic, patients failed to present changes in cerebrospinal fluid and the epidemic was known as atypical polio (Hyde, 1992). Only rarely do patients with polio develop cfs/me. The postpolio syndrome is postponed by several decades. Why?
Epidemics that presented with similar features as the Cumberland and Los Angeles epidemics were included in the proposed designation benign myalgic encephalomyelitis in 1956 although the –itis was difficult to establish as such. Variability with respect to findings in cerebrospinal
fluid (Ramsay, 1986) strengthened the notion that viral infections were crucial in initiating this condition when agents were not identified. These findings do not, however, preclude the notion that cfs/me is an erratic expression or a forme fruste of the classical inflammatory reaction and, albeit harmful, may be perceived as a type of general
reaction mode to various inflammatory agents, in keeping with vast clinical experience.
References 1. Chia JKS and Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol 2007; 0:1-6 (online)
2. Wallis, AL. An investigation into an unusual disease seen in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years. University of Edinburgh 1957, M.D. Thesis.
3. Hyde, BM (ed). The clinical and scientific basis of myalgic encephalomyelitis chronic fatigue syndrome. Ottawa 1992, The Nightingale Research Foundation
4. Ramsay, AM. Postivral fatigue syndrome The saga of Royal Free disease. London 1986, Gower Medical Publishing
The TMPRSS2-ERG has been described in several prostate cancer patients' cohorts. The article by Ashish et al. describes the frequency of this fusion in another patient cohort. It further demonstrates that the frequency of TMPRSS2-ERG is increased in moderate to poorly differentiated tumors. We would like to congratulate the authors on their interesting study and advocate that more work still has to be carrie...
The TMPRSS2-ERG has been described in several prostate cancer patients' cohorts. The article by Ashish et al. describes the frequency of this fusion in another patient cohort. It further demonstrates that the frequency of TMPRSS2-ERG is increased in moderate to poorly differentiated tumors. We would like to congratulate the authors on their interesting study and advocate that more work still has to be carried out to investigate and characterize the true frequency and association of TMPRSS2-ERG gene fusion in prostate cancer. Earlier reports have generated conflicting results about the association of the TMPRSS2-ERG with Gleason score. It has been demonstrated earlier that the rate of fusion positive tumours is actually lower in the poorly differentiated tumours.1 This latest finding was confirmed by our own study (data not published). These results should be further confirmed in larger and multiple cohorts as we investigate the TMPRSS2-ERG gene fusion as a biomarker of aggressive prostate cancer.
References: 1. Tu et al Modern Pathology (2007) 20, 921-928
Intracavitatory metastases may either be left-sided, as documented
in a recent case report1, or right-sided, as documented in two previous
case reports2,3, both cases in the latter two reports2,3
characterised by symptomatic right-sided cardiac failure attributable, in
the second of the two cases to the fact that tumour cells originating from
the right intracavitatory...
Intracavitatory metastases may either be left-sided, as documented
in a recent case report1, or right-sided, as documented in two previous
case reports2,3, both cases in the latter two reports2,3
characterised by symptomatic right-sided cardiac failure attributable, in
the second of the two cases to the fact that tumour cells originating from
the right intracavitatory secondary deposit had been seeded into the
pulmonary circulation3(fig. 4), mimicking pulmonary thromboembolism. The tumour itself was composed of papillary glandular epithelium with vesicular nuclei charcterised by moderate mitotic activity.
What also distinguished the intracavitatory deposit in the latter case was
that no primary tumour could be identified, even after an extensive post-
mortem examination. This was contrary to the expectation that cardiac
metastases are typically associated with an identifiable primary tumour,
as was the case in 56 out of 57 patients with cardiac metastases
documented in one necropsy study4. Arguably, as well, the seeding of
tumour deposits from the right intracavitatory tumour deposit to the
pulmonary circulation was an example of what might be better termed
"tertiary" dissemination, given the fact that it originated from an
identifiable secondary deposit, via a haematogenous route unique to the
site of that secondary deposit, rather than being an example of secondary
dissemination from an unknown primary. This implies that, in that
particular instance, the heart itself was the sole site of secondary
dissemination from the unknown primary. For the heart to be the "only
target of metastases" is distintly unusual, having been documentd in only
10 out of 662 cases in one series, all ten of those cases having an
identifiable primary site of origin of the cardiac metastases5.
Oscar M Jolobe
References
(1) Gupta K., Joshi K., Aggarwal AN., Vaiphei K
Asymptomatic polypoidal intracavitatory cardiac metastases from pulmonary
adenocarcinoma
Journal of Clinical Pathology 2008:61:142
(2) Hull HK., Usmani O
Intracavity right ventricular metastasis
Lancet 2006:367:424
(3) Jolobe OMP
Cor pulmonale: variation on a theme
Postgraduate Medical Journal 2001:77:675-77: correction of erratum in
Postgraduated Medical Journal 2002:78:62
(4) Metastatic and invasive tumours involving the heart in a geriatric
population: a necropsy study
Virchows Archiv A Pathological Anatomy and Pathology 1991:419:183-9
(5) Bussani R., De-Giorgio F., Abbate A., Ailvestri F
Cardiac metastases
Journal of Clinical Pathology 2007:60:27-34
We read with interest the paper by Borgquist et al (2008),
published recently in Journal of Clinical Pathology1. In their article
the authors aimed to investigate the impact of ERbeta expression on breast
cancer outcome using a cohort of 512 tumours represented in tissue
microarray (TMA). Since the discovery of ERbeta over a decade ago, this
has been the goal of many research groups. However pr...
We read with interest the paper by Borgquist et al (2008),
published recently in Journal of Clinical Pathology1. In their article
the authors aimed to investigate the impact of ERbeta expression on breast
cancer outcome using a cohort of 512 tumours represented in tissue
microarray (TMA). Since the discovery of ERbeta over a decade ago, this
has been the goal of many research groups. However progress in this area
has been impeded by the lack of a consensus in terms of choice of primary
antibody and cut-off value used to determine ERbets postivity2,3.
Additionally, we know that ERbeta exists as 5 isoforms (ERbeta1-5), each
formed by alternative splicing of the last coding exon4,5, which has
further complicated interpretation of immunohistochemical studies.
Comparative studies have been conducted to help determine the most
suitable antibody for a number of applications and of these, 2 reliable
antibodies have emerged for immunohistochemistry: 14C8 (AbCam, Cambridge,
UK), located in the N-terminus of the ERbeta peptide and which detects
most isoforms of ERbeta and PPG5/10 (Serotec, Oxford, UK) which is
specific for ERbeta12,6,7. We routinely use both these antibodies in
our immunohistochemical studies. Borgquist et al1 used a different
antibody, EMR02 (Novocastra, Newcastle-upon-Tyne), which is claimed
through epitope mapping studies to show specific reactivity to a 17-amino
acid sequence present in the C-terminus of full length wild type ERbeta
and which is absent in ERbeta2/ERbetacx 8. While Borgquist et al1 show
immunohistochemical and Western blot analysis of ERbeta in a panel of
breast cell lines we find it remarkable that they showed no staining of
their breast TMAs especially as all the survival data presented in the
paper was obtained from these. Using cell lines to validate antibodies is
certainly a step in the right direction but it is insufficient as tissue
characteristics and processing protocols will almost certainly differ
substantially from those used in cell lines and these may alter antibody
specificity and sensitivity.
In addition, the authors used a very low cut off value to define
ERbeta positivity (1%) and with such a value we find it surprising that
the percentage of ERbeta positive tumours was only 50% - substantially
less than in many previous studies6,9-12. We believe this could
indicate an issue with antibody specificity and suggest this be confirmed
through peptide absorption studies.
Finally, as part of or on-going programme to understand the
significance of ERbeta in breast carcinogenesis, when EMR02 antibody
became available, we compared its efficacy to the well-validated 14C8 and
PPG5/10 antibodies which we use routinely. As illustrated in Figure 1, we
were unable to achieve robust and consistent staining using EMR02, while
TMA and full sections of breast carcinoma were clearly stained with 14C8
and PPG5/10.
Figure 1 - Serial sections of TMAs (top panel) and full sections (bottom panel) of breast carcinomas stained with EMR02 (a, d), 14C8 (b, e) and PPG5/10 (c, f). Consistent staining was only observed for 14C8 and PPG5/10 with EMR02 unable to detect the protein.
There still remains a great deal of controversy and indeed suspicion
surrounding the potential importance of ERbeta in breast cancer. We
believe to a large extent this is due to the use of poorly validated
antibodies which have poisoned the field somewhat. We urge all scientists,
clinicians and journals to be aware of the need for carefully validated
studies to help eliminate these controversies which, more than a decade
on, still continue to cloud ERbeta.
Valerie Speirs
References
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beta show different associations to clinicopathological parameters and
their co-expression might predict a better response to endocrine treatment
in breast cancer. J Clin Pathol 2008;61:197-3.
2. Carder PJ, Murphy CE, Dervan P, et al. A multi-centre investigation
towards reaching a consensus on the immunohistochemical detection of
ERbeta in archival formalin-fixed paraffin embedded human breast tissue.
Breast Cancer Res Treat 2005;92:287-93.
3. Shaaban AM, Speirs V. Estrogen receptor beta - which one and where
should we draw the line? Hum Pathol 2006;37:498.
4. Moore JT, McKee DD, Slentz-Kesler K, et al. Cloning and
characterization of human estrogen receptor beta isoforms. Biochem Biophys
Res Commun 1998;247:75-8.
5. Poola I, Abraham J, Baldwin K, et al. Estrogen receptors beta4 and
beta5 are full length functionally distinct ERbeta isoforms: cloning from
human ovary and functional characterization. Endocrine 2005;27:227-38.
6. Skliris GP, Parkes AT, Limer JL, et al. Evaluation of seven oestrogen
receptor beta antibodies for immunohistochemistry, western blotting, and
flow cytometry in human breast tissue. J Pathol 2002;197:155-62.
7. Weitsman GE, Skliris G, Ung K, et al. Assessment of multiple different
estrogen receptor-beta antibodies for their ability to immunoprecipitate
under chromatin immunoprecipitation conditions. Breast Cancer Res Treat
2006;100:23-31.
8. Rees ML, Marshall I, McIntosh GG, et al. Wild-type estrogen receptor
beta expression in normal and neoplastic paraffin-embedded tissues. Hybrid
Hybridomics 2004;23:11-8.
9. Saunders PT, Millar MR, Williams K, et al. Expression of oestrogen
receptor beta (ERbeta1) protein in human breast cancer biopsies. Br J
Cancer 2002;86:250-6.
10. Shaaban AM, O'Neill PA, Davies MP, et al. Declining estrogen receptor-
beta expression defines malignant progression of human breast neoplasia.
Am J Surg Pathol 2003;27:1502-12.
11. Fuqua SA, Schiff R, Parra I, et al. Estrogen receptor beta protein in
human breast cancer: correlation with clinical tumour parameters. Cancer
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