Recent eLetters

Dear Editor,

Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase. If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life [1]. Cancer cells have the ability to divide infinitely and yet preserve their telomeres. How do they escape cellular senescence? One explanation became apparent with the finding that cancer cells often have increased telomerase activity [1] Telomeres, repeated sequences of DNA at the end of chromosomes, prevent degradation of genetic material. Each time chromosomes replicate a small amount of the DNA at both ends is lost, by an uncertain mechanism. Because human telomeres shorten at a much faster rate than many lower organisms, we do speculate that this telomere shortening probably has a beneficial effect for humans, namely mortality. The telomere hypothesis of aging postulates that as the telomeres naturally shorten during the lifetime of an individual, a signal or set of signals is given to the cells to cause the cells to cease growing (senesce). At birth, human telomeres are about 10,000 base pairs long, but by 100 years of age this telomere reduces to about 5,000 base pairs. Scientists discovered an important enzyme that can turn the telomere production on the DNA molecule "on" and "off." It's called telomerase. It seems that as we get older, the amount of telomerase in our cells decreases. Naturally, the exploration of this enzyme is now the focus of much investigation, but unfortunately the research is aimed at understanding how to turn telomeres "off" to limit the spread of "immortal" cancer cells. Telomerase is actually an enzyme (a catalytic protein) that is able to arrest or reverse this shortening process. Normally, telomerase is only used to increase the length of telomeres during the formation of sperm and perhaps eggs, thus ensuring that our offspring inherit long "young" telomeres to propagate the species. The telomere hypothesis of cancer is that the function of telomere shortening is to cause cells that have lost normal control over growth to senesce (i.e. stop growing) before being able to replicate enough times to become a tumor, thus decreasing the frequency of cancer. Immortal cells like cancer have an unfair advantage over normal human cells which are designed to senesce. But nature seems to have planned this human telomere shortening perhaps to prolong life by hindering the otherwise unchecked growth of non-immortal or benign tumors. Malignant, or immortal tumors can simply outlive the rest of the organism. Malignant cancer cells are being studied because they appear to have altered the shortening of telomeres by turning "on" the telomerase. Thus it appears that some cancers and aging are both connected with the biology of telomeres. So telomerase-inhibiting drugs would probably kill the cancer cells before much damage is done to normal cell

Today reduction in mortality in breast cancer is due to early detection through screening by mammography. However at least 25% reduction in mortality could have been achieved due this screening procedure [early-stage pre menopausal breast cancer, for example, 10-year survival rates is today 68% for African Americans versus 77% for Caucasians]. Besides these there played other factors also and these are 1) systemic or improved systemic treatment with chemotherapy 2) adjuduvant therapies after surgery to eliminate micro metastasis like Her2 Nue antagonist Herpentine and to prevent recurrences. Women with steroid hormone receptor[ER+ or PR+] positive and negative cases are benefited by Cyclopshomide & methotraxate & 5 FU chemotherapeutic agents. More effective adjuduvant endocrine treatments are with variuous aromatase inhibitors like letrozole or anastrozole. Cases of breast cancers occur even when there is no family history or only a few cases in elderly relatives are known as sporadic breast cancer. Hereditary breast cancer is different from those of sporadic breast cancer .The increased risk of breast cancer for those with a family history may be caused by inherited factors (genes) like BRCA1 and BRCA2,[both the genes protects breast cells from developing cancer. Certain mutations in BRCA1 stop the gene working properly and therefore make it more likely that breast cancer will develop],or a combination of inherited factors and lifestyle like no breast feeding or unmarried women. Having an increased genetic risk by mutation of these two genes can lead to breast cancer developing even at an earlier age. BRCA1 and TP53 genes are of high penetrance genes for breast Cancers. Mutations in the rare high penetrance breast cancer predisposing genes are BRCA1 and BRCA2 and they account for 16 to 25% of the inherited component of breast cancers in the world scenario.This, in turn, can have an impact on raising your family. So is it today possible to do BRCA1 gene test for people that know they carry a specific mutation that predisposes them to suffer from breast cancer. It is a real fact that most Breast cancers develop sporadically and not related with a familial history or hereditary BRCA genes. It is thought that less than 5% of people those develop breast or bowel cancer do so because of an inherited fault. Unless there is a strong family history of breast cancer in you it is unlikely that your child will inherit a gene that increases the risk of developing cancer. So splicing off BRCA1 gene before embryo may be an advancement for medical technology [2]. Mutations in TP53, which at same time may cause the Li Fraumeni syndrome, STK11 gene causing Peutz Jeghers syndrome, and PTEN causing Cowden syndrome are however very uncommon sporadic causes of breast cancers of NOS type, as are mutations in CDH1, although these mutations may be highly penetrant for breast cancer The intermediate penetrance breast cancer susceptibility genes are mutations in ATM, CHEK2, BRIP1, BARD1, and PALB2. They can cause an increased odds ratio for breast cancer of 2 to 4. These genes are all involved in the same DNA repair pathways, but it is curious that they do not confer the high risk of breast cancer seen in women who carry mutations in BRCA1 and BRCA2. Also of great interest is that biallelic mutations in BRCA2, BRIP1, and PALB2 cause Fanconi anaemia subtypes FANC D, J, and N respectively, further indicating overlap in the functions of these genes. There are also good evidences now that there are up to eight polymorphisms, which are reproducibly found to influence breast cancer risk, particularly the FGFR2 gene. Carriers of two low risk rs2981582 alleles at the FGFR2 locus (frequency 38% of the population) have a relative risk of breast cancer of 0.83 compared with the general population, carriers of one high-risk and one low-risk allele (47%) have a relative risk of 1.05, and carriers of two high-risk alleles (14%) have a relative risk of 1.26

Telomere crisis is also an important early event in the development of breast cancer. In the breast, cells in a milk-collecting duct occasionally proliferate excessively due to development of a regulatory defect and results usual ductal hyperplasia." The chromosomes in these growing cells lose a hundred or so base pairs of DNA every time they divide," ,because the usual DNA replication processes don't copy DNA all the way out to the ends of the chromosomes. This erodes the DNA sequences that interact with proteins to form structures called telomeres, which protect the chromosome ends. Eventually the DNA ends erode so much they can no longer protect the chromosomes. When this happens the chromosomes become unstable, and damage-control mechanisms kick in that kill the unstable cells. This process, known as "telomere crisis Cells in which telomerase is activated can then proliferate indefinitely to form the next stage of cancer, known as 'ductal carcinoma in situ.' The mean telomere length is found decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers of breast. It was therefore proposed that breast cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity[1] "

Authors

Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.) Mr. Ritwik Bhattacharya, B.Com(cal) Mr. Rupak Bhattacharya BSc Mrs Dahlia Mukherjee BA (hons) Miss Upasana Bhattacharya of Mahamyatala, Dr. Debashis Bhattacharya Ms(cal) FRCS(Edin) Dr. Diptendra Narayan Sarkar Dr. Tarun Biswas MBBS(cal)- Dr. Satyaki Mitra MD(PGT) Dr. Avisnata Das MBBS(cal),

References
1] Press Release on the 5 October 2009 “The Nobel Prize in Physiology or Medicine 2009â€� by The Nobel Assembly, consisting of at Karolinska Institutet, Sweden

2] Response by Professor Pranab Kumar Bhattacharya Published by BMJ on 4th feb 20009 .for the BMJ case reports Blog unnatural selection by author Dean Jankens, published on 9th Jan 2009

Dear Editor

We thank Drs Rotimi and Reall for their comments, but would suggest that their criticisms have been framed by a perspective that is different from our own. Their perspective is the “most striking result” was that sessile serrated adenomas (SSAs) were predominantly right sided. They are welcome to highlight this point, which is readily apparent from the data presented.

Our perspective is that the right sided predominance of SSAs is well known, and widely reported in the literature. Hence we did not highlight this finding. Their perspective is that a frequency of 4% of all polyps is not “common”. From our perspective, four in every 100 polyps is “common”, and we believe this point is worth emphasising because in many practices SSAs are reported rarely, if ever. Again, the quantitative information is available to readers, who are welcome to interpret it as they see fit.

We would argue that although “common” is a relative and qualitative term, it is misleading to propose that SSAs are not common in routine practice. Finally, Drs Rotimi and Reall are concerned that our statistical tests may have been inappropriate. We have the happy perspective of knowing the age distribution of the groups in question (serrated and non- serrated polyps). We can assure them that these distributions are normal, and that the use of parametric tests is indeed appropriate in this case.

Nicholas J Hawkins, Norman J Carr, King L Tan, Hema Mahajan, Robyn L Ward,

Dear Editor,

Re: Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma

We read with interest the article by Carr NJ et al (J Clin Pathol 2009;62:516-518). The article describes the prevalence of different colorectal polyps in an unselected population with a focus specifically on sessile serrated adenomas (SSAs) and their correlation with BRAF mutation.

We found the most striking result in this paper presented in Table 1. SSAs (as defined by the authors) were predominantly seen in the right side of the colon (51 on the right and 6 on the left; a ratio of almost 9:1). This result is all the more emphasized by the fact that not all the patients had full colonoscopy. However, the authors failed to highlight this important result and ultimately reported that serrated polyps were more likely to be left-sided. This observation of a right-sided predominance of SSAs is in agreement with many other publications(1, 2). The finding of more right-sided SSAs have been reported to correlate with the higher number of serrated adenocarcinomas found in the right colon in other studies(3).

Also, the authors over-emphasize the prevalence of SSAs, concluding that they are seen ‘commonly in routine endoscopy practice’. The SSAs accounted for 11% of all serrated lesions and only 3.9% of all polyps in this study and such low percentages cannot and should not be reported as being encountered commonly in routine practice.

In addition, use of Student’s t test to analyse the relationship between polyp type and age may have been inappropriate given the most likely non-normal distribution of data, especially with the small numbers in the polyp subgroups. A non-parametric statistical test would have been more appropriate.

Olorunda Rotimi, FRCPath, PGDip Health Research, Georgina Reall, FRCPath

References

1. Higuchi T, Sugihara K, Jass JR. Demographic and pathological characteristics of serrated polyps of colorectum. Histopathology 2005;47:32–40.

2. Amy E. Noffsinger. Serrated Polyps and Colorectal Cancer: New Pathway to Malignancy. Annual Review of Pathology, Mechanisms of Disease 2009;4:343–64.

3. M. J. Makinen, S. M. C. George, P. Jernvall, J. Makela, P. Vihko and T. J. Karttunen. Colorectal carcinoma associated with serrated adenoma - prevalence, histological features, and prognosis. Journal of Pathology 2001; 193: 286-294

Department of Histopathology St James's University Hospital Leeds, UK

Dear Editor,

Dr. Aslam presented a rare case with peritoneal lymphomatosis and concluded that a histologic examination is crucial in the diagnosis, while cytology might sometimes mislead the workup.1 However, we present here another such case with raised CA 125 and demonstrate that cytology with a flow cytometry examination can help in the diagnosis.

This 44-year-old female suffered from autoimmune disorder and had been using steroids for several months. She was admitted to our ward due to progressive abdominal fullness, back soreness and shortness of breath. An abdominal echo revealed a pelvic mass with ascites. A computed tomography (CT) scan showed bilateral ovarian masses and multiple lymphadenopathies over the pelvic, abdominal and retroperitoneal areas. Biomarkers including CEA, SCC, AFP, CA 199, CA 153 were all within normal range except for a raised CA 125 level (125.27 U/ml, normal range 2.4~36.6 U/ml).

Ascitic fluid showing a turbid appearance was aspirated and sent for cytologic and microbiologic studies, however no micro-organisms grew from the culture. The cytologic study revealed massive lymphocytes with bizarre morphology. Flow cytometry was used to determine the characteristics of the cells, and showed positive for CD10, CD19, CD20, and negative for CD7.

Under the impression of suspected lymphoma with peritoneal lymphomatosis, CT guided biopsy of the lymph node was done. The resulting histology examination revealed a diffuse large B cell lymphoma which was positive for LCA, CD20 and negative for cytokeratin and CD7 (fig 1). She received systemic chemotherapy with R-CEOP regimen, but unfortunately died of sepsis.

Peritoneal lymphomatosis is a rare manifestation of malignant lymphoma. Although there are some criteria that tell the difference of peritoneal lymphomatosis from carcinomatosis, most of the cases are indistinguishable from the clinical presentations and image studies.2,3 Even the tumor markers, such as a raised CA 125 as in this case, cannot rule out the diagnosis of peritoneal lymphomatosis completely.4 These factors stress the importance of putting lymphoma into the list of diagnoses in such patients. We also highlight the important role of cytology examinations with flow cytometry, which might also help the physician in the diagnosis of peritoneal lymphomatosis and avoid unnecessary studies and treatment.

Hui-Hua Hsiao,^{1, 2} Yi-Chang Liu,^{1, 2} Jui-Feng Hsu,¹ Sheng-Fung Lin^1,2

1 Faculty of Medicine, College of Medicine, Kaohsiung Medical University; and

2 Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Correspondence to: Dr SF Lin, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100, Tzu-You 1st Road, Kaohsiung 801, Taiwan. E-mail: shlin@cc.kmu.edu.tw

Competing interests: none

REFERENCES

1. Aslam MB. Peritoneal lymphomatosis, a morphological look alike to peritoneal carcinomatosis: a autopsy report. J Clin Pathol 2009;62:480.

2. Kim Y, Cho O, Song S, et al. Peritoneal lymphomatosis: CT findings. Abdom Imaging 1998;23:87-90.

3. Karaosmanoglu D, Karcaaltincaba M, Oguz B, et al. CT findings of lymphoma with peritoneal, omental and mesenteric involvement: Peritoneal lymphomatosis. Eur J Radiol 2008; in press

4. Horger M, Muller-Schimpfle M, Yirkin I, et al. Extensive peritoneal and omental lymphomatosis with raised CA 125 mimicking carcinomatosis: CT and intraoperative findings. Br J Radiol 2004;77:71-3.

FIGURE LEGEND

Diffuse infiltration of medium-sized, monotonous round cells with hyperchromatic nuclei and scant cytoplasm (H&E stain, x400). Upper right: Positive CD20 reaction to the lymphoma cells and no reaction to endothelial cells.

Dear Editor

Warthin tumor (WT) of the salivary gland (so called papillary cystadenoma lymphomatosum or adenolymphoma) is a benign neoplasm of the salivary gland epithelium with a proliferative epithelial component associated with a variably prominent stroma.[1] As reported by Saxena [1], histogenesis of this entity is very controversial. WT and malignant lymphoma are rarely associated, and most are examples of involvement of the lymphoid stroma of WT by a disseminated lymphoma.[1] Less commonly, malignant lymphomas are first detected in the lymphoid stroma of WT.[1] Most of reported cases are low-grade follicular lymphoma.[2] To the best of our knowledge no well-documented cases of nodal marginal B-cell lymphoma arising from WT in the same site have been described so far.

We report the case of a 74-year-old man with a fast enlarging right parotid mass. On physical examination the mass was firm, painless, developed in the lower pole of the parotid gland. A partial parotidectomy was performed. At gross examination, the tumour measured 4.2 x 3.1 x 1.7 cm and cut surface revealed an irregular, brown mass replacing parotid gland. Histologically, the tumour was composed of cystic spaces with typical bilayered oxyphilic epithelium.(Figure 1A) This epithelium was surrounded by malignant lymphoma characterized by diffuse infiltrate of small to medium lymphoid cells composed of centrocyte-like B-cells, plasmocytoid B-cells, scattered centroblast and immunoblast-like cells.(Figure 1B) No germinal center, lympho-epithelial lesion or necrotic areas were observed. The immunohistological study demonstrated a phenotypical profile (CD20/CD79a/BCl-2+; CD3/CD5/CD10/CD21/cycline D1-) consistent with marginal zone B-cell lymphoma. (Figure 1C, D)

On the basis of morphological and immunohistological findings, a diagnosis of nodal marginal zone B-cell arising of WT's lymphoid stroma was established. A thorough staging examination, including cervical, thoracic and abdominal scans revealed no evidence of other peripheral lymph nodes involvement. All laboratory test results were normal except a small monoclonal serum protein and mild lymphocytosis which slowly increased since 2004. The immunophenotypage showed a monotypic B-cell lymphoid population with moderate Lambda light chain expression. No bone marrow biopsy was done. Because of localised disease, no treatment was started. At this time, the patient has been followed-up for 21 months, without evidence of recurrent tumoral syndrome.

Distribution of WT localization (parotid glands and periparotid lymph node and its absence from other salivary tissue lacking incorporated lymph node) seems to show that WT's histogenesis results from heteropic salivary ductal inclusions in intra- or peri-parotid lymph nodes.[3] This theory explains that most lymphomas arising of WT are follicular lymphomas, which are the most frequent of systemic lymphomas.[4] No marginal zone B-cell lymphoma arising of WT was yet reported. Only one case reported in the same parotid gland the association of two differents lesions: a WT and an extranodal mucosa-associated lymphoid tissue lymphoma.[4] Extranodal marginal zone B-cell lymphoma is probably the most common type of lymphoma truly of salivary gland origin [3] and should be distinguished from nodal lymphomas presenting in intraparotid lymph nodes which usually carry a worse prognosis. [5] Most of cases occur in women, particulary aged over 50, with a history of Sjögren's syndrome or other autoimmune disease. In our case, no history of Sjögren's syndrome or other autoimmune disease was mentioned. Futhermore, the absence of lympho-epithelial lesion is a supplementary argument for the nodal origin of the marginal zone B-cell lymphoma. This finding confirm also WT's histogenesis. Nodal marginal zone B-cell lymphomas arising of intraparotidal Warthin's tumour are real nodal lymphomas and require a thorough staging examination.

References

1. Saxena A., Memauri B, and Hasegawa W. Initial diagnosis of small lymphocytic lymphoma in parotidectomy for Warthin tumour, a rare collision tumour. J Clin Pathol. 2005;58:331-333.

2. Park CK, Manning JT, Battifora H, Medeiros LJ. Follicle center lymphoma and Warthin tumor involving the same anatomic site. Report of two cases and review of the literature. Am J Clin Pathol. 2000;113:113-119.

3. Marioni G, Marchese-Ragona R, Marino F et al. MALT-type lymphoma and Warthin's tumour presenting in the same parotid gland. Acta Otolaryngol. 2004;124:318-323.

4. Isaacson PG, Müller-Hermelink HK, Piris MA et al. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Jaffe ES, Harris NL, Stein H, Vardiman JW eds. WHO Classification Tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press, 2001:157-160.

5. Simpson RHW, Sarsfield PTL. Benign and malignant lymphoid lesions of the salivary glands. Current Diagnostic Pathology. 1997;4:91-99.