Tumour markers in malignancies
BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7232.424 (Published 12 February 2000) Cite this as: BMJ 2000;320:424All rapid responses
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Dear Editor,
Lindblom and Liljegren's review of tumour markers in
malignancies gave an interesting overview (1). One area in Head and Neck
Oncology where tumour markers can be useful is with Nasopharyngeal
Carcinomas (NPC).
NPC is a relatively rare tumour in the western world, comprising
0.25% of all cancers in North America. However, it accounts for 18% of all
cancers amongst the Chinese, and has been estimated to be the commonest
cancer in males from Taiwan (2).
Epstein-Barr virus (EBV) is associated aetiologically with NPC in high and
low incidence areas, particularly the non keratinising and
undifferentiated types. The importance of viral markers in NPC has been
intensely studied and
discussed world wide (3). They can be used in diagnosis and clinical
management of NPC, and have the potential to be used for screening
programs in high-risk areas. Indirect immunofluorescence techniques are
used to test the serum IgA assays to EBV viral capsid antigen, the diffuse
component of
early antigen and anti Epstein-Barr nuclear antigen. Positive antibody
titres may help to confirm the diagnosis of NPC in the patient who
presents only with malignant cervical lymphademopathy and an occult
primary (4).
A.P.Coatesworth
Specialist Registrar in Otolaryngology
J. Vermeiren
SHO in Otolaryngology
Leeds General Infirmary, Great George
Street, Leeds. LS1 3EX
1) Lindblom A, Lliljegren A. Tumour markers in malignancies. BMJ
2000; 320:424-7.
2) Hsu M-M, Huang S C, Lynn S C, Hsien T, Tu S M. The survival of
patients with nasopharyngeal carcinoma. Otolarygol Head Neck Surg 1982;
90:289.
3) Ablasti D V, Levine P A, Prasad U, Pearson G R. Fourth
international symposium on nasopharyngeal carcinoma: application of field
and laboratory studies to the control of NPC. Cancer Res 1983; 43:2375.
4) British Association of Otorhinolaryngologists Head and Neck
Surgeons. Effective Head and Neck Cancer Management. 1998; 76.
Competing interests: No competing interests
Linbolm and Liljegren (1) in their comments about oestrogen receptor
in their clinical review of tumour markers in malignancies failed to
acknowledge that two isoforms of the oestrogen receptor, namely ERa and
ERb, now exist and to distinguish between the two. This is important as it
is now
incorrect both scientifically and clinically to talk solely about ER as if
it were one entity.
The oestrogen receptor that they referred to in their article is the
classical oestrogen receptor or ERa (2), as noted it is a predictor of
response to endocrine treatment in the adjuvant setting and correlates
with a better prognosis. Not noted in their table is that the use of ERa
immunohistochemistry extends into the metastatic setting as a diagnostic
investigation where there is a primary of unknown origin or that ERa
expression does not guarantee response to endocrine therapy with 30-40% of
such tumours failing to respond (3).
Oestrogen receptor beta or ERb is the more recently discovered isoform,
ERa and ERb represent two separate gene products with distinct biological
roles and ligand binding specificity (4). With reference to the breast the
expression of ERb, its role in the normal and malignant breast, the
interactions between it and ERa and its use as a tumour marker are
currently being investigated. However recent immunohistochemistry of ERb
in human breast cancer has shown it to correlate with ERa positivity, low
grade and
negative axillary lymph node status ie good prognostic factors (5).
However the independent predictive value of ERb has yet to be established.
The presence of a further oestrogen receptor has opened up new avenues of
research which will lead to a clearer understanding of hormonally
dependent breast cancer and to more precise methods of predicting response
to hormonal
therapy. In addition the possibility exists for the development of more
effective hormonal treatment for breast cancer based on receptor
specificity.
Dr Carlo Palmieri
CRC Clinical Research Fellow/Honorary SpR in Medical Oncology
Mr Sam Fishpool
Medical Student
Prof R.C. Coombes
Professor of Medical Oncology
References
(1) Lindblom A and Liljegren A. Tumour markers in malignancies. BMJ
2000; 320:424-427.
(2) Jensen EV, DeSombre ER and Jungblut PW. Estrogen receptors in
hormone-responsive tissues and tumours. In Wissler RW, Dao TL, Wood S eds.
Endogenous factors Influencing Host-Tumor Balance. Chicago, IL:University
of Chiago Press, 1967: 15-30.
(3) Locker GY. Hormonal therapy of breast cancer. Cancer Treat Rev
1998; 24:221-240.
(4) Gustafsson, J-?. Estrogen receptor b- a new dimension in
estrogen mechanism of action. Journal of Endocrinology 1999; 163: 379-383.
(5) Jarvinen TAH, Pelto-Hukko M, Hollo K and Isola J. Estrogen
receptor b is coexpresed with ERa and PR and associated with nodal status,
grade and proliferation rate in breast cancer. Am J Path 2000; 156: 29-35.
Competing interests: No competing interests
Dear Sir,
In the review of “Tumour markers in malignancies” (February 12 2000)
by Lindblom and Liljegren, there is a glaring error which should have been
noted by the authors, their eleven (!) acknowledged sources, and the BMJ
reviewing editors. In the section “Tumour markers in various diseases”, it
is stated that “the Philadelphia chromosome in chronic lymphocytic
leukemia is the best known example” – referring to translocations creating
fusion proteins in haematologic diseases. This contradicts their earlier
(correct) statement that “the Philadelphia chromosome in chronic myeloid
leukemia is the best known example” (of a fusion protein associated with
malignancy).
Respectfully submitted,
Kenneth S Wilson MD FRCPE FACP FRCPC.
Competing interests: No competing interests
In their review on tumour markers Linbolm and Liljegren1 dismiss the
role of bone marrow micrometases and refer to only one review on the
subject. This is misleading and ignores important information on the
subject.
Bone marrow micrometastases can be identified in over one
quarter of patients undergoing curative resection for gastro-intestinal
cancers2,3. The diagnostic yield of this procedure is greatly enhanced by
submitting resected rib segments, rather than marrow aspirates,to
analysis3. These micrometastases
have been demonstrated to be tumourigenic and angiogenic3.
Similarly,
micrometastases have been identified in the bone marrow of a significant
number of women with node negative breast cancer4. Up to 38% of patients
with stage I and stage II breast cancer have demonstrable micrometastases
and their
presence in bone marrow reduces relapse-free survival time5.
Bone marrow micrometastases are a marker of poor prognosis in several
epithelial tumours and in malignant melanoma3,6.The detection of bone
marrow micrometastases provides objective evidence of residual disease and
may prove to be a more valuable staging parameter than tumour markers.This
ought to be discussed in any comprehensive review of tumour markers.
1.Lindblom A, Lilejegren A. Tumour markers in malignancies. BMJ
2000;320:424-427.
2.O'Sullivan GC, Collins JK, O'Brien F, Crowley K, Murphy K, Lee G,
Shanahan F. Micrometastases in bone marrow of patients undergoing curative
surgery for gastrointestinal cancer. Gastroenterology 1995;109:1535-1540.
3.O'Sullivan GC, Sheehan D, Clarke A, Stuart R, Kelly J, Kiely MD,
Walsh T, Collins JK, Shanahan F. Micrometases in esophagogastric cancer:
High detection rate in resected rib segments. Gastroenterology
1999;116:543-548.
4.Relihan N, McGreal G, Kelly J, Ryan D, O'Sullivan GC, Redmond HP.
Combined sentinel lymph-node mapping and bone-marrow micrometastatic
analysis for improved staging in breast cancer.Lancet. 1999 Jul
10;354(9173):129-30.
5.Cote RJ, Rosen PP, Lesser ML, Old LJ, Osborne MP. Prediction of
early relapse in patients with operable breast cancer by detection of
occult bone marrow micrometastases.
J Clin Oncol 1991; 9: 1749-56.
6.Gershenwald JE, Colome MI, Lee JE, Mansfield PF, Tseng C, Lee JJ,
et al. Patterns of recurrence following a negative sentinel lymph node
biopsy in 243 patients with stage I
or II melanoma. J Clin Oncol 1998; 16(6): 2253-2260.
Desmond C. Winter,
Specialist Registrar,
Department of Surgery, Cork
University
Hospital, Cork, Ireland.
Brian McNamara,
Specialist Registrar,
Department of Clinical
Neurophysiology,
Addenbrookes Hospital, Cambridge,CB2 2QQ.
Gerald C.O'Sullivan,
Director,
Cork Cancer Reasearch Centre, National
University
of Ireland, Cork.
Competing interests: No competing interests
I am a breast cancer survivor. In the United States, about one in
eight women will be diagnosed with breast cancer. In Marin, County,
California, my residence, one in seven women will be diagnosed with breast
cancer. Mammography does not diagnose many of these cancers prior to
metastasis. There is a crying need for a tumor marker test akin to the PSA
for breast cancer to facilitate earlier diagnosis. Moreover, some breast
cancer survivors would like to know if they have a recurrance prior to
developing symptoms. While outcome is not affected by such information,
some of us would plan our live differently. I therefore applaud your work
on tumor markers and pray for the early development of an accurate tumor
marker for breast cancer.
Competing interests: No competing interests
The authors fail to mention the original and still most valuable of
tumour markers, in that it is the only one used as the primary diagnostic
method for its tumour, in addition to determining length of treatment. The
marker in question is beta-hCG, used to diagnose and follow gestational
trophoblastic disease. The combination of this marker with effective
chemotherapy results in cure rates in excess of 95% for trophoblastic
disease.
The authors also make no mention of the use of alpha-fetoprotein in
monitoring ovarian endodermal sinus tumours.
Competing interests: No competing interests
Two New Tumor Markers in Malignant Melanoma
Dear Sirs - With great interest we read the article by Lindblom and
Liljegren on tumour markers in malignancies (1).
In this context, we would like to suggest adding the markers S100B protein
and MIA (melanoma inhibitory activity) for malignant melanoma to the table
on p. 426, as these markers have been found to be useful in the staging
and follow-up of
melanoma patients.
Antibodies against S100 are widely used for confirmation of
amelanotic malignant melanoma in immunohistology. The subunit S100B
measured in serum was found to be increased in 79% of metastasized
melanoma patients in stage IV(2). MIA was previously identified within
growth-inhibitory activities purified from tissue culture supernatant of
malignant melanoma cells in vitro and it was shown to
be especially increased in stage IV melanoma patients (3).
In a recent blind study (4) of four different centers in Germany, 22 out
of 37 (59%) of stage III and 157 out of 176
(89%) stage IV patients were preoperatively found to have increased MIA
serum levels. Decrease of tumor load under therapy is also correlated with
decreasing serum levels of MIA (3,4) and S100B (5) and, under progression,
serum levels are rising.
In our opinion, this data and several other studies provide sufficient
evidence to recommend MIA and S 100B measurements for the staging and
follow-up of melanoma patients with a high risk of the subsequent
development of metastases.
1. Lindblom A, Liljegren A. Tumor markers in malignancies. BMJ 2000;
320:424-7
2. Henze G, Dummer R, Joller-Jemelka HI, Böni R, Burg G. Serum S100--
a marker for disease monitoring in metastatic melanoma. Dermatology
1997;194:208-212.
3. Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R,
Stolz W, Buettner R. Melanoma-inhibiting activity, a novel serum marker
for progression of malignant melanoma. Cancer Research 1997; 57: 3149-3153
4. Bosserhoff AK, Hauschild A, Hein R, Schadendorf D,
Stockfleth E, Bogenrieder T, Landthaler M, Buettner R, Stolz
W. Elevated MIA serum levels are of relevance for
management of metastasized malignant melanomas: results of a
German multicenter study. J Invest Dermatol 2000; 114:395-396.
5. Hauschild A, Engel G, Brenner W, Glaser R, Monig H, Henze E,
Christophers E. Predictive value of serum S100B for monitoring patients
with metastatic melanoma during chemotherapy and/or immunotherapy. Br J
Dermatol 1999;140:1065-1071
Prof. Dr. Wilhelm Stolz
Department of Dermatology,
University of Regensburg,
Franz-Josef-Strauß-Allee 11,
D-93042 Regensburg
Prof. Dr. Michael Landthaler
Chairman of the Department of Dermatology,
University of Regensburg,
Franz-Josef-Strauß-Allee 11,
D-93042 Regensburg
Prof. Dr. Wilhelm Stolz
Ltd. Oberarzt
Dermatologische Klinik der Universität Regensburg,
Franz-Josef-Strauß-Allee 11,
D-93042 Regensburg
Competing interests: No competing interests