Question

What is the optimal screening for the primary tumour in patients presenting with brain metastases with an unknown primary tumor?

Recommendation

The diagnosis of a primary tumour in patients presenting with brain metastases should take place on the basis of the patient's history, physical examination, and chest/abdomen CT (or chest CT with abdomen ultrasound). There is no indication, initially, for performing a PET scan.

The guideline development group recommends referring patients, for whom diagnostics do not lead to diagnosis of the primary tumour within 2 weeks, to the neurosurgeon for histological diagnosis of the brain metastasis, but only when this is anticipated to have therapeutic consequences. The aim should be to obtain a histological diagnosis within 4 weeks following imaging of the brain.

Conclusions

Level 3
There are indications that in 60%of the patients diagnosed with one or more brain metastases without known malignancy, a lung carcinoma is the primary tumour of origin, while the primary tumour remains unknown in 26% of cases.
B: Agazzi, 2004 (1)

Level 3
There are indications that 10-40% more lung carcinomas are found with a chest X-ray compared to a chest X-ray in patients with one or more brain metastases derived from an unknown primary malignancy.
B: Van de Pol, 1996 (2)
C: Latief, 1997 (3)

Level 3
There are indications that the added value of a PET-CT in addition to a chest/abdominal CT for retrieving an unknown primary tumour is only 0-4%.
C: Kim, 1998 (8);Jeong, 2002 (7)

Level 3
There are indications that immunohistochemical testing after resection or biopsy of brain metastases may provide clues as to the localisation of the primary tumour.
C: Drlicek, 2004 (11);Perry, 1997 (10);Prok and Prayson, 2006 (12);Strickland-Marmol, 2007 (13);Giordana, 2000 (14)

Literature summary

Sixty four percent of patients diagnosed with brain metastases has a history of malignancy (Agazzi, 2004 (1)). The relative frequency of tumour subtype differs between patients with a known and those with an unknown primary tumour. In the case of brain metastases with an unknown primary tumour, further examinations reveal a lung carcinoma more often (60% versus 40%) than a breast carcinoma (2% vs 20%) or melanoma (3% vs 10%). The primary tumour is found outside the chest in only 14% of cases (renal cell carcinoma (4%), colon carcinoma (3%), melanoma (3%), breast carcinoma (2%)), and in a quarter of cases the primary tumour is not retrieved at all (Agazzi, 2004 (1)). Since lung carcinoma forms the underlying malignancy in the majority of patients who primarily present with brain metastasis, additional diagnostics should firstly focus on this option, the more so in case the patient's history and physical examination provide no indications for another malignancy and if the patient has a smoking history. It has been shown that chest X-ray misses 10-40%of lung carcinomas whereas they may be detected with a CT scan (Van de Pol, 1996 (2);Latief, 1997 (3)).

When CT scanning does not lead to detection of a primary lung carcinoma, it is questionable whether extensive diagnostics for another primary tumour is of added value. The prognosis of patients presenting with brain metastasis of unknown origin is not worse than that of patients with a known primary tumour (D'Ambrosio and Agazzi, 2007 (4)) and may sometimes even be better (Nguyen, 1998 (5)). Favourable prognostic factors for patients presenting with brain metastasis of unknown origin are: treatment with SRS or neurosurgery followed by WBRT, discharge home after treatment and absence of systemic disease (D'Ambrosio and Agazzi, 2007 (4)). Median survival under these favourable factors is just over a year. The factor 'discharge home' probably forms an indicator for a good performance status prior to treatment as shown by previous research (Gaspar, 1997 (6)); the patients in this study had a KPS of >70%.

Various studies have examined the added value of the FDG-PET scan for detection of a primary tumour. The sensitivity and specificity for detection are 78% and 94%, respectively (Jeong, 2002 (7)). The added value compared to the CT scan varies; in 0% (Kim, 1998 (8)) to 4% (Jeong, 2002 (7)) of patients, the chest CT was negative while the PET was positive. The PET scan was of added value with other primary locations in 7% of cases, but in 9% of patients, the PET scan was negative while CT scans were positive (Jeong, 2002 (7)). Although studies on unknown primary tumours have generally demonstrated the cost-effectiveness of the PET scan, the situation is probably different for brain metastasis since the primary tumour is usually localised in the lung (Sengupta, 1995 (9)). Comparative studies are not available.

The presence of extracranial disease is an important indicator for survival after treatment of brain metastases (D'Ambrosio and Agazzi, 2007 (4)) and it is therefore worthwhile to exclude extracranial disease activity as much as possible. In 20% of cases, the patient history and physical examination provide points of reference for further tests (excluding patients with lung carcinomas) that lead to localisation of the primary tumour (Van de Pol, 1996 (2)). Aside from the patient history and physical examination (and additional examination conducted on the basis of these), orientating laboratory tests for renal and liver functions (including LDH) may provide an indication as to the likelihood of extracranial disease. Standard additional examination for liver metastases, using ultrasound or CT, may be considered because these are associated with a poor prognosis. According to an earlier recommendation (Van de Pol, 1996 (2)), examination should only be extended beyond a chest CT on indication. However, this recommendation was based upon the objective of identifying the primary tumour, not for predicting patients' prognosis. Since the extent and activity of extracranial disease is associated with a poor prognosis, the presence of liver metastases should be taken into consideration in deciding whether a radical treatment such as neurosurgical intervention or stereotactic irradiation is worthwhile.

In 4% of patients whose tumour is initially unknown, the metastases turn out to be from a renal cell carcinoma (Agazzi, 2004 (1)). In the absence of extracranial metastases, it is probably worthwhile to remove the primary tumour with a likely chance of long-term systemic remission. Studies suggest that diagnostics may also be extended to the kidneys, although it remains unclear whether this leads to a long-term survival advantage (the studies' sample sizes were too small to allow for conclusions). Imaging of the kidneys may take place through ultrasound or by extending the chest CT with an abdominal CT scan.

There is no literature on the frequency of testis carcinomas patients who initially present with brain metastasis, although these patients are encountered in practice. Given the fact that this tumour may be treated effectively, investigations should also be directed to this possibility in (young) men, which includes palpating the testes during physical examination. Determination of tumour markers is probably unnecessary since chest/abdominal CT scan will anyhow expose the typical extracranial pattern of metastasis.

The value of additional histological diagnosis
If a primary tumour is not found during the patient history taking / physical examination / chest/abdominal CT, the next step in the diagnostic process is to obtain a histological diagnosis, on the condition that diagnosis is anticipated to have therapeutic consequences. A biopsy or resection of brain metastases should only be performed if it is possible to do so safely. In most cases, histology will reveal an adenocarcinoma. Limited immunohistochemical analysis may already provide an indication of the primary tumour. Various retrospective series have demonstrated the added value of TTF-1, CK-7 and CK-20. TTF-1+, CK-7+, CK-20- indicates the possibility of a primary lung carcinoma, while TTF-1 -, CK 7-,CK-20+ indicates a gastrointestinal malignancy (Perry, 1997 (10);Drlicek, 2004 (11);Prok and Prayson, 2006 (12);Strickland-Marmol, 2007 (13)). HMB45/vimentine/S100 may be in line with a melanoma (Giordana, 2000 (14);Drlicek, 2004 (11)). The extent to which immunohistochemistry is of added value alongside a chest/abdominal CT has not been examined (Taweevisit, 2003 (15);Wesseling, 2007 (16)).

Upon the indication of the primary tumour by immunohistochemical testing of the removed brain metastasis, further tests may be performed. Surveillance by an medical oncologist may be appropriate, depending on the location of the primary tumour and expected complications in the event of tumour progression.

Click here for evidence tables.

References

  1. 1 - Agazzi S, Pampallona S, Pica A, Vernet O, Regli L, Porchet F, et al. The origin of brain metastases in patients with an undiagnosed primary tumour. Acta Neurochir (Wien ) 2004 Feb;146(2):153-7.
  2. 2 - van de Pol M, van Aalst V, Wilmink JT, Twijnstra A. Brain metastases from an unknown primary tumour: which diagnostic procedures are indicated? J Neurol Neurosurg Psychiatry 1996 Sep;61(3):321-3.
  3. 3 - Latief KH, White CS, Protopapas Z, Attar S, Krasna MJ. Search for a primary lung neoplasm in patients with brain metastasis: is the chest radiograph sufficient? AJR Am J Roentgenol 1997 May;168(5):1339-44.
  4. 4 - D'Ambrosio AL, Agazzi S. Prognosis in patients presenting with brain metastasis from an undiagnosed primary tumor. Neurosurg Focus 2007;22(3):E7.
  5. 5 - Nguyen LN, Maor MH, Oswald MJ. Brain metastases as the only manifestation of an undetected primary tumor. Cancer 1998 Nov 15;83(10):2181-4.
  6. 6 - Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997 Mar 1;37(4):745-51.
  7. 7 - Jeong HJ, Chung JK, Kim YK, Kim CY, Kim DG, Jeong JM, et al. Usefulness of whole-body (18)F-FDG PET in patients with suspected metastatic brain tumors. J Nucl Med 2002 Nov;43(11):1432-7.
  8. 8 - Kim DG, Kim CY, Paek SH, Lee DS, Chung JK, Jung HW, et al. Whole-body [18F]FDG PET in the management of metastatic brain tumours. Acta Neurochir (Wien ) 1998;140(7):665-73.
  9. 9 - Sengupta MS, Lee SJ, Hoh CK, Phelps ME, Maddahi J. Utility and cost effectiveness of FDG whole body PET in patients with unknown primary malignancies [abstract 226]. J.Nucl.Med. 36(Suppl), 56P. 1995.
  10. 10 - Perry A, Parisi JE, Kurtin PJ. Metastatic adenocarcinoma to the brain: an immunohistochemical approach. Hum Pathol 1997 Aug;28(8):938-43.
  11. 11 - Drlicek M, Bodenteich A, Urbanits S, Grisold W. Immunohistochemical panel of antibodies in the diagnosis of brain metastases of the unknown primary. Pathol Res Pract 2004;200(10):727-34.
  12. 12 - Prok AL, Prayson RA. Thyroid transcription factor-1 staining is useful in identifying brain metastases of pulmonary origin. Ann Diagn Pathol 2006 Apr;10(2):67-71.
  13. 13 - Strickland-Marmol LB, Khoor A, Livingston SK, Rojiani A. Utility of tissue-specific transcription factors thyroid transcription factor 1 and Cdx2 in determining the primary site of metastatic adenocarcinomas to the brain. Arch Pathol Lab Med 2007 Nov;131(11):1686-90.
  14. 14 - Giordana MT, Cordera S, Boghi A. Cerebral metastases as first symptom of cancer: a clinico-pathologic study. J Neurooncol 2000 Dec;50(3):265-73.
  15. 15 - Taweevisit M, Isarakul P, Chaipipat M, Keetacheeva K, Wattanasirmkit V, Shuangshoti S. Cytokeratin 7 and 20 as immunohistochemical markers in identification of primary tumors in craniospinal metastases: do they have a significant role? Neuropathology 2003 Dec;23(4):271-4.
  16. 16 - Wesseling P, von Deimling A, Aldape KD. Metastatic tumours. In: Louis DN, Cavenee W, Ohgaki H, Wiestler O, editors. WHO-Classification of Tumours of the Central Nervous System.Lyon, France: IARC Press; 2007.

Considerations

A comprehensive diagnosis may not be achievable in all cases, and extending diagnostics beyond chest/abdominal CT scanning should not result in patients' condition deteriorating to the extent that optimal therapy is no longer possible.

Authorization date and validity

Last review : 01-07-2011

Last authorization : 01-07-2011

The period of validity of the guideline (maximum of 5 years) is being monitored by IKNL. For various reasons, it may be necessary to revise the guideline earlier than intended. Sections of the guideline will be amended in the interim, when required.

Initiative and authorization

Initiative : Nederlandse Vereniging voor Neurologie

Authorized by:
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  • Nederlandse Vereniging voor Medische Oncologie
  • Nederlandse Vereniging voor Neurochirurgie
  • Nederlandse Vereniging voor Neurologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie
  • Verpleegkundigen en Verzorgenden Nederland
  • Nederlandse Vereniging voor Psychosociale Oncologie
  • Nederlands Instituut van Psychologen

Scope and target group

Objective

The guideline covers the processes of diagnosis, treatment, information provision and guidance of adult patients with metastases in the brain originating from solid tumours, thereby focusing on topical clinical problems encountered in daily practice. The guideline's recommendations aim to aid practitioners in their decision-making support when facing these problems. The recommendations are based on the highest available grade of scientific evidence and on consensus within the guideline development group. The guideline provides information on how the recommendations have been reached from the evidence.

 

The guideline may be used to provide information to patients and offers points of reference for transmural agreements or local protocols to facilitate implementation.

Users

The guideline is intended for all professionals involved in the diagnostics, treatment and guidance of adult patients with brain metastases of solid tumours. These professionals include:

  • Primary specialists: neurologists, neurosurgeons, radiotherapists, medical oncologists, pulmonologists, (oncology) nurses, general practitioners, specialists (working) in palliative care
  • Supporting specialists: radiologists, pathologists
  • Healthcare providers specialised in psychosocial care: social workers, psychologists, psychiatrists and geriatric medicine specialists

 

Members of the guideline panel

2011:

Chair:

mw. dr. J.M.M. Gijtenbeek, neuroloog, Universitair Medisch Centrum St Radboud, Nijmegen

Other members:

dr. L.V. Beerepoot, medisch oncoloog, St. Elisabeth Ziekenhuis, Tilburg

dr. W. Boogerd, neuroloog, Nederlands Kanker Instituut / Antoni van Leeuwenhoekziekenhuis, Slotervaartziekenhuis, Amsterdam

mw. S. Bossmann, nurse practitioner, Universitair Medisch Centrum St Radboud Nijmegen

mw. dr. M. van Dijk, internist-oncoloog, Maastricht Universitair Medisch Centrum, Maastricht

mw. dr. A.C. Dingemans, longarts, Maastricht Universitair Medisch Centrum, Maastricht

mw. dr. C. van Es, radiotherapeut-oncoloog, Utrecht Universitair Medisch Centrum, Utrecht, niet actief betrokken (is betrokken geweest bij het initiëren van de werkgroep maar kon vanwege onvoorziene omstandigheden niet aan de totstandkoming van de richtlijn meewerken)

dr. A. de Graeff, medisch oncoloog, Utrecht Universitair Medisch Centrum, Utrecht

dr. P.E.J. Hanssens, radiotherapeut-oncoloog, Gamma Knife Centrum, Tilburg

dr. H.F.M. van der Heijden, longarts, Universitair Medisch Centrum St Radboud, Nijmegen

dr. M.A.A.M. Heesters, radiotherapeut-oncoloog Universitair Medisch Centrum Groningen, Groningen

dr. P.A. M. Hofman, neuroradioloog, Maastricht Universitair Medisch Centrum, Maastricht

dr. R.L.H. Jansen, medisch oncoloog, Maastricht Universitair Medisch Centrum, Maastricht, niet actief betrokken

drs. E. Kurt, neurochirurg, Medisch Centrum Alkmaar

dr. F. J. Lagerwaard, radiotherapeut-oncoloog, Vrije Universiteit Medisch Centrum, Amsterdam

mw. prof.dr. J.B. Prins, klinisch psycholoog, Universitair Medisch Centrum St Radboud, Nijmegen

drs. J.H.C. Voormolen, neurochirurg, Leids Universitair Medisch Centrum, Leiden

drs. V.K.Y. Ho, epidemioloog/procesbegeleider, Integraal Kankercentrum Nederland (IKNL), locatie Utrecht

mw. M.L. van de Kar, ambtelijk secretaris, Landelijke Werkgroep Neuro-Oncologie (LWNO), Bussum

Ondersteuning methodologie

mw. dr. M. Brink, epidemioloog, IKNL, locatie Utrecht

drs. J.M. van der Zwan, MSc, epidemiologisch onderzoeker, IKNL, locatie Enschede

 

Leden werkgroep voorgaande revisie (2004)

dr. R.H. Boerman, neuroloog, Rijnstate Ziekenhuis, Arnhem (voorzitter)

dr. W. Boogerd, neuroloog, Nederlands Kanker Instituut / Antoni van Leeuwenhoekziekenhuis, Slotervaartziekenhuis, Amsterdam

mw. dr. W.M.H. Eijkenboom, radiotherapeut-oncoloog, Daniel den Hoed Kliniek, Rotterdam

dr. P.E.J. Hanssens, radiotherapeut-oncoloog, Dr. Bernard Verbeeten Instituut, Tilburg

dr. R.L.H. Jansen, medisch oncoloog, Academisch Ziekenhuis Maastricht

dr. F. J. Lagerwaard, radiotherapeut-oncoloog, Vrije Universiteit Medisch Centrum, Amsterdam

prof.dr. C.J.A. Punt, inetrnist-oncoloog, Academisch Ziekenhuis Nijmegen

drs. J.H.C. Voormolen, neurochirurg, Leids Universitair Medisch Centrum, Leiden

prof.dr. J.T. Wilmink, neuroradioloog, Academisch Ziekenhuis Maastricht

dr. J.G. Wolbers, neurochirurg, Academisch Ziekenhuis Dijkzigt, Rotterdam

 

 

Declaration of interest

All guideline working group members were asked to fill in a conflict of interest declaration, in which they stated ties with the medical industry at the start and completing the guideline process. An overview of these conflict of interest declarations can be found below. The remaining guideline working group members have declared that at this moment or in the last three years they have not performed any activities on invitation or with subsidy/sponsoring by the medical industry.
   

Lid

Firma

Activiteit

Overig

Dr. L.V. Beerepoot

Pfizer

Merck

Cephalon

consultatie / advisering

congres

congres

congres

Dr. W. Boogerd

Mundipharma

 

congres

Dr. M. van Dijk

Schering Plough

 

congres

Dr. A.C. Dingemans

Roche

 

Lilly

Astra Zeneca

 

Glaxo

consultatie / advisering / wetenschappelijk onderzoek

consultatie / advisering

consultatie / advisering / wetenschappelijk onderzoek

consultatie / advisering / wetenschappelijk onderzoek

congres

 

cursus

Dr. C.A. van Es

Elektra

 

congres

Dr. A. de Graeff

 

Nycomed

Wyeth

consultatie / advisering

consultatie / advisering

 

Dr. P.A.M. Hofman

Strijker NL B.V.

Medtronics Spinal

Bayer Health Care

Johnson & Johnson

 

congres

congres

congres

congres

Dr. H.F.M. van der Heijden

Astra Zeneca

Sanofi Aventis

Lilly

 

Roche

consultatie / advisering

consultatie / advisering

consultatie / advisering / wetenschappelijk onderzoek

 

congres

congres

congres

 

congres

Dr. R.L.H. Jansen

Pfizer

Roche

Sanofi Aventis

Diverse firma's

 

 

wetenschappelijk onderzoek

studies

congres

congres

congres

Dr. F.J. Lagerwaard

Roche Nederland

Roche NL-longadviesraad

Brain Lab

Varian Medical Systems

wetenschappelijk onderzoek

consultatie / advisering

 

 

 

congres

congres

   

Method of development

Evidence based

Implementation

Considerations concerning the implementation of the guideline as well as the feasibility of recommendations have been taken into account as much as possible in drafting the revised guideline.

 

The guideline is summarised and may be consulted in its entirety on http://www.oncoline.nl/. The guideline has been brought to the attention of members of the LWNO, hospitals in the Netherlands, oncology commissions, as well as the scientific and professional associations involved. To further stimulate awareness and implementation of the guideline, regional tumour working groups on neuro-oncology of IKNL were invited to discuss its recommendations.

 

Given the highly progressive and unfavourable course of the disease, the guideline development group decided not to develop care indicators to measure the level of guideline implementation.