Role of Integrated Pet-CT in Cancer of Unknown Primary

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Role Of Integrated Pet-Ct In Cancer Of Unknown Primary

Poster No.: R-0218

Congress: RANZCR-AOCR 2012

Type: Scientific Exhibit

Authors: A. Swaminathan, B. Raghavan, R. Aarafath, M. Logudas, R. Balaji,P. G, J. Govindaraj

Keywords: Oncology, PET-CT, Localisation, Staging, Cancer, Metastases

DOI: 10.1594/ranzcraocr2012/R-0218

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Purpose

CUP is a clinical syndrome that represents much type of cancers wherein the primary siteis not identified after standard clinical & pathological evaluation. As diagnostic techniquesimprove, the spectrum of patients with CUP continues to evolve.(1).

Whilst earlier Whole body CT played an important role in detecting the primary sitepresently, Integrated Positron emission tomography (PET) and computed tomography(CT) can play an important role in patients with unknown primary as it combinesthe advantage of cross sectional imaging with the diagnostic advantages of PET.(2)Conventional cross sectional imaging like CT fails to identify the primary in cases wherethe lesions are very small or they are non enhancing in normal sized structures. This isof particular significance in CUP, as the primary in most of the cases are very small.(2)

Functional or metabolic changes can occur without producing anatomical changes. Thislimits the use of anatomical imaging alone like CT or MRI and improves the potential ofPET to be an excellent alternative diagnostic modality in patients with CUP.(3) The useof the radiotracer 18 F-fluoro-deoxy-glucose (FDG) for PET imaging is because most ofthe malignant tumors exhibit increased glucose metabolism.(4)

The CT component of PET CT allows accurate localization of sites of FDG uptake,thereby reducing problems of physiological uptake being misinterpreted as pathologicaland false localization of disease and it also allows more accurate image guided biopsyof suspected primary sites.(5)

The use of integrated PET CT over CT or PET alone is supported by various studies, suchas Roh et al (6) have shown that sensitivity of FDG PET CT (87.5%) was significantlyhigher (p=0.016) than that of CT alone (43.7%) in detecting primary tumours in 44patients, who presented with cervical metastases of unknown origin. Gutzeit et al (7) intheir series of 45 patients reported that CT alone depicted the primary in 8 patients (18%),whereas combined FDG PET- CT detected primary in 15 patients (33%).

CUP is the fourth commonest cause of cancer related death in both sexes and is theseventh to eighth most frequently occurring cancer in the world, 2and accounts forapproximately 2.3-4.2% of cancer in both sexes. The incidence of CUP per one lakhpopulation is 7-12 in the USA and 18-19 in Australia. Based on the number, locationand histology of metastases, patients of CUP can be classified into favourable andunfavourable subsets. Due to its aggressive biological and clinical behaviour, the mediansurvival rate ranges from 2 to 10 months.(2) Detection of the primary tumour may improvetreatment planning and patient outcome.(8)

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The purpose of this study was -

1. To detect primary focus of Tumor in Cancer of Unknown Primary using IntegratedPET-CT.

2. To evaluate the role of PET-CT versus CT alone in detection of the primary focusin CUP.

3. To evaluate the capability of PET-CT in detecting additional lesions.

4. To evaluate the role of PET- CT in assessing disease burden & staging.

Methods and Materials

MATERIALS AND METHODS

Our study population consisted of 69 patients of Cancer of Unknown Primary who werereferred for PET CT facility for a 12 month period from November 2010 to October 2011.

Among these 69 patients, 48 were males and 11 were female patients.Their average agewas 57 yrs. PET-CT imaging was performed on all these patients after informed consentand 6 hours fasting. (Glucose free water was allowed during this period.) Blood sugarwas checked in a peripheral vein (ideally should be around 150 mg/dl) and 5mCi of 18F-Fluorodeoxy glucose was injected.

Patients were made to rest for 40 minutes after the administration of FDG and wereinstructed not to talk, swallow, chew excessively or move about immediately before andafter FDG administration to avoid physiological pharyngeal, laryngeal and muscle uptake.

Images were acquired in the PET/CT scanner (PHILIPS GEMINI 64 slice TF, Fig.1) witha field of view from vertex of skull to mid-thigh except in patients suspected to have lowerlimb disease, where the scan included a whole body field of view. Oral and non-ionicintravenous contrast agents (1ml/kg body weight with saline bolus chasing) were usedin all patients to improve the CT diagnostic accuracy. Serum creatinine was checked inall these patients for the use of intravenous contrast media prior to performing the scan.Use of intravenous contrast was deferred in patients with creatinine more than 2mg/dl.The scanning time is about 10-12 minutes for both the CT and PET with the 64 slice TOFPETCT scanner.

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Since the CT images have to be taken in breath hold position and PET in shallowbreathing, a limited breath-hold method was used to avoid mis-registration of thediaphragmatic outline. Delayed CT and PET images were taken after 3-4 hours whereverindicated.

Since in our setup, a whole body cross sectional imaging was not separately performedprior to PET CT in most of the patients, the CT performed is of diagnostic quality with300-360 mAs and 120-Kvp with a collimation of 2.5mm. To avoid potential errors due tooral and intravenous contrast agents, the PET data sets were reviewed with and withoutattenuation correction.

Routinely all the CT & PET data were read independently by experienced radiologists &nuclear medicine physicians. Findings were documented & then the fused images wereread & the final report was a combined report of the fused studies.

For this study Whole-body CT and combined PET-CT data was read evaluated &documented in separate sessions for identification of the presenting lesion, primary lesion& additional foci if present for size, morphology, SUV & other disease manifestations.The study was blinded to avoid observer bias.

On CT images the primary was identified by the detection of contrast enhancing lesionsand also additional morphological features like local invasion and in PET images, a cut-off of 2.5 for SUV was taken.

Images for this section:

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Fig. 1: PET CT SCANNER

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Results

Carcinoma of unknown primary (CUP) is the presence of histologically proven metastaticdisease, without evidence of primary tumour. Prognosis in patients of CUP is generallypoor. Patient care and survival rates are dependent on the knowledge of the primarytumour and localized or disseminated disease.(9-11)

Out of the 69 patients who were referred to us with carcinoma of unknown primary, wewere able to detect primary sites in 49 (71 %) patients (Fig. 2). 35 lesions out of 49 wereconfirmed with targeted biopsy and histopathology (Fig. 3) PET CT showed false positivein 5 patients, 6 patients were lost to follow up and in 3 cases the diagnosis was made withCT (2 cases of primary peritoneal carcinomatosis and 1 case of small cell lung cancer).Despite thorough scanning, the primary was not identified in 20 patients (29%).

The primary site accurately in 50% of the patients referred to us, 7.2% were falsepositives , in 29% patients the site of primary was not identified and the remaining werelost to follow up. The percentage of primary identified in our study is more than the otherstudies where it ranged between 21-33%.

The most common site of the metastatic site were cervical nodes (30%), followed byskeletal (19%), hepatic (16%), extracervical nodes (12%) and others. (Fig. 3)

Among the histological subtypes, adenocarcinoma accounted for the most (68%),squamous cell carcinoma (11%), poorly differentiated carcinoma (16%) and others. (Fig.4)

In the 49 patients, where the primary site was identified, 15 were in the lung and was thesingle most common site (31 %). 13 lesions were distributed in the head and neck (26 %)and 21 lesions (43%) distributed in the abdominal organs. (Fig. 3, Image 1) Colorectalwas the most common site within abdomen. (Fig. 5, 6)

Lung cancer is the most frequently reported primary tumour in patients with CUP (12-16)and it was confirmed in this study also. It is important to remember that lung is oneof the most common location for false positivity in PET because of the widespreadincidence of infectious and inflammatory disorders. Especially in a tropical country likeours, where tuberculosis and other infectious disorders are rampant it is importantto differentiate these lesions. Though the morphological appearance of these lesionsby CT can reasonably differentiate, for example pneumonias are lobar or segmental.

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Peripheral lesions should be differentiated from infarction, which are usually wedgeshaped. The importance of delayed PET imaging needs to be emphasised here. Thelesion to background contrast improves significantly in delayed images.PET CT alsohelps in planning guiding the site for biopsy of the primary lesion.

The average size of these lung lesions varied from 1.5-2.3 cms (Fig 7) and were eitherlocated in a place where they are obscured in a X-ray or not very characteristic in CT.The addition of PET helps to show the metabolic activity of the lesion, the average SUVwasb5.82. In one patient with biopsy proved small cell carcinoma, no mass lesion wasidentified. But there was large ipsilateral hilar and mediastinal adenopathy with skeletalmetastases. A diagnosis of small cell carcinoma of lung was made as a subset of thesepatients can present with no discernible parenchymal lesion and only with nodal massesas seen in this case.

The second most common sites were the head and neck and colorectal regions.Maximum numbers of lesions were in the oropharynx (Fig. 8,9) Oropharynx is a difficultarea to evaluate because of the physiological uptake in the adenoids and in the

Waldeyers ring. This overlap may impair the diagnostic performance.17 Among the 13lesions in the head and neck region, 7 (54%) were in the oropharynx. The average sizeof these lesions was 1.5-1.7 cms and their average SUV was 6.1. Since most of thelesions were in the oropharynx, delayed PET images were taken in all patients to avoidmisinterpretation of physiological uptake.

Histopathological diagnosis and metastatic pattern may suggest possible sites of primary.In patients with upper and mid cervical nodes, a primary in the head and neck shouldbe searched for. In patients with left supraclavicular node, a primary gastrointestinaltumour should be considered(17). In patients with peritoneal carcinomatosis a primaryfrom the ovaries can be considered. In our study there were two patients of peritonealcarcinomatosis and elevated CA-125 levels. Both these patients had undergonehysterectomy with bilateral salpingo oophorectomy 5-10 years back for non malignantreasons. Hence, a diagnosis of primary peritoneal carcinomatosis was made in these 2cases.

In 28% of patients, the primary was still unidentified(Fig. 10,11) Common reasons includespontaneous regression or immune mediated destruction of the primary tumour or theinherent small size of the tumour, where metastatic spread is favoured over local growth(18,19) and inability of PET to demonstrate lesions less than 1cm. Primary tumors maydisappear after seeding metastases because of their angiogenic incompetence leads tomarked apoptosis and cell turnover (20).

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The inability to identify the primary prevents the optimization of therapeutic strategies,which is dependent on tumour differentiation, tumour location and tumour stage asdetermined according to the TNM system(21). Identification of the primary significantlyimproves the survival rate of patients of unknown primary as it helps to optimize treatmentplanning.

Out of the total 49 patients where PET CT identified the sites of possible primary, in 15patients either CT alone was not able to identify the lesion or it is equivocal. In rest ofthe 34 lesions CT alone was able to delineate the lesion which was confirmed with PET.(Fig. 12,13).

In a study on oropharyngeal cancers, it was shown that the identification of the primarylesion helps improving the survival rate. The 3 yr survival rate was 100 % for patients

where the primary was identified compared to 58% where the primary was not identified.22

In our study, staging changed in only 3 out of 49 patients with possible primary sites (Fig.14). 16 (33%) out of 49 patients had additional findings other than the metastatic siteof presentation and the primary which required treatment modification, for example likeincluding cranium for irradiation for cerebral metastases or widening the radiation field ifmore number of nodes are involved.(Fig. 15)

Images for this section:

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Fig. 13: DISTRIBUTION OF CASES ACCORDING TO THE IMAGING MODALITY BYWHICH THE PRIMARY SITE WAS IDENTIFIED

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Fig. 14

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Fig. 15

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Conclusion

In conclusion, this study identified the primary site accurately in more number of patientsbecause, whole body cross sectional imaging was not performed routinely in all patientsprior to PET CT. Most of the patients were in stage III or IV disease further warranting aPET CT directly rather than to image with cross sectional imaging first, thereby reducingthe radiation burden. It is also cost effective, diagnosis and staging are achieved withina shorter period of time, and thereby treatment can be initiated earlier. Thus, integratedPET/CT can be considered as a primary diagnostic modality for those presenting withmetastatic disease without evidence of a primary lesion.

Personal Information

B.Raghavan : Senior consultant Radiologist, Apollo Speciality Hospitals,Chennai , India.

email: drbagyam@gmail.com

A. Swaminathan: Registrar, Apollo speciality Hospitals, Chennai, India.

email: aarthiswaminathan_84@yahoo.co.in

References

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2. Pavlidis N, Fizazi K. Carcinoma of unknown primary (CUP). Crit Rev Oncol Hematol2009;69:271-8.

3. Rege S, Maass A, Chaiken L, Hoh CK, Choi Y, Lufkin R, et al. Use of positron emissiontomography with fluorodeoxyglucose in patients with extracranial head and neck cancers.Cancer 1994;73:3047-58.

4. Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET in oncology.Radiology 2004;231:305-32.

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5. Mawlawi O, Townsend DW. Multimodality imaging: an update on PET/CT technology.Eur J NuclMed Mol Imaging 2009;36(Suppl 1):S15-29.

6. Roh JL, Kim JS, Lee JH, Cho KJ, Choi SH, Nam SY, et al. Utility of combined (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography in patientswith cervical metastases from unknown primary tumors. Oral Oncol 2009;45:218-24.

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8. Haas I, Hoffmann TK, Engers R, Ganzer U. Diagnostic strategies in cervical carcinomaof an unknown primary (CUP). Eur Arch Otorhinolaryngol 2002;259:325-3.

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10. Culine S, Kramar A, Saghatchian M, et al.Development and validation of a prognosticmodel to predict the length of survival in patients with carcinomas of an unknown primarysite. J Clin Oncol 2002; 20:4679-4683.

11. Hubner G, Wildfang I, Schmoll HJ. CUP. In: Schmoll HJ, ed.Compendium inoncology:band 2. Berlin, Germany: Springer-Verlag, 1999; 2137-2182.

12. Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown primarytumors: systematic review and meta-analysis.Eur Radiol 2009;19:731-44.

13. Al-Brahim N, Ross C, Carter B, Chorneyko K. The value of postmortem examinationin cases of metastasis of unknown origin-20-year retrospective data from a tertiary carecenter. AnnDiagn Pathol 2005;9:77-80.

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clinicopathologic correlations. APMIS 2003;111:1089-94.

15. Mayordomo JI, Guerra JM, Guijarro C, García-PratsMD, Gómez A,López-Brea M, etal. Neoplasms of unknown primary site: a clinicopathological study of autopsied patients.Tumori 1993;79:321-4.

16. Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G,Spielmann M, et al.Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302consecutive autopsied patients. Arch Intern Med 1988;148:2035-9.

17. Fukui MB, Blodgett TM, Snyderman CH, Johnson JJ, Myers EN,Townsend DW, et al.Combined PET-CT in the head and neck:part 2. Diagnostic uses and pitfalls of oncologicimaging.Radiographics 2005;25:913-30.

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18. Pentheroudakis G, Briasoulis E, Pavlidis N. Cancer of unknown primary site: missingprimary or missing biology? Oncologist 2007;12:418-25.

19. van de Wouw AJ, Jansen RL, Speel EJ, Hillen HF. The unknown biology of theunknown primary tumour: a literature review. Ann Oncol 2003;14:191-6.

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21. Greene L. AJCC cancer staging manual.New York, NY: Springer, 2002.

22. Haas I, Hoffmann TK, Engers R, Ganzer U.Diagnostic strategies in cervical carcinomaof an unknown primary (CUP). Eur Arch Otorhinolaryngol 2002; 259:325-333.

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