¹⁸F-FDG PET/CT findings of unknown primary cancer with occult lesions but large metastases

Introduction

Carcinoma of unknown primary (CUP) is a metastatic malignant disease for which the primary site remains undetectable despite a standardized diagnostic workup. It is clinically aggressive, often marked by rapid progression and early dissemination (1). Most such tumors are histopathologically classified as adenocarcinoma (60%) or undifferentiated carcinoma (30%) (2,3). The case detailed herein was ultimately identified as metastatic lung adenocarcinoma. On positron emission tomography/computed tomography (PET/CT), metastatic lesions typically exhibit high metabolic activity, yet the primary site may remain occult due to small size and only mild metabolic elevation. Detecting such inconspicuous primary lesions in the context of widespread metastasis remains a significant diagnostic challenge. This case report aimed to detail a CUP case characterized by the striking imaging finding of ‘prominent metastases with an occult primary’, focusing on the critical role of 18F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT in identifying minute primary lesions easily missed by conventional workup, guiding targeted biopsy, and altering clinical decision-making, thereby providing a reference for diagnosing similar complex cases.

Case presentation

A 44-year-old female was admitted with complaints of low back pain, nausea, and abdominal distension. Her mental state, appetite, and sleep were normal, with no notable weight loss. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen demonstrated multiple enlarged retroperitoneal lymph nodes and left adrenal gland thickening, suggestive of lymphoma. Serum tumor marker analysis revealed elevated human epididymal protein 4, carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), and neuron-specific enolase; other markers were within normal limits. A retroperitoneal lymph node biopsy confirmed malignant infiltration, prompting further diagnostic evaluation to determine the tumor origin. ¹⁸F-FDG PET/CT was performed for whole-body assessment (Figure 1). The scan revealed multiple lymph nodes with abnormally increased glucose metabolism throughout the body, extensive thickening of the peritoneal surfaces with intense FDG uptake [maximum standardized uptake value (SUVmax) =7.7 and mean standardized uptake value (SUVmean) =5.0], mild hypermetabolism in the enlarged left adrenal gland (SUVmax =4.0 and SUVmean =2.9), an 8-mm nodule in the posterior basal segment of the right lower lobe with slight FDG avidity (SUVmax =2.1 and SUVmean =1.2), and focally increased metabolism in the third lumbar vertebra (SUVmax =5.7 and SUVmean =3.3). Subsequent immunohistochemical staining of the lymph node tissue was positive for Napsin A, TTF-1, and CK7, confirming the diagnosis of metastatic poorly differentiated lung adenocarcinoma. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Correlative imaging of the primary lung lesion. The MIP (A) image demonstrated multiple enlarged lymph nodes with abnormally increased glucose metabolism in the entire body. Axial PET (B), CT (C), and corresponding fusion image (D) showed a nodule with a diameter of 8 mm in the posterior basal segment of the lower lobe of the right lung (arrows) with slightly increased glucose metabolism (SUVmax =2.1). (E-G) Representative metastatic sites. Fusion PET/CT images showed there were extensive thickening of abdominal cavity and pelvic peritoneum with abnormally increased glucose metabolism (SUVmax =7.7); enlargement of the left adrenal gland with mildly increased glucose metabolism (SUVmax =4.0); focal increased glucose metabolism in the third lumbar vertebra (SUVmax =5.7, red arrows). CT, computed tomography; ¹⁸F-FDG PET/CT, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography; MIP, maximum intensity projection; MRI, magnetic resonance imaging; SUVmax, maximum standardized uptake value.

Discussion

Occult primary tumors are malignancies in which conventional imaging fails to identify the primary site despite histologically confirmed metastases. Diagnostic challenges often stem from the primary tumor’s small size, indolent growth, low metabolic activity, or location in anatomically complex areas. On ¹⁸F-FDG PET/CT, metastatic lesions may show pronounced FDG uptake, whereas the primary tumor demonstrates only mild or negligible metabolic activity, increasing the risk of oversight or misdiagnosis. The present case notably demonstrates its value in detecting a relatively low-metabolic, tiny primary lung adenocarcinoma against the backdrop of extensive, massive metastatic disease throughout the body. This stark contrast underscores the irreplaceable sensitivity of PET/CT in whole-body screening, especially when conventional CT falls short due to the lesion’s small size and lack of typical morphological features. Although imaging is critical for detection and staging, histopathological confirmation remains the gold standard for definitive diagnosis and guiding systemic treatment decisions.

As an imaging modality that integrates metabolic and anatomical information, ¹⁸F-FDG PET/CT provides significant advantages in evaluating systemic malignancies. It allows non-invasive assessment of glucose metabolism, delivering comprehensive information on metabolic activity, dissemination patterns, and disease extent. It is particularly useful in identifying primary tumors, staging, and re-staging (4,5). In this case, PET/CT successfully detected multiple metastatic sites with high metabolic activity—including retroperitoneal lymph nodes, peritoneal deposits, left adrenal gland, and the third lumbar vertebra—while also revealing a subtle pulmonary nodule with mild FDG uptake (SUVmax =2.1). Immunohistochemistry subsequently confirmed lung origin, correlating with the imaging findings. The primary lesion’s small size and low metabolic activity are typical of occult primary tumors.

Although ¹⁸F-FDG PET/CT plays a central role in CUP evaluation, emerging radiotracers may further improve diagnostic precision. Fibroblast activation protein inhibitor (FAPI) agents, for example, have shown promise in visualizing tumors with high stromal activity, potentially offering superior tumor-to-background contrast for certain cancers. Other targeted tracers, such as those for prostate-specific membrane antigen (PSMA) or somatostatin receptors, may also help to identify specific tumor origins in select cases. Future studies comparing these novel agents with ¹⁸F-FDG in CUP cohorts are warranted to optimize imaging strategies.

However, PET/CT has limitations. Well-differentiated tumors, very small lesions, or those with low glycolytic activity may yield false-negative results. Additionally, false-positive uptake can occur due to inflammatory or infectious conditions. Thus, integrating clinical history, laboratory results (including tumor markers), imaging features, and histopathological and immunohistochemical findings is essential for accurate diagnosis (6,7).

Conclusions

¹⁸F-FDG PET/CT plays a critical role in the diagnostic evaluation of occult primary carcinomas. It offers valuable metabolic and anatomical information to guide biopsy planning and therapeutic decisions. A comprehensive approach incorporating patient history, tumor markers, imaging, pathology, and immunohistochemistry is necessary. Ongoing advances in imaging technology, such as PET/MRI and novel radiotracers, are expected to enhance the detection and diagnostic accuracy of occult primary tumors in the future.

Acknowledgments

None.

Footnote

Funding: This work was supported by a grant from the Guangdong Province Basic and Applied Basic Research Foundation (No. 2021A1515220068 to Y.Y.).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-2031/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Natoli C, Ramazzotti V, Nappi O, Giacomini P, Palmeri S, Salvatore M, Landriscina M, Zilli M, Natali PG, Tinari N, Iacobelli S. Unknown primary tumors. Biochim Biophys Acta 2011;1816:13-24. [Crossref] [PubMed]
2. Briasoulis E, Pavlidis N, Felip EESMO Guidelines Working Group. Cancers of unknown primary site: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:154-5. [Crossref] [PubMed]
3. Qaseem A, Usman N, Jayaraj JS, Janapala RN, Kashif T. Cancer of Unknown Primary: A Review on Clinical Guidelines in the Development and Targeted Management of Patients with the Unknown Primary Site. Cureus 2019;11:e5552. [Crossref] [PubMed]
4. Kwee TC, Basu S, Cheng G, Alavi A. FDG PET/CT in carcinoma of unknown primary. Eur J Nucl Med Mol Imaging 2010;37:635-44. [Crossref] [PubMed]
5. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer 2004;101:2641-9. [Crossref] [PubMed]
6. Olivier T, Fernandez E, Labidi-Galy I, Dietrich PY, Rodriguez-Bravo V, Baciarello G, Fizazi K, Patrikidou A. Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm? Cancer Treat Rev 2021;97:102204. [Crossref] [PubMed]
7. Moran S, Martinez-Cardús A, Boussios S, Esteller M. Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. Nat Rev Clin Oncol 2017;14:682-94. [Crossref] [PubMed]