Atypical Response Patterns and Immune-related Adverse Events Detected by FDG PET/CT in Patients Receiving Immunotherapy: A Case Series and Literature Review

INTRODUCTION

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by restoring antitumor immune responses, yet they are frequently associated with immune-related adverse events (irAEs) affecting multiple organ systems.^[1] These adverse effects may involve virtually any organ system, with the endocrine, gastrointestinal, cutaneous, and pulmonary systems being most commonly affected. These irAEs, along with atypical response patterns such as pseudoprogression and dissociated responses, pose diagnostic challenges during response assessment.^[2] 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) plays a pivotal role in detecting metabolic changes linked to both tumor activity and immune-related inflammation, often preceding structural changes seen on conventional imaging.^[3]

However, increased metabolic activity in irAEs may mimic disease progression, potentially leading to premature treatment alteration. Awareness of these imaging pitfalls is essential in the immunotherapy era. This case series highlights a spectrum of atypical response patterns and irAEs identified on PET/CT in patients receiving ICIs, emphasizing the importance of clinical correlation, imaging timing, and lesion-based interpretation to guide appropriate management.

CASE SERIES

Case 1

A 52-year-old female presented with epigastric pain upon evaluation revealed suspected gallbladder thickening and enlarged locoregional lymph nodes. 18F-FDG PET/CT scan revealed metabolically active soft tissue thickening measuring approx 16 mm, (standard uptake value [SUV] max 6.8) in gallbladder abutting the liver surface and multiple active enlarged lymph nodes largest measuring 35 mm × 24 mm, (SUV max 6.4). Further histopathological confirmation was done from para-aortic lymph node and immunohistochemistry (IHC) showed no Programmed Death-Ligand 1 (PDL1) staining in tumour cells. Patient was started on palliative chemoimmunotherapy with 3 weekly injections cisplatin, gemcitabine, and durvalumab 1500 mg (Topaz-1 protocol). She was evaluated with 18F-FDG PET/CT scan after 3 cycles, just before initiation of the fourth cycle, which revealed increased in size and metabolic activity of gallbladder primary and locoregional lymph nodes. Upon clinical correlation, it was found that the patient had a documented decrease in pain medication and overall sense of well-being, leading to a diagnosis of unconfirmed pseudoprogression requiring a follow-up scan after 4–8 weeks shown in Fig 1. Upon follow up the patient was discontinued from immunotherapy despite clinical response misguided by the PET/CT findings due to lack of awareness, which on further scan showed new lesions in the liver and nodal sites.

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Fig 1:

Locally advanced gall bladder carcinoma on palliative chemoimmunotherapy including durvalumab; (a) metabolically active enlarged periportal and portocaval lymph nodes (black arrow) shown in maximum intensity projection (MIP) of 18F-FDG PET/CT at baseline; (b) axial CT images [upper row] showing gall bladder thickening (red arrow), FDG avid [middle row] enlarged periportal and portocaval (black arrow) and low grade FDG uptake [lower row] in paraesophageal node (green arrow) ; (c) response evaluation scan after 3 cycles shows pseudoprogression as shown in axial CT images [upper row] showing gall bladder thickening (red arrow), FDG avid [middle row] enlarged periportal and portocaval (black arrow) and low grade FDG uptake [lower row] in paraesophageal node (green arrow); (d) MIP of response evaluation scan shows increased metabolic activity in paraesophageal (green arrow) and periportal nodes (black arrow). MIP: Maximum intensity projection; FDG: Fluorodeoxyglucose; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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Case 2

A 58-year-old male was earlier diagnosed with papillary renal cell carcinoma (RCC) and underwent right radical nephrectomy. He presented with our centre with suspicious neck nodes 5 years later, which on histopathological evaluation showed atypical cells in papilloid clusters, and IHC further showed CK7, PAX8 positivity, and TTF1 negative, suggesting metastasis likely from RCC. 18F-FDG PET/CT scan revealed multiple sites of metastasis, including brain, cervical and mediastinal nodes, and lung metastases. Next-generation sequencing showed a missense mutation with a VAF of 28% in the MET protooncogene. He was planned for tab cabozantinib 20 mg and injection nivolumab 240 mg. He underwent WBRT in 10 fractions of a total dose of 36 Gy, which he tolerated well. His 18F-FDG PET/CT scan done after 6 cycles showed clinical response in brain lesions post WBRT, but cervical and mediastinal lymph nodes showed dissociated response, with a few left cervical and mediastinal lymph nodes showing an increase in size and metabolic activity which others show interval response shown in Fig 2.

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Fig 2:

A case of papillary RCC with biopsy proven cervical and mediastinal metastases undergoing cabozantinib and nivolumab; (a) maximum intensity projection (MIP) of 18F-FDG PET/CT at baseline with multiple enlarged mediasinal nodes (blue arrow); (b) FDG avid [upper row] multiple paratracheal nodes (blue arrow), coronal CT enhancing enlarged right paratracheal node (black arrow) [middle row] and fusion images (green arrow) [lower row] of small volume left lateral cervical nodes; (c) response evaluation scan after 6 cycles shows dissociated response with faint FDG uptake [upper row] multiple paratracheal nodes (blue arrow), coronal CT enlarged right paratracheal node with interval decrease in size (black arrow) [middle row] and fusion images (green arrow) [lower row] of enlarged FDG avid left lateral cervical nodes; (d) MIP of response evaluation scan showing decreased uptake in paratracheal (blue arrow) and increased in cervical nodes (green arrow). RCC: renal cell carcinoma; MIP: Maximum intensity projection; FDG: Fluorodeoxyglucose; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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Case 3

A 62-year-old was complaining pain in the abdomen, sonography revealed a nodular lesion in the right lobe of the liver with severely elevated serum alpha-fetoprotein (S-AFP) levels (>2000 ng/ml). A triphasic CT scan showed additional portal vein thrombosis. 18F-FDG PET/CT scan revealed increased metabolic activity in the liver lesion, along with an enlarged metabolically active portocaval lymph node and tumor thrombus in the portal vein. He received inj atezolizumab 1200 mg and bevacizumab, 18F-FDG PET/CT scan showed a durable response over the course of treatment. Postcycle 11 evaluation showed multiple enlarged metabolically active cervical, mediastinal, and abdominal lymph nodes with liver primary showing a decrease in size and metabolic activity. S-AFP levels were within normal limits with no clinical symptoms and were diagnosed as sarcoid-like reaction to immunotherapy, which on later follow-up showed complete resolution with continued durable response shown in Fig 3.

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Fig 3:

A case of HCC in right lobe of liver with portal vein thrombosis receiving atezolizumab showed durable response during the course of treatment on 18F-FDG PET/CT; (a) post cycle 11, 18F-FDG PET/CT showed new multiple enlarged metabolically active mediastinal (green arrow) and symmetric retroperitoneal nodes (black arrow) shown in MIP; (b) coronal CT [upper row] and fusion images [middle row] multiple enlarged FDG avid abdominal node (black arrows), coronal fusion image [lower row] FDG avid enlarged paratracheal node (green arrow); (c) follow up scan after 3 months shows coronal CT [upper row] and fusion images [middle row] shows decrease in FDG avidity and size of abdominal nodes, coronal fusion image [lower row] non FDG avid small volume right paratracheal node; (d) no obvious FDG avidity on MIP in follow up scan likely a sarcoid like reaction due to immunotherapy which resolved in a follow up scan after 3 months. MIP: Maximum intensity projection; FDG: Fluorodeoxyglucose; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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Case 4

A 69-year-old male was diagnosed to have multiple well defined, round hyperechoic lesions in both lobes of the liver with normal S-AFP and CEA levels. 18F-FDG PET/CT scan showed arterial phase enhancement with rapid washout in multiple liver lesions and non-FDG-avid multiple lung nodules. Liver biopsy was suggestive of well-differentiated hepatocellular carcinoma (HCC). He received inj atezolizumab 1200 mg and bevacizumab, 18F-FDG PET/CT scan showed a durable response over the course of treatment. Postcycle 19 evaluation showed accelerated tumor growth kinetics both in liver and lung lesions with normal alpha-fetoprotein (AFP) level, likely late-onset hyperprogression or immune escape-driven growth shown in Fig 4. The largest lesion in the liver showed stable SUV max of 8, but multiple enhancing bilobar new lesions in the liver were noted on the follow-up scan after long disease stabilisation, and two two-fold increase in lung lesions in size with low-grade FDG uptake.

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Fig. 4:

A case of metastatic HCC on atezolizumab shows durable response on regular follow up done, (a) bulky mass lesion in liver shown in MIP of 18F-FDG PET/CT; (b) axial CT image [upper row] no obvious enhancing liver nodules, coronal fusion image [middle row] FDG avid bulky exophytic hepatic mass lesion, sagittal lung window [lower row] lung nodule in upper lobe of lung (black arrow); (c) axial CT image [upper row] multiple new enhancing liver nodules (blue arrow), coronal fusion image [middle row] FDG avid bulky exophytic hepatic mass lesion no obvious change on comparison, sagittal lung window [lower row] interval increase in lung nodule in upper lobe of lung (black arrow); (d) during response evaluation post cycle 19 shows accelerated tumor growth kinetics both in liver and lung lesions (black arrow) with normal AFP level. HCC: Hepatocellular carcinoma; MIP: Maximum intensity projection; FDG: Fluorodeoxyglucose; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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Case 5

A 73-year-old female presented with right loin pain, found to be lower pole lesion in the right kidney. She underwent right radical nephrectomy, postoperative histopathology confirmed clear cell RCC (pT3aN0). She was on adjuvant pembrolizumab 200 mg, during the course she was diagnosed with hypothyroidism likely irAE due to ICI. Her 18F-FDG PET/CT scan done for status evaluation showed no evidence of disease recurrence, but diffuse increased metabolic activity in the pancreas with no clinical symptoms. On follow-up, she complained of intermittent abdominal pain, which was suspicious for recurrence. On PET/CT evaluation showed no signs of recurrence, but diffuse pancreatic atrophy was noted causing pancreatic insufficiency shown in Fig 5. Retrospectively, diagnosed as clinically apparent immune-related pancreatitis leading to pancreatic insufficiency.

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Fig 5:

A case of RCC , post surgery on adjuvant pembrolizumab was found to be hypothyroid post treatment; (a)18F-FDG PET/CT scan reveals diffuse increased metabolic activity in pancreas shown in MIP (black arrow); (b) axial CT [upper row] and fusion [lower row] images show diffuse uptake (black arrow) in pancreas with no signs of acute pancreatitis; (c) axial CT [upper row] and fusion [lower row] images shows atrophied pancreas (black arrow) likely causing intermittent abdominal pain due to pancreatic insufficency; (d) MIP image with no metabolic activity in pancreas. RCC: Renal cell carcinoma; MIP: Maximum intensity projection; FDG: Fluorodeoxyglucose; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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DISCUSSION

The expanding role of ICIs across solid tumors has ushered in a parallel need to evolve our interpretation of imaging responses. Immune-mediated therapies, particularly anti-PD-1/PD-L1 and CTLA-4 inhibitors, have led to a new lexicon of atypical response patterns such as pseudoprogression, dissociated responses, sarcoid-like lymphadenopathy, and irAEs. They often blur the lines between treatment response and disease progression. In this series, 18F-FDG PET/CT played a crucial role in delineating these patterns, especially in settings where conventional anatomical imaging lacked clarity or failed to capture early inflammatory signals.

Atypical responses may be encountered at various stages of therapy and across all histologies. In our clinical experience, pseudoprogression was observed in the setting of gallbladder carcinoma receiving chemoimmunotherapy. FDG PET/CT demonstrated increased metabolic activity and lesion size early in treatment. However, clinical improvement raised a possible diagnosis of pseudoprogression. This phenomenon is increasingly reported and understood to result from T-cell infiltration and immune activation, leading to transient lesion enlargement or metabolic flare.^[4] In lung cancer, pseudoprogression has been observed in 14% of patients undergoing ICIs, often correlating with favourable long-term outcomes if treatment is continued.^[5]

A contrasting phenomenon, like dissociated response, was noted in a patient with papillary RCC harboring a MET protooncogene mutation. While cerebral metastases regressed following whole-brain radiotherapy and immunotherapy, mediastinal and cervical lymph nodes showed interval progression. Dissociated responses, defined by the simultaneous regression of some lesions and progression of others, were reported in nearly 48% of RCC patients receiving ICIs.^[6] This highlights intrapatient tumor heterogeneity and variable immune microenvironments. Notably, Wong et al. advocate for therapy continuation in these scenarios, especially when the dominant disease burden is responding.^[6] PET/CT’s ability to assess individual lesion metabolism allows a nuanced, lesion-specific evaluation, crucial for decisions on adding local therapy versus systemic change.

Among the not uncommon but clinically significant findings was a case of sarcoid-like reaction. Here, a patient with HCC showed significant lymphadenopathy in cervical, mediastinal, and abdominal regions following an favourable metabolic response at the primary liver site. These nodes resolved on serial imaging without clinical intervention, consistent with benign granulomatous inflammation. Sarcoid-like reactions, although uncommon, are increasingly reported in ICI-treated patients and may mimic nodal progression. They are typically symmetric, involve the mediastinum or hilar regions, and are often asymptomatic.^[7] Awareness of such patterns is imperative to prevent misclassification as metastatic spread and avoid unnecessary biopsies or therapy changes.

In contrast to these inflammatory mimics of progression, one patient with HCC exhibited genuine tumor acceleration after an extended period of durable response. Postcycle 19 of atezolizumab–bevacizumab therapy, there was rapid growth in both liver and lung lesions with unchanged AFP levels. This presentation aligns with emerging descriptions of late-onset hyperprogression. Although hyperprogressive disease typically presents early within 6–8 weeks oftherapy initiation, there is increasing recognition of delayed immune escape phenomena where tumor suppression is lost, potentially due to exhaustion of T cells or immunoediting by tumor clones.^[8,9] While the mechanisms remain poorly understood, clinicians should be vigilant for such turnarounds even in previously controlled disease.

A particularly instructive example of irAE detection involved a case of immune-mediated pancreatitis. FDG PET/CT revealed diffuse pancreatic uptake in an asymptomatic patient receiving pembrolizumab. Retrospective correlation with pancreatic atrophy and exocrine insufficiency led to a diagnosis of immune-related pancreatitis. This irAE is rarely reported in <1% of ICI-treated patients, but may be underrecognized due to subclinical presentation.^[10] PET/CT, with its high sensitivity to metabolic inflammation, may uncover such findings earlier than CT or MRI, particularly when structural changes are absent.

To summarise, our experience reinforces clinical context as paramount. Imaging interpretation must be integrated with symptoms, biomarkers, and temporal evolution. For instance, in the case of gallbladder cancer with pseudoprogression, a declining pain burden and improved performance status challenged against disease progression despite metabolic flare. Similarly, in the sarcoid-like case, the absence of symptoms with continued response in primary and symmetric nodal distribution was a crucial clues.

The lesion-based analysis, as enabled by PET/CT, can essentially quantify SUVmax across multiple sites, facilitating the detection of dissociated response or even pseudoprogression within individual lesions. Finally, the burden of decision-making in these scenarios lies in a multidisciplinary understanding of the immune phenomenon. Radiologists and nuclear medicine physicians must be aware of these patterns and communicate findings in a probabilistic rather than deterministic terms, recommending follow-up imaging when necessary. The European Association of Nuclear Medicine and newer response criteria such as iRECIST (immune-related Response Evaluation Criteria in Solid Tumors) and whole-body score PERCIST (wsPERCIST ) now recommend continued immunotherapy with follow-up scans in clinically stable patients to differentiate true progression from immune-related changes.^[11]

CONCLUSION

In conclusion, our experience adds to the growing body of evidence that FDG PET/CT is not merely a tool for measuring tumor bulk but an immunologic barometer reflecting the host and tumor interface under ICI therapy. Recognizing atypical response patterns and irAEs is critical for accurate response assessment, prevention of premature treatment discontinuation, and improved patient outcomes. As immunotherapy continues to expand into new indications and combinations, imaging will play a central role in decoding the complexity of immune response.