cancer patient case study

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• Published: 03 May 2020

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family

• Elisabeth Niemeyer   ORCID: orcid.org/0000-0002-1530-3720 1 ,
• Hamid Mofid 2 ,
• Carsten Zornig 3 ,
• Eike-Christian Burandt 4 ,
• Alexander Stein 1 ,
• Andreas Block 1   na1 &
• Alexander E. Volk 5   na1  

BMC Gastroenterology volume  20 , Article number:  129 ( 2020 ) Cite this article

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Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1–3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer.

Case presentation

A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient’s young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient’s father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy.

Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

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Gastric cancer is the fifth most commonly diagnosed malignancy and the third most deadly cancer in males worldwide [ 1 ]. Gastric adenocarcinoma can be classified according to Lauren’s criteria, which define two major histological subtypes: intestinal and diffuse type adenocarcinoma [ 2 ]. These two subtypes have a variety of distinct clinical and molecular pattern. While the more common intestinal type of adenocarcinoma has a stronger association with Helicobacter pylori infection and dietary risk factors, diffuse gastric cancer more often has a genetic etiology [ 3 ]. Intestinal type of gastric cancer is frequently preceded by long-standing, precancerous, ulcerous lesions and is easily detectible by gastroscopy [ 4 ]. In contrast, diffuse gastric cancer typically develops within the submucosa with small foci of signet cells dispersed throughout the tissue, often not easily detected by routine upper endoscopy and can be missed in superficial biopsies [ 5 ]. Diffuse gastric cancer is typically associated with an aggressive growth pattern and poor prognosis [ 3 ].

Germline mutations in the CDH1 gene, encoding E-cadherin, are associated with an autosomal-dominant inherited susceptibility for diffuse gastric cancer (hereditary diffuse gastric cancer/HDGC [Online Mendelian Inheritance in Man®/OMIM entry #137215). Mutations in CDH1 can be identified in up to 54% of HDGC cases by sequence analysis and gene-targeted analysis for deletion and duplication [ 6 ] Although rare, other genetic causes of HDGC are still under investigation, including mutations in the CTNNA1 gene and mutations in other genes [ 7 ]. Invasion of carcinomas into surrounding tissues and their eventual metastasis requires the process of epithelial-mesenchymal transition (EMT). Downregulation or dysfunction of E-cadherin is the hallmark event in EMT, as E-cadherin deficient cells lose their ability to adhere to each other and gain individual cell motility [ 8 ]. In the case of HDGC, E-cadherin deficiency leads to a diffuse growth pattern of cancer cells throughout the submucosa. The gastric mucosa is intact and appears normal during gastric endoscopy even in late disease [ 5 ]. Loss of expression of E-cadherin in immunohistochemistry may be an indicator for a CDH1 -associated gastric cancer. The cumulative life time risk for carriers of a pathogenic variant in CDH1 to develop gastric cancer is 70% for men and 56% for women [ 5 , 7 ]. Women carrying a CDH1 mutation also have an increased risk for breast cancer, especially lobular breast cancer (42% lifetime risk with an average age of onset of 53 years [ 6 ]). It is still unresolved whether CDH1 -mutation carriers also have an increased risk of colon cancer [ 5 ].

A 37-year-old male (Fig.  1 , III.2) was referred to the emergency room with acute abdominal pain and fever. Physical examination showed signs of an acute peritonitis and lab tests revealed elevated inflammation markers (C-reactive protein). CT-scan showed a pneumoperitoneum and an emergency exploratory laparoscopy was performed. Since the site of the perforation could not be detected by laparoscopic approach, the procedure had to be converted to an open laparotomy. A gastric perforation (2 mm in diameter) was found, excised and sutured. Unexpectedly, the surgeons noted a rigid thickened stomach wall (consistent with linitis plastica) during operation. Furthermore, a tumor mass invading the minor omentum and the mesentery was found. Intra-surgical frozen section analysis confirmed the initial suspicion and revealed diffuse growing gastric cancer with signet cells. Finally, the patient was diagnosed with a diffuse gastric cancer (pT4bN3M1).

Pedigree of a large German family segregating autosomal dominant CDH1 -associated gastric cancer. Circles represent females and squares males. Filled symbols indicate clinically affected individuals and a plus sign carriers of the CDH1 mutation c.1137G > A

The young age at diagnosis and histological subtype prompted the surgeon to refer the patient and his family to genetic counselling. Evaluation of the family history revealed that the patient’s paternal grandfather (Fig. 1 , I.1) died of abdominal cancer at the age of 40. No other family members suffered from cancer, especially not the father (61 years old; Fig. 1 , II.1). Both the father and the healthy older brother (Fig. 1 III.1) underwent elective gastroscopies. In both patients, endoscopy showed an unremarkable mucosa (Fig.  2 c/d, data for brother not shown). Multiple random “button hole biopsies” were taken during gastroscopy and diffuse growing malignant cells could be detected in one out of three of the biopsies taken from the father. Genetic testing revealed the heterozygous germline mutation c.1137G > A of CDH1. This genetic alteration affects the last exonic nucleotide at the canonical splice donor site leading to impaired splicing and consequently to a dysfunctional E-cadherin molecule (Human Gene Mutation Database/HGMD® No. CS0060517). As this mutation has already been described in other HDGC patients, the diagnosis of HDGC in the father and also in the index patient carrying the same mutation was confirmed. Surprisingly, despite the presence of a CDH1 mutation, E-cadherin expression could still be immunohistochemically detected in tumor tissue with a monoclonal antibody raised against E-cadherin (Fig.  3 , Agilent Dako FLEX Monoclonal Mouse Anti-Human E-Cadherin, Clone NCH-38).

Endoscopic images of the paternal aunt ( a/b ) and the father ( c/d ) showing normal appearance of the gastric mucosa despite later confirmed signet cell adenocarcinoma in the submucosa

a Low power view of perigastric fat infiltrated by the gastric cancer (HE). b High power view showing diffuse growing isolated cancer cells (HE). c High power view of an E-cadherin immunohistochemistry stain with Antibody: Agilent Dako FLEX Monoclonal Mouse Anti-Human E-Cadherin, Clone NCH-38 showing strong membranous positivity of the cancer cells. With knowledge of the molecular data the E-cadherin antibody most probably detects a non-functional E-cadherin protein

With identification of a pathogenic CDH1 mutation, index patient’s healthy brother (38 years old; Fig. 1 III.1) as well as the three paternal aunts (53-, 56-, 58- years old, respectively, Fig. 1 , II.2, II.3, II.4) had an a-priori risk of 50% to also carry the CDH1 mutation. Ultimately, all four relatives underwent predictive testing after genetic counselling. While the mutation was detected in the brother and one aunt (Fig.  1 , II.4), two aunts did not inherit the mutation. As a result, his brother and his aunt underwent prophylactic gastrectomy. While no malignant cells were found in the histologic examination of the brother’s stomach, a diffuse growing adenocarcinoma was detected during histologic workup in the stomach of the aunt. Despite a macroscopically unremarkable appearance of the surgical specimen, two isolated cancer foci of signet cells located 7 mm from one another were detected in the upper third of the lamina propria of the cardiac region. Similar to the index patient’s father /herbrother, this diffuse gastric cancer was not macroscopically detectable during gastroscopy (Fig. 2 a/b) before gastrectomy was performed, not even after retrospectively analyzing the affected sites in the endoscopic images. Further staging showed no involvement of lymph nodes or distant metastasis in her case (pT1a pN0 (0/16) cM0).

The father, brother and aunt recovered well after their surgeries. Unfortunately, the condition of the index patient worsened quickly due to perioperative complications. Systemic chemotherapy could not be administered due to his poor general condition. He died 2.5 months after diagnosis.

Discussion and conclusions

Given that monogenic factors are rare and account only for 1–3% of gastric cancers, awareness among health care professionals is of utmost importance. Regardless of the family history, a personal history of a diffuse gastric cancer under the age of 40 qualifies for genetic testing of the CDH1 gene following the latest International Gastric Cancer Linkage Consortium (IGCLC) consensus guidelines. Furthermore, a CDH1 mutation should be suspected if two or more family members have been diagnosed with diffuse gastric cancer at any age or in a family if two family members were diagnosed with diffuse gastric cancer or lobular breast cancer with one diagnosis before the age of 50 years (Table  1 , [ 5 ]). In our family, the young age of the index patient and the family history with abdominal cancer of the paternal grandfather lead to genetic testing and the identification of the causal CDH1 mutation in the family. With the identification of the underlying genetic defect, all family members had the chance to learn about their exact individual risks. First degree relatives of a mutation carrier have a 50% chance to inherit the mutation. Extensive genetic counseling and discussion of the clinical management is especially important when detecting a mutation by predictive testing in healthy relatives. If a family member has not inherited the mutation, he and his progeny have no increased risk to develop gastric cancer. On the other hand, if the pathogenetic mutation is detected, the individual is faced with the cancer risks previously mentioned. As diffuse gastric cancer is difficult to detect at an early and treatable stage, mutation carriers may either choose prophylactic gastroscopy or endoscopic surveillance according to the Cambridge protocol [ 9 ]. This protocol recommends targeted biopsies of any suspicious lesion in the gastric mucosa as well as a minimum of 6 random biopsies taken from each anatomic area of the stomach (antrum, transitional zone, body, fundus, cardia) and should begin 5–10 years prior to the diagnosis of the youngest family member [ 9 , 10 ]. Current recommendations suggest prophylactic gastrectomy in healthy CDH1 mutation carriers rather than endoscopic surveillance [ 5 ]. The estimated risk for diffuse gastric cancer is 1% by the age of 20 years and around 4% by the age of 30 years [ 10 ]. Therefore, most authors recommend offering a gastrectomy to CDH1 mutation carriers between ages 20 and 30 [ 5 , 10 ]. The mortality rate of gastrectomy itself is less than 1% but it has a high morbidity for nutritional, metabolic and psychological well-being. Most patients report rapid intestinal transit, reflux, dumping syndrome and diarrhea after surgery. After gastrectomy patients need life-long vitamin supplementation. In our family, all mutation carriers chose to undergo gastrectomy, and gastric cancer was diagnosed at an early stage in two individuals. In both cases, preoperative endoscopy failed to detect the cancer. However, in random biopsies taken from endoscopically normal gastric mucosa, cancer cells were detected. Considering the overall small tumor size in both patients, the detection of tumor cells through random biopsies was a very fortunate incident for our family and underlines the need for taking a minimum of 30 deep biopsies as recommended in the Cambridge protocol. Despite advanced endoscopic techniques, the overall detection rate through preoperative endoscopic biopsies is low. In 87.9% of CDH1 -mutation carriers, foci of signet cells were initially detected after prophylactic gastrectomy [ 11 ].

In addition, women carrying a CDH1 mutation have an increased risk for lobular breast cancer. There is insufficient evidence for a risk-reducing mastectomy, although it might be discussed in individual cases based on the family history [ 12 ]. Compared to non-lobular breast cancers, there is a reduced sensitivity to detect lobular breast cancer by mammography [ 13 ]. Extrapolated from the data for high-risk hereditary breast cancer, surveillance programs for early detection include e.g. bilateral MRIs beginning at the age of 30 years [ 12 ]. Following the recommendation of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), our patient was offered annual MRIs and ultrasound of the breast until the age of 70 years. Although it is still unclear whether colon cancer is part of the CDH1- related tumor spectrum, we recommended colonoscopies more frequently and at a younger age for all mutation carriers (every 3 years starting at age 40) compared to our current national guidelines (every 5 years starting at age 50).

The diagnosis of diffuse gastric cancer with signet cells will likely prompt the pathologist to an immediate histopathological workup including immunohistochemistry for E-cadherin. However, these steps should be taken with great caution. As the CDH 1 gene is a tumor suppressor gene, the inactivation of both alleles is necessary for tumor initiation. The inactivation of the second allele in mutation carriers occurs mainly by hypermethylation of the CDH1 promotor [ 14 ]. While hypermethylation itself will result in a silencing of the respective allele and ultimately to a loss of its protein, some mutations give rise to a translated but non-functional protein. Currently, more than 180 pathogenic germline mutations in the CDH1 gene are listed in HGMD® Professional (2019.4). Most of these are truncating mutations which are predicted to elicit nonsense-mediated mRNA decay [ 15 ], which would again result in a loss of the protein. Around 20% of all the published pathogenic alleles are missense mutations which are more prone to result in non-functional, but translated and therefore potentially immunohistochemically detectable protein. The latter could result in an erroneous exclusion of a CDH1 -associated disease. The mutation identified in our family was shown before in another publication to escape nonsense-mediated mRNA decay and lead to aberrantly spliced RNA [ 16 ]. Indeed, E-cadherin expression was immunohistochemically detected in the histopathological workup in the surgical specimen of our index patient and could have led to the misinterpretation of a non- CDH1- associated diffuse gastric cancer. Given this assumption, no genetic testing would have been performed, and the underlying genetic cause would not have been unraveled. In the case of our family, this again would have hindered predictive testing for relatives at risk and the identification of two mutation carriers and three non-mutation carriers. Considering the poor prognosis of patients suffering from invasive diffuse gastric cancer, the patient’s father, brother and aunt (and potentially their progeny) had a major benefit from this genetic testing. The index patient’s child and the brother’s child (Fig. 1 , IV. 2, IV. 1) were infants at the time of genetic counseling. Predictive testing in individuals at risk younger than 18 years is a controversial issue. Rare cases of hereditary diffuse gastric cancer in individuals before the age of 18 have been reported [ 17 , 18 ]. It has therefore been suggested to offer predictive testing to individuals before the age of 18 on a case by case basis [ 5 ]. The IGCLC has agreed that genetic testing of minors at risk should consider the earliest age of cancer onset in the respective family as well as their physical and psychological resources.

In our case, we decided to evaluate future recommendations for clinical management for families affected by hereditary diffuse gastric cancer and offer genetic counseling to the minors involved in their teens. Because of an independent but severe medical illness, the aunt (III.) and her husband as the legal guardians, decided not to test their daughter. With regard to prenatal testing, there are a number of ethical issues as well as legal provisions to be addressed, especially if testing is being considered for the purpose of pregnancy termination rather than early detection and surveillance. This sensitive issue was thoroughly discussed with the brother of the index patient. The German national legal framework allows invasive prenatal testing in case of a potential treatment during pregnancy or childhood (not applicable in case of CDH1 -associated diffuse gastric cancer) or in case of an expected disease manifestation before the age of 18 years (subject of interpretation in case of CDH1 -associated diffuse gastric cancer, see above). During consultation the family ruled out invasive prenatal testing for further family planning due to ethical reasons, although preimplantation genetic diagnosis was an option the family would consider in the future.

In this case of a young patient with sudden death, awareness and recognition of a CDH1-associated hereditary diffuse gastric cancer facilitated the detection of one additional case of early gastric cancer in a family member and most likely prevented two more relatives (and potentially their progeny) from developing gastric cancer, which has a poor prognosis. Therefore, a family history leading to the suspicion of a hereditary cause of diffuse gastric cancer should prompt genetic counseling and low-threshold genetic testing of the CDH1 gene despite histological expression of E-cadherin.

Availability of data and materials

Abbreviations.

Computed tomography

Hereditary Diffuse Gastric Cancer

International Gastric Cancer Linkage Consortium

(messenger) Ribonucleic Acid

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Acknowledgements

We are indebted to all family members for the participation in this study.

Author information

Andreas Block and Alexander E. Volk contributed equally to this work.

Authors and Affiliations

Department of Medical Oncology and Hematology, University Cancer Center Hamburg, University Hamburg-Eppendorf, Hamburg, Germany

Elisabeth Niemeyer, Alexander Stein & Andreas Block

Department of Surgery, Regio Klinikum Pinneberg, Pinneberg, Germany

Hamid Mofid

Israelitisches Krankenhaus, Hamburg, Germany

Carsten Zornig

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Eike-Christian Burandt

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Alexander E. Volk

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Contributions

MH and CZ were the referring physicians and surgeons of the patients. EB performed pathologic workup. AEV performed genetic counseling and testing. AB, AS and EN performed genetic counseling and was involved in the oncological treatment. EN, AB and AEV wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Elisabeth Niemeyer .

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All participants were referred for routine diagnostic testing and genetic counseling. All participants gave their written informed consent for genetic testing. This study is in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). A copy of the consent form is available for review by the editor of this journal.

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Niemeyer, E., Mofid, H., Zornig, C. et al. Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family. BMC Gastroenterol 20 , 129 (2020). https://doi.org/10.1186/s12876-020-01283-2

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Received : 03 September 2019

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DOI : https://doi.org/10.1186/s12876-020-01283-2

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Case report of long-term survival with metastatic triple-negative breast carcinoma

Treatment possibilities for metastatic disease.

Editor(s): NA.,

Lifespring Cancer Treatment Center, Seattle, WA.

∗Correspondence: Bryce Douglas La Course, Lifespring Cancer Treatment Center, 510A Rainier Avenue South, Seattle, WA (e-mail: [email protected] ).

Abbreviations: ALL = acute lymphoblastic leukemia, CA = cancer antigen, CT = computed tomography, DC = dendritic cell, ER = estrogen receptor, GM-CSF = granulocyte-macrophage-colony-stimulating factor, HER2 = human epidermal growth factor receptor 2, MTD = maximum tolerated dose, PET = positron emission tomography, PR = progesterone receptor, TNBC = triple-negative breast cancer, Tregs = regulatory T cells.

Written informed consent was obtained from the patient in the study for publication of this case report and any accompanying images.

The authors have no conflicts of interest to disclose.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Rationale: 

Breast cancer is the most common as well as one of the most devastating cancers among women in the United States. Prognosis is poor for patients with metastatic breast cancer, especially for patients with so-called “triple-negative” disease. The lack of effective therapies for metastatic triple-negative breast cancer outlines the need for novel and innovative treatment strategies.

Patient concerns: 

A 58-year-old underwent a mastectomy which revealed a recurrent triple-negative breast carcinoma. Afterward, she presented with a growing mass in her left axilla and chest wall. A computed tomography scan showed axillary and supraclavicular adenopathy, nodules in the left upper and lower lobe of the lungs, and 2 areas of disease in the liver. A bone scan showed lesions in the ribs.

Diagnosis: 

The patient was diagnosed with a recurrent metastatic triple-negative breast carcinoma that spread to the lung, liver, and bones.

Interventions: 

The patient was treated with metronomic chemotherapy, sequential chemotherapy regimens, and immunotherapy.

Outcomes: 

The patient is now over 15 years out from her diagnosis of metastatic disease without any evidence of recurrent disease, likely due to the patient's treatment strategy which included sequential metronomic chemotherapy regimens and immunotherapy.

Lessons: 

Sequential metronomic chemotherapy regimens in combination with immunotherapy might be an effective treatment option for patients with metastatic triple-negative breast cancer. We hope that this case can provide some guidance for the treatment of metastatic triple-negative breast cancer and motivate research that can potentially lead to more cases of long-term survival for patients who develop this dismal disease.

1 Introduction

Breast cancer remains the most common cancer diagnosed among women in the United States and is the second leading cause of cancer-related deaths, with approximately 41,000 patients projected to die from this disease in 2018 alone. [1] The prognosis for patients with metastatic breast cancer varies based on many factors including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. Tumors that do not express the ER, PR, or HER2 receptors are known as “triple-negative” breast cancers (TNBCs) and represent approximately 11% of all breast cancers. [2] This subtype of breast cancer is known for being aggressive, having a high probability of distant recurrence after adjuvant therapy, and progressing quickly on palliative chemotherapy treatment in the metastatic setting. [2,3] Patients with metastatic TNBC have a poor prognosis, with a median overall survival of 13.3 months with treatment. [3] Continuing chemotherapy treatment until disease progression is currently the standard of care for patients with metastatic TNBC, with no preferred chemotherapy regimens established at this time. The lack of effective therapies for this aggressive disease highlights the need for the development of novel treatment strategies. Here we report the case of a patient with metastatic TNBC that metastasized to the lungs, liver, and bones who achieved long-term remission without evidence of disease recurrence after 15 years. Her case is followed by a discussion of the treatment strategy which likely has led to her remarkable survival.

2 Case report

A Caucasian female initially presented with a nodule in her left breast in March 2001 at the age of 56. Before this, the patient was a homemaker with a relatively unremarkable past medical history aside from some mild arthritis. Her father and brother had prostate cancer, and her mother apparently had uterine cancer. Her social history was negative for tobacco, alcohol as well as illicit drug use. A core biopsy performed in mid-April 2001 showed a high-grade infiltrating ductal carcinoma, with a Bloom–Richardson score of 9/9. Immunohistochemistry showed that the tumor was positive for ER expression and negative for PR expression and HER2 overexpression. The patient underwent a left lumpectomy with an axillary lymph node dissection shortly after the biopsy. Pathology revealed a 2.0 × 1.8 × 1.3 cm high-grade invasive ductal carcinoma. 0 of the 15 left axillary lymph nodes examined were positive for carcinoma, and no lymphatic invasion was identified. The patient declined adjuvant chemotherapy and radiation therapy.

In the spring of 2003, the patient noticed another mass under the nipple of her left breast. An ultrasound-guided left breast biopsy was performed in early May 2003 which revealed a high-grade ductal carcinoma. The patient then underwent bilateral simple mastectomies to remove the left breast tumor in late May 2003. Pathology of the left breast mass showed a poorly-differentiated carcinoma that measured 3.0 × 3.5 × 2.0 cm with a Bloom–Richardson score of 9/9. The tumor was negative for ER, PR, HER2 by immunohistochemistry, and for amplification of the HER2 gene by fluorescence in situ hybridization, indicating she had triple-negative recurrent disease ( Fig. 1 ). The patient again declined any treatment.

In early September 2003, the patient noticed a growing mass in her left axilla and chest wall. A computed tomography (CT) scan of the chest showed a 3.8 cm necrotic left axillary lymph node with axillary and supraclavicular adenopathy. Nodules were also seen in the left upper and lower lobe of the lungs along with 2 subtle areas of low attenuation in the liver. A bone scan performed in December 2003 revealed bone lesions along the left 3rd and 6th ribs posterolaterally. The patient was concluded to have metastatic disease to the lungs, liver, and bones. Unfortunately, these images have been destroyed by the imaging facility and cannot be used in this publication. The details of the scans were obtained from the official written scan reports.

After consulting with the patient, she decided to proceed with chemotherapy treatment. She was given 4 sequential chemotherapy regimens ( Table 1 ) to try and control her cancer along with monthly zoledronic acid to try to prevent bone complications due to her osseous metastases. Granulocyte-macrophage-colony-stimulating factor (GM-CSF) was used throughout the treatment to prevent or treat chemotherapy-induced neutropenia as well as stimulate the immune system. After 14 doses of weekly paclitaxel and carboplatin, there was remarkable tumor shrinkage in the left chest wall and axillary area on her physical examinations. Her cancer antigen (CA) 27.29 (normal range: <38 U/mL) also decreased from a pretreatment level of 52.1 to 19.8 in mid-April 2004 which was consistent with the patient's physical exam findings. The patient's CA 27.29 then remained within normal range from this point onward. The patient was then switched to weekly doxorubicin liposome in June 2004. Twelve doses were planned, but she only received 8 doses due to developing palmar-plantar erythrodysesthesia. Her symptoms resolved after the drug was withdrawn in late July 2004. The patient then continued chemotherapy treatment and received 6 doses of weekly gemcitabine and cisplatin from August 2004 to October 2004. The patient developed thrombocytopenia and her second to the last dose of this regimen was given with a reduced dose of cisplatin. Gemcitabine was dose reduced during her last infusion of this regimen. She was then switched to weekly vinorelbine in early December 2004 and completed 12 doses of chemotherapy treatment in late February 2005.

Aside from developing neutropenia and thrombocytopenia secondary to chemotherapy treatment and palmar-plantar erythrodysesthesia secondary to doxorubicin liposome, the patient tolerated her treatment relatively well. A CT scan performed in March 2005 showed no evidence of disease in the lung and liver. The patient was taken off of chemotherapy treatment but continued on monthly zoledronic acid and pursued a watchful waiting approach from February 2005 to June 2005.

In June 2005 the patient developed several small skin nodules in her left axillary chest wall. A positron emission tomography (PET) and CT scan performed shortly after showed minimal thickening of the left chest wall, suspicious for recurrent disease, although no biopsy was performed. There was no other evidence of metastatic disease. She was started on imiquimod cream, which was applied on the skin nodules, for immune stimulation. The patient reported pruritus and erythema in the applied area, but she did not complain of having any pain. These nodules resolved after a few weeks. In October 2005, the patient noticed several pea-sized nodules in her left axilla which were also suspicious for disease recurrence. The patient continued applying imiquimod cream to the area. She developed erythema, ulceration, and skin breakdown in that area, but this resolved after stopping imiquimod. The skin nodules resolved by January 2006. The patient's condition continued to improve, and the frequency of her zoledronic acid infusions was reduced to every other month in May 2006, and then quarterly in September 2007. In December 2008 she continued with biannual infusions of zoledronic acid. A germline BRCA1 and BRCA2 analysis performed in December 2009 did not detect any mutations. Routine PET/CT and CT scans continue to show no evidence of recurrent or persistent metastatic disease. The patient is now 73 years old and is enjoying a good quality of life. She is currently over 15 years out from her diagnosis of recurrent metastatic TNBC.

3 Discussion

The prognosis of this patient before starting treatment was particularly poor, not only because her tumor did not express the ER, PR, or HER2 receptors, but also because she had stage IV disease with multiple visceral metastases. With the typical prognosis of metastatic TNBC being slightly over 1 year, the 15-year survival of this patient is quite remarkable, especially given that she is currently free of disease and has not received any chemotherapy treatment since late February 2005. To our knowledge, this patient is the longest reported survivor of metastatic TNBC. Her long-term survival without recurrence suggests that this patient may be cured of a cancer that is not thought to be curable. We believe that our treatment methodology, which included using metronomic chemotherapy, switching chemotherapy regimens before anticipated disease progression, and utilizing immune therapies, all contributed to her outstanding survival. Below, we will describe each of these treatment strategies in detail.

3.1 Metronomic chemotherapy

The dosing of a standard chemotherapy regimen is based on a maximum tolerated dose (MTD). This dose is typically the highest possible dose that is not lethal to the patient. The idea of an MTD was originally developed with the logic that “more is better” to try and maximize the amount of cancer cell death. A high dose of chemotherapy can kill cancer cells, but due to the relatively nonspecific mechanism of action of most chemotherapy agents, this high dose of chemotherapy can also result in clinical toxicities which is why standard chemotherapy regimens are often administered every 3 weeks. The breaks in between standard chemotherapy doses are crucial for the recovery of normal tissues, but logically this can also give time for cancer cells to grow and progress as well. Thus, the dosing of chemotherapy agents and the frequency of chemotherapy administration may play an important role in the efficacy of treatment as well as the patient's quality of life.

This patient received lower doses of chemotherapy on a more frequent basis, also known as “metronomic chemotherapy.” Although lower doses of chemotherapy agents were given to this patient during each administration, the overall dose intensity (the total dose of chemotherapy administered per unit time) of her chemotherapy agents was a similar, if not higher, dose intensity, compared to the standard dosing of each respective chemotherapy agent. Studies have shown that reducing dose intensity, most commonly due to myelosuppression, correlates with poorer disease-free survival and overall survival, while maintaining a relatively high planned dose intensity is associated with better clinical outcomes. [4] Due to the lower doses used during each administration, metronomic chemotherapy regimens can minimize severe adverse events and prolonged drug-free breaks. In addition, a more steady dosing schedule may actually kill more cancer cells by maintaining a more constant drug concentration in the body. This logic may explain why dose-dense regimens (chemotherapy regimens with an increased frequency of administration) have been shown to be more effective in the treatment of several kinds of cancer, including breast cancer, when compared to standard treatment. [5] We have also treated pancreatic cancer patients using a similar dosing strategy, which has yielded exciting results. [6,7]

The main mechanism of action of metronomic chemotherapy was initially thought to be its effects on endothelial cells resulting in antiangiogenic effects. There is a fair amount of literature that suggests that paclitaxel has antiangiogenic effects when administered in lower doses more frequently. [8] Likely due to their aggressive nature, TNBCs are known to have enhanced angiogenesis. [9] The proangiogenic tumor microenvironment creates an abnormal vascular network that can result in increased interstitial pressure and decrease drug penetration, ultimately decreasing the efficacy of systemic treatment. [10] By blocking angiogenesis and normalizing the tumor vasculature, more chemotherapy can reach the tumor, potentially improving the efficacy of treatment.

In addition to having direct cytotoxic and antiangiogenic effects, it has been discovered that metronomic chemotherapy can also have antistromal and immunostimulatory effects. [11–13] There are even some thoughts that the effects that metronomic chemotherapy has on the tumor microenvironment can decrease the rate of acquired chemotherapy resistance. [11,12] Targeting both cancer cells and the tumor microenvironment may play an important role in the future of cancer treatment.

3.2 Sequential chemotherapy regimens

The standard way to administer chemotherapy treatment is to continue a single chemotherapy regimen until noticeable disease progression. Patients with metastatic TNBC tend to relapse quickly on chemotherapy treatment, likely due to acquired disease resistance. [3] Drug resistance is seen as the primary cause of failure of chemotherapy treatment for cancer and continuing a chemotherapy regimen until disease progression will inevitably breed chemotherapy-resistant disease. Switching chemotherapy regimens before disease progression, as we did for this patient, may prevent the development of disease resistance, allowing for a continual decrease in the number of cancer cells, and perhaps a better chance of achieving long-term survival.

Tumors are known to have a large amount of genetic diversity, even within a single mass, and chemotherapy treatment can induce strong selective pressure for cells that have intrinsic or acquired mutations which can resist treatment. [14] Switching chemotherapy agents may eradicate cancer cells that developed resistance to the cytotoxic agents in the previous regimen, especially if the new chemotherapy agents have a different mechanism of action. There are even some suggestions that cancer cells can become dependent on certain therapies after long-term drug exposure, and switching the drugs used may increase treatment efficacy by inducing cell death of the cancer cells that have become “addicted” to the previous therapy. [12,13] The idea of switching chemotherapy treatments before the development of disease resistance has broad implications and could transform the idea of cancer being an acute disease to more of a chronic illness. In addition to potentially increasing treatment efficacy and preventing the development of disease resistance, switching treatment regimens can also help prevent the accumulation of chemotoxicity from a single chemotherapy regimen, which can improve the quality of life of patients receiving treatment.

This idea of sequential chemotherapy regimens has been successfully introduced in the treatment of metastatic non-small cell lung carcinoma. Patients who responded to first-line chemotherapy and pursued a switch maintenance therapy were found to have improved overall survival compared to placebo or observation, and switch maintenance therapy was also less toxic compared to continuous maintenance therapy. [15] A similar treatment strategy has also been applied and has found major success in the treatment of pediatric acute lymphoblastic leukemia (ALL). A diagnosis of ALL was fatal for children in the 1950s. Currently, this disease has a cure rate of more than 80% in children. The current treatment for ALL involves several combination chemotherapy regimens that are given sequentially to eliminate any remaining disease. [16] Sequential chemotherapy regimens in ALL has been considered one of the greatest achievements in the field of oncology to date.

This patient received several different chemotherapy regimens sequentially ( Table 1 ). Her first regimen consisted of paclitaxel and carboplatin. Paclitaxel that is administered on a weekly basis has been shown to be superior to paclitaxel that is administered every 3 weeks in the treatment of metastatic breast cancer, with increased response rates, time to progression, as well as survival. [17] Moreover, there is some evidence that platinum-based chemotherapy regimens improve the overall survival of patients with metastatic TNBC. [18] The addition of platinum agents to treatment regimens has likely been slow to catch on due to the significant toxicity of the standard doses of these agents. However, the carboplatin dose of AUC 2.25 and cisplatin dose of 15 to 20 mg/m 2 that was given on a weekly basis were tolerated relatively well by this patient.

After she received 14 doses of paclitaxel and carboplatin, she was switched to weekly doxorubicin liposome. Anthracyclines are known to be very effective in the treatment of breast cancer, but carry a risk of cardiotoxicity and significant myelosuppression. We prefer to use doxorubicin liposome instead of doxorubicin because doxorubicin liposome has a favorable toxicity profile, less hematological toxicity, and has been found to cause less cardiotoxicity compared to doxorubicin. [19] This is an important consideration to reduce potential comorbidities in the future, especially if patients have the potential to achieve long-term survival. The patient tolerated treatment with weekly doxorubicin liposome well aside from developing palmar-plantar erythrodysesthesia, but perhaps this treatment might be more tolerable if it was administered every 2 weeks due to doxorubicin liposome's relatively long half-life. This treatment might also be more effective if it was combined with weekly paclitaxel.

The patient's next regimen, gemcitabine, and cisplatin, has been shown to improve outcomes in patients with metastatic TNBC compared to patients without metastatic TNBC. [20] The patient also tolerated this regimen well aside from developing thrombocytopenia, but maybe this could be lessened by starting with a dose of gemcitabine 600 mg/m 2 and cisplatin 15 mg/m 2 instead of gemcitabine 750 mg/m 2 and cisplatin 20 mg/m 2 , which is what we have done subsequently with other patients. Her final regimen consisted of vinorelbine, which is another effective drug for the treatment of metastatic breast cancer patients who have been exposed to anthracyclines and taxanes in previous treatments. [21] Since the patient's diagnosis 15 years ago, there are several new treatments available that may be more effective than vinorelbine, such as eribulin or irinotecan.

By giving this series of effective treatments sequentially, we believe that this prevented disease resistance and allowed the patient to achieve complete remission after approximately 1 year of treatment. The combination of agents was chosen to avoid overly additive side effects, such as myelosuppression, so that the patient could receive continuous treatment without interruption and also maintain a relatively high overall dose intensity. In regards to the order of these regimens, it is unknown whether or not this is the most optimum sequence of regimens and this should be further investigated.

3.3 Immunotherapy

More evidence is accumulating suggesting that some subtypes of metastatic TNBC can be particularly responsive to immunotherapy, with some studies showing promising results. [22] However, cancers can escape an antitumor immune response in several ways such through the upregulation of regulatory T cells (Tregs) and secretion of immunosuppressive cytokines into the tumor microenvironment as well as through the expression of immunosuppressive proteins, such as programmed death-ligand 1, on the cell surface. [22–24] The situation is further exacerbated by the immunosuppressive effect of standard dose chemotherapy. [25] When the immunosuppressive activity of the tumor outweighs the body's antitumor immune response, this is thought to promote tumor progression.

Metronomic chemotherapy, in addition to having a lesser impact on blood counts, is thought to have immunomodulatory properties. In preclinical studies, low-dose paclitaxel and gemcitabine have been shown to decrease the number and viability of Tregs as well as myeloid-derived suppressor cells in the tumor microenvironment, which could potentially allow for a more potent antitumor immune response. [26] Moreover, the antiangiogenic effects of metronomic chemotherapy may be synergistic with its immunostimulatory properties. Normalizing the tumor vasculature could allow the immune system to better reach the tumor bed, just as it is thought to allow more chemotherapy treatment to reach the tumor. Interestingly, the patient also received zoledronic acid due to her bone metastases, which may also have immunomodulatory properties. This effect seems to be more prevalent in ER-positive breast cancer cells, but more research will need to be conducted to assess the immunomodulatory properties in ER-negative breast cancer. [27]

The patient also received several immunostimulatory agents which may have played a role in her long disease-free remission. While receiving chemotherapy treatment, the patient received GM-CSF to prevent or treat chemotherapy-induced neutropenia. We prefer the use of GM-CSF compared to other colony-stimulating factors because GM-CSF stimulates both the granulocyte as well as the monocyte/macrophage and dendritic cell (DC) lines, while other colony-stimulating factors only stimulate the granulocyte cell line. DCs are crucial for antigen presentation and activation of the adaptive immune system and macrophages can remove dead tumor cells via phagocytosis. Moreover, preclinical evidence suggests that low-dose paclitaxel can stimulate DC maturation and the anthracyclines can promote the phagocytosis of tumor cells by DCs, suggesting a synergistic role of GM-CSF in combination with 2 of the patient's chemotherapy regimens. [28]

The patient also applied imiquimod topically to small superficial lesions in her left axillary region that were likely secondary to recurrent disease. Imiquimod has known antitumor activity in superficial basal cell carcinoma and it is thought to work by stimulating the innate and adaptive immune system in the applied area via toll-like receptor 7. [29] The patient's left axillary lesions resolved after she applied imiquimod cream to the area, suggesting that imiquimod may be able to be used to treat superficial metastases from TNBC. One small study also had similar findings, and it would be interesting to investigate whether metastatic TNBC was more responsive to local immunotherapy than other breast cancer types. [30] Perhaps the success of imiquimod in this patient was due to the minimal tumor burden the patient had at the time, especially considering that a smaller tumor size in basal cell carcinoma is correlated with a more favorable prognosis after treatment with imiquimod.

4 Conclusion

The patient described in this case report is now 15 years out from her diagnosis of recurrent metastatic TNBC without evidence of persistent or recurrent metastatic disease. Her treatment, which included the use of sequential metronomic chemotherapy regimens as well as several immunotherapies, was tolerated relatively well and likely contributed to her remarkable survival. Although this is only 1 case, we have treated another patient with metastatic TNBC with a similar strategy who is now over 6 years out and free of disease as well as a few other patients who achieved longer than average survivals. We are planning to publish this data in a small case series in the future. We hope that this encouraging case can offer hope to those who are suffering from this debilitating disease and spark the formation of larger clinical trials to further evaluate this treatment strategy due to the potential significant medical, psychological, and economic implications. These ideas not only have the possibility to shift the paradigm of treating metastatic TNBC, but also potentially other metastatic cancers as well.

Acknowledgments

We would like to thank Max Tse and Jeffrey Wang for drafting earlier versions of this paper, and Emmanuel De Dios, without whom none of this work could have been done.

Author contributions

Conceptualization: Ben Man-Fai Chue, Bryce Douglas La Course.

Formal analysis: Ben Man-Fai Chue, Bryce Douglas La Course.

Writing – original draft: Ben Man-Fai Chue, Bryce Douglas La Course.

Writing – review and editing: Ben Man-Fai Chue, Bryce Douglas La Course.

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Case 1: 48-Year-Old Patient With HER2+ Metastatic Breast Cancer

EP: 1 . Best Practices: HER2+ MBC With Brain Mets

EP: 2 . Frontline Standards of Care for HER2+ MBC

EP: 3 . Case 1: 48-Year-Old Patient With HER2+ Metastatic Breast Cancer

EP: 4 . Treatment Strategies for Relapsed/Refractory HER2+ MBC

EP: 5 . Case 2: 61-Year-Old Patient With R/R HER2+ MBC

EP: 6 . Cancer Network Around the Practice: Relapsed/Refractory HER2+ Metastatic Breast Cancer

Adam M. Brufsky, MD, PhD: Let’s talk about this case. This is a 48-year-old woman who presented to her primary care physician a number of years ago with a lump in her breast. She had a 4.4-cm left breast mass and 3 palpable axillary lymph nodes. Her ultrasound and mammogram confirmed these physical findings.

She was referred to a medical oncologist and had a core needle biopsy that showed ER- [estrogen receptor-negative]/PR- [progesterone receptor-negative], HER2 [human epidermal growth factor receptor 2]-positive by IHC [immunohistochemistry score] that was 3+. A CT scan of the chest, abdomen, and pelvis showed 3 liver lesions, the largest being 3.1 cm. This is the de novo patient we always talk about. She had an MRI of the brain and it was negative for metastasis. She received 6 cycles of THP [docetaxel, trastuzumab, pertuzumab], followed by HP [trastuzumab, pertuzumab] for another 12 months. That’s 18 months of therapy.

She had a partial response in her breast mass, and her liver lesions fully responded. Later, she suddenly began to have rapid unexplained weight loss. The CT scan only showed 2 new liver lesions, so not quite the symptom I would imagine. She then got a brain MRI that showed about 30 widely scattered lesions, the largest being about 0.5 or 0.6 [cm]. They have all these little punctate ones; you’ve all seen those.

The question is: what treatment would you give this person? Let’s say the brain MRI shows 3 lesions, all in the frontal cortex, with the largest being 1.5 cm. That makes it a little bit of a different question because if there are widely scattered lesions, we’re not going to want to do SRS [stereotactic radiosurgery]. We are probably going to want to do whole brain radiation. Let’s say she’s asymptomatic with no edema. The polling question is: what treatment would you recommend? T-DM1 [trastuzumab emtansine], tucatinib/trastuzumab/capecitabine, SRS to the brain metastases, clinical trial, or other.

You guys could answer that question. Let me start with Sara. How would you approach this?

Sara A. Hurvitz, MD, FACP: They’re not totally mutually exclusive, right? You could do SRS and switch systemic therapy. She is progressing systemically in the liver, so I think switching systemic therapy makes sense. I like tucatinib because it does penetrate the blood-brain barrier, but I would still be tempted and would probably talk to my radiation oncology and neurosurgery colleagues. We’d probably end up doing both the SRS and tucatinib-based therapy.

Adam M. Brufsky, MD, PhD: That’s reasonable. VK, do you have any other comments on this?

VK Gadi, MD, PhD: Yes, I agree. The tolerability of the regimen is good. You might even give this lady an opportunity to fly without SRS and have that in your back pocket. If you’re not seeing control, you can go to SRS at a later time. I don’t think there’s a wrong answer here. You could probably do it both ways.

Adam M. Brufsky, MD, PhD: Neil, do you have something to add?

Neil M. Iyengar, MD: No. She fits perfectly into the HER2CLIMB population, so I agree with everything that has been said because there is demonstrated activity of the tucatinib-based regimen in terms of CNS [central nervous system] response. Coupling that with SRS is reasonable. This is the patient we were talking about earlier with whom we would discuss foregoing local therapy to the brain. That’s a reasonable discussion here. It’s a tricky poll question because my kneejerk response would be to put her on a clinical trial. We should all be trying to prioritize clinical trials, but in the absence of that clinical availability, tucatinib plus or minus radiation is a reasonable option.

Adam M. Brufsky, MD, PhD: There’s a clinical trial that’s great; it’s not scientifically spectacular, but clinically, it’s fabulous. I believe it’s called DESTINY. In fact, I put a patient on it today with trastuzumab deruxtecan and tucatinib together. That’s a great trial that’s going to accrue quickly. If we could put as many people as we can on that, we can answer the clinical question quickly. I would agree.

I have 1 last question before we go on to the last 25 minutes and the last segment. What do you tell people about [adverse] effects? Are you seeing a lot of [adverse] effects with tucatinib? Do you have to dose reduce it at all when you give it? These are questions people who haven’t had a lot of experience with it usually ask. I’ll start with Neil. Do you see a lot of diarrhea? Do you have to dose reduce with tucatinib?

Neil M. Iyengar, MD: In my experience, this regimen is quite tolerable. We all, as oncologists, have unfortunately become very comfortable with managing diarrhea, along with oncology nursing and so forth. What I have found with the tucatinib-based regimen is that with the initiation of antidiarrheal agents, the diarrhea usually resolves or improves pretty quickly. People have to know about it and be prepared to deal with it immediately. It does come on early, usually within the first cycle.

The other consideration to keep in mind with tucatinib is that many of the [adverse] effects are likely related to capecitabine. We’re all very comfortable with managing capecitabine-related toxicity and dose modifying capecitabine as needed. We see in the HER2CLIMB data that patients in the tucatinib arm stayed on study longer and were therefore exposed to capecitabine for longer than those in the placebo arm. I think a lot of the toxicities are familiar ones that are related to capecitabine and are quite manageable.

Adam M. Brufsky, MD, PhD: Great. VK and Sara, do you have any other comments about this toxicity? Do you see any toxicity at all with this, more than you’d expect?

Sara A. Hurvitz, MD, FACP: It’s well tolerated. About 13% had grade 3/4 diarrhea. Before getting on this call, I had to dose reduce a patient on this therapy. It’s hard to tell. On the clinical trial we enrolled patients, and I had a patient on who had severe colitis, hospitalization, etc, and I was sure she was getting tucatinib. When she was unblinded after the data came out, it turned out that she wasn’t on tucatinib. She was on placebo. I completely agree that these are [adverse] effects we’re used to with capecitabine. There’s not a whole lot of difference. Tucatinib is pretty well tolerated.

VK Gadi, MD, PhD: I agree. I think the capecitabine is the real culprit. The people on the trial were actually on it for so much longer that the toxicities from capecitabine emerged ongoing on the study. That has been my experience. Something important we don’t yet have is the PRO [patient-reported outcomes] data from these studies. A lot of my colleagues, especially those in communities where patients come in from a long way away, know that this is a tremendous pill burden with this regimen. Sometimes a parenteral regimen that you’re giving every 3 weeks is better for patients. I’m curious to see what those data look like when they come out. From our perspective as physicians, this is a slam dunk and it’s easy to give, but that’s not always the perspective that matters.

Adam M. Brufsky, MD, PhD: I agree.

Sara A. Hurvitz, MD, FACP: Yes, I think the quality of life PRO data were presented at the San Antonio [Breast Cancer Symposium]. I’m trying to pull it up. I don’t have it right at my fingertips, but my recollection was that it looked fairly good, that the quality of life was maintained.

Adam M. Brufsky, MD, PhD: Right, but they’re not going to tell you that they’re struggling to take all those pills. It’s a lot.

Sara A. Hurvitz, MD, FACP: That’s true.

Adam M. Brufsky, MD, PhD: It’s about 9 pills a day, which is a lot.

Neil M. Iyengar, MD: The quality of life data are always interesting because the end point of choice is time to deterioration and whether we are avoiding that. I think that’s a fairly low bar.

Adam M. Brufsky, MD, PhD: Exactly. Women are going to do anything they can.

Transcript edited for clarity.

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Improving care in pediatric oncology: why patient- and family-centered support is essential throughout the cancer survivorship continuum

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M.C. is supported by the Four Diamonds Research Funds, Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children’s Hospital, Hershey, PA, USA. A.L. is a recipient of the Doctoral Research Award from the Canadian Institutes of Health Research (CIHR).

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These authors contributed equally: Maxime Caru, Ariane Levesque.

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Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children’s Hospital, Hershey, PA, USA

Maxime Caru

Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA, USA

Department of Psychology, University of Montreal, Montreal, QC, Canada

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Association of thyroid autoantibodies with aggressive characteristics of papillary thyroid cancer: a case-control study

• Hai-Long Tan 1   na1 ,
• Zi-En Qin 1 , 2   na1 ,
• Sai-li Duan 1 ,
• Ya-Ling Jiang 3 ,
• Neng Tang 1 , 6 &
• Shi Chang 1 , 4 , 5 , 6 , 7 , 8  

World Journal of Surgical Oncology volume  22 , Article number:  224 ( 2024 ) Cite this article

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Although the potential association between autoimmune thyroiditis and papillary thyroid cancer (PTC) has been acknowledged, whether the clinicopathological features of PTC will be affected by thyroid autoantibodies remains unknown.

Patients and methods

We conducted a case-control study to investigate the association of thyroid autoantibodies with clinicopathological characteristics of PTC in 15,305 patients (including 11,465 females and 3,840 males) from 3 medical centers in the central province of China. Logistic regression and restricted cubic spline models were performed to analyze the association of thyroid autoantibodies with clinicopathological features of PTC.

In total, out of the 15,305 patients enrolled in this study, 10,087 (65.9%) had negative thyroid autoantibodies, while 5,218(34.1%) tested positive thyroid autoantibodies. Among these individuals, 1,530(10.0%) showed positivity for TPOAb only, 1,247(8.2%) for TGAb only and a further 2,441(15.9%) exhibited dual positivity for both TPOAb and TGAb combined. Thyroid autoantibodies level demonstrated significant correlations with certain aggressive features in PTC. Specifically, TGAb level displayed a direct correlation to an increased likelihood of multifocality, bilateral tumor, extrathyroidal extension, lymph node metastasis, as well as more than five affected lymph nodes. However, TPOAb level exhibited an inverse association with the risk associated with extrathyroidal extension, lymph node metastasis, and more than five affected lymph nodes.

Elevated level of TGAb were positively correlated with the risk of aggressive features in PTC, while high level of TPOAb were inversely associated with the risk of extrathyroidal extension and lymph node metastasis.

Introduction

Papillary thyroid cancer (PTC) represents the most prevalent pathological subtype of thyroid cancer, accounting for over 90% of cases [ 1 , 2 ]. Despite its classification as a low-grade malignant tumor, a considerable proportion of PTC exhibits aggressive features such as extrathyroidal extension and lymph node metastasis, which significantly impact patient prognosis [ 3 , 4 , 5 ]. Thus, proper preoperative evaluation of clinicopathological features is crucial for deciding treatment strategies and surgical scope for PTC.

Thyroid autoimmunity stands as one of the most common autoimmune diseases, with the presence of serum thyroid autoantibodies against thyroid antigens (primarily thyroperoxidase and thyroglobulin) serving as the primary marker for diagnosing thyroid autoimmunity [ 6 , 7 , 8 , 9 ]. Thyroid autoantibodies have the potential to instigate an immune response against thyroid follicular cells themselves through their reactivity to thyroid antigens [ 10 , 11 ]. Consequently, we hypothesize that these antibodies may trigger an immune response against malignant tumor cells originating from thyroid follicular cells, thereby influencing the biological characteristics of thyroid cancer. However, whether or not clinicopathological features of PTC are affected by thyroid autoantibodies remains unproven; if they are indeed impacted, their clinical significance and association remain unknown.

In this study, we conducted a case-control study to investigate the association of thyroid autoantibodies with clinicopathological features of PTC with the aim of elucidating the effect of these antibodies on the aggressive characteristics associated with PTC.

Study design and participants

We performed a multicenter study, and retrospectively collected electronic medical records of 28,986 cases from three medical centers: (1) Xiangya Hospital; (2) Changsha First Hospital; (3) LiXian People’s Hospital. The Ethics Review Committee of each central approved the study and waived the informed consent requirement because of the retrospective and anonymous nature of the study.

Patients with benign thyroid nodules or other thyroid malignant neoplasms, primary hyperthyroidism, a history of neck surgery, or incomplete clinical information were excluded from this study. Finally, 15,305 participants were enrolled in this study (Fig.  1 ).

Selection and exclusion of participants and the flow of study design

Evaluation of clinicopathological characteristics

We conducted a review of medical records and extracted various data, including sex, age at diagnosis, BRAF V600E mutation status, thyroid autoantibodies level, primary tumor size, multifocality, bilateral tumor occurrence, extrathyroidal extension presence, and lymph node stage. The serum level of thyroid autoantibodies were measured using two methods: electrochemiluminescence immunoassay and chemiluminescent assays within 30 days prior to surgery. When the level of thyroid autoantibodies exceeded the normal range, it was classified as positive. Diagnosis of Hashimoto’s thyroiditis (HT) was confirmed through histologic examination of postoperative paraffin-embedded tissue specimens.

Statistical analysis

Categorical variables are presented as counts and percentages (%), while continuous variables are described using median and interquartile range (IQR). The Mann-Whitney U test was used to compare continuous variables between groups; the chi-square test was employed for comparing categorical variables. Logistic regression analysis was performed to explore the relationship between thyroid autoantibodies and clinicopathological features of PTC. To assess the linear and non-linear association between level of thyroid autoantibodies measured via electrochemiluminescence immunoassay with aggressive characteristics of PTC, restricted cubic spline models with three knots positioned at the 10th, 50th, and 90th centiles were employed. Statistical significance was determined at P  < 0.05. Statistical analyses were carried out using SPSS 26.0 for Windows (IBM SPSS Inc., Chicago IL USA) and R version 4.2.1 (R Foundation for Statistical Computing).

Characteristics and baseline of the participants

A total of 15,305 participants were enrolled in the study, comprising 11,465 (74.9%) female and 3,840 (25.1%) male cases, with a median age of 42 years [interquartile range (IQR) 33–51] at diagnosis. Furthermore, 10,087 (65.9%) patients tested negative thyroid autoantibodies while 5,218 (34.1%) with positive. Those testing positive included 1,530 individuals (10.0%) with anti-thyroid peroxidase antibody (TPOAb) positive alone, 1,247 individuals (8.2%) with anti-thyroglobulin antibody (TGAb) positive alone, and 2,441 individuals (15.9%) with TAb-positive (both of TPOAb and TGAb positive). Moreover, thyroid autoantibodies positivity is more prevalent in female PTC patients, whether for the TPOAb positive alone (80.4%) or the TGAb positive alone (89.1%), or both positive (88.2%) ( P  < 0.001) (see Table  1 ).

Table l illustrates our investigation into disparities in clinicopathological features among PTC patients across different thyroid autoantibodies groups. Significant variations were observed in such clinicopathologic characteristics as sex, age at diagnosis, primary tumor size, BRAF V600E mutation status, TSH level, presence of multifocal and bilateral tumors, extrathyroidal extension, primary tumor stage, lymph node stage, and number of metastatic lymph nodes > 5 ( P  < 0.001, all).

Association of thyroid autoantibodies with aggressive characteristics of papillary thyroid cancer

We conducted logistic regression to analyze the risk associated with thyroid autoantibodies for the aggressive characteristics of PTC. Our findings revealed a significant correlation between the thyroid autoantibodies and the aggressive characteristics of PTC. Comparing PTC cases with thyroid autoantibodies negative, those with TGAb positive was identified as having a higher risk for multifocality, bilateral tumors, larger tumor size, lymph node stage, and number of metastatic lymph nodes > 5 ( p  < 0.05, all). Similarly, PTC cases in the TPOAb-positive or TAb-positive groups also demonstrated a tendency towards multifocality, bilateral tumors, but with lower lymph node stage ( p  < 0.05, all). Moreover, TAb-positive patients showed a higher risk for larger tumor size, and more than 5 metastatic lymph nodes ( p  < 0.05, all). Additionally, a strong association between BRAF V600E mutation and thyroid autoantibodies was observed, indicating that PTC patients with thyroid autoantibodies positive had a lower rate of BRAF V600E mutations ( p  < 0.001). Nonetheless, no significant differences were noted in other aggressive characteristics, such as extrathyroidal extension, and primary tumor stage ( p  > 0.05, all) (Table  2 ).

Furthermore, we conducted an analysis of the linear and nonlinear relationships between thyroid autoantibodies level and aggressive characteristics of PTC using restricted cubic spline (RCS) curves. Our finding revealed a strong correlation between thyroid autoantibodies level and specific aggressive characteristics of PTC. Specifically, TPOAb level exhibited a significant positive correlation with the risk of bilateral tumors (p for overall < 0.001), as well as a borderline significant linear relationship (p for overall = 0.057) with the risk of multifocality in PTC patients. Conversely, there was a significant inverse association was found between TPOAb level and BRAF V600E mutation (p for overall < 0.001), extrathyroidal extension (p for overall = 0.047), lymph node metastasis (p for overall < 0.001), and number of metastatic lymph nodes > 5 (p for overall = 0.002) after adjusting for confounders. Of note, TPOAb level displayed a linear inverse relationship with the risk of extrathyroidal extension (p for nonlinear = 0.281), lymph node metastasis (p for nonlinear = 0.182), and number of metastatic lymph nodes > 5 (p for nonlinear = 0.396) (Fig.  2 ).

Association of Anti-Thyroid Peroxidase Antibody Level with Aggressive Characteristics of Papillary Thyroid Cancer. ( A ) BRAF V600E mutations. ( B ) Multifocality. ( C ) Bilateral tumor. ( D ) Extrathyroidal extension. ( E ) Lymph node metastasis. ( F ) No. of metastatic lymph nodes > 5

In addition, we observed a significant positive correlation between TGAb level and the risk of multifocality (p for overall = 0.037), bilateral tumors (p for overall < 0.001), lymph node metastasis (p for overall < 0.001), and the presence of more than 5 metastatic lymph nodes (p for overall < 0.001). Futhermore, there was a clear linear positive relationship between TGAb level and lymph node metastasis (p for nonlinear = 0.166). Interestingly, we also discovered a negative association between TGAb level and BRAF V600E mutation (p for overall < 0.001), though this relationship shows J-shaped curve (p for nonlinear < 0.001) as shown in Fig.  3 .

Association of Anti-Thyroglobulin Antibody Level with Aggressive Characteristics of Papillary Thyroid Cancer. ( A ) BRAF V600E mutations. ( B ) Multifocality. ( C ) Bilateral tumor. ( D ) Extrathyroidal extension. ( E ) Lymph node metastasis. ( F ) No. of metastatic lymph nodes > 5

Association of thyroid autoantibodies with aggressive characteristics of papillary thyroid cancer stratification by HT

Additionally, we conducted a logistic regression analysis to examine the relationship between thyroid autoantibodies and the aggressive characteristics of PTC stratified by HT. Noteworthy, no significant association was found between thyroid autoantibodies status and the aggressive characteristics of PTC with HT, except for BRAF V600E mutation status and primary tumor size (Table S1 ). However, we did find that thyroid autoantibodies were strongly associated with aggressive characteristics of PTC without HT (Table S2 ). In cohorts without HT, TGAb-positive and TAb-positive statuses were identified as independent risk factors for multifocality, bilateral tumor, larger tumor size, advanced lymph nodes stage, and more than 5 metastatic lymph nodes ( p  < 0.05, all). Moreover, we noted that PTC cases in the TPOAb-positive group were more prone to bilateral tumors ( p  < 0.001), but there were no differences in other aggressive characteristics such as multifocality, extrathyroidal extension, primary tumor diameters, primary tumor stage, lymph nodes stage, and number of metastatic lymph nodes > 5 ( p  > 0.05, all) (Table S2 ).

In linear and nonlinear relationships analyses, we observed that TPOAb level showed a significant positive linear correlation with the risk of bilateral tumors (p for overall < 0.001 and p for nonlinear = 0.017), but inverse nonlinear association with the risk of extrathyroidal extension (p for overall = 0.003 and p for nonlinear = 0.045) in none-HT cohorts. Furthermore, TPOAb level was inversely associated with the risk of BRAF V600E mutation (p for overall < 0.05), and lymph node metastasis (p for overall < 0.001) both in HT and none-HT cohorts, as well as with more than 5 metastatic lymph nodes (p for overall < 0.001) in HT cohorts (Figure S1 ).

Similarly, we observed that TGAb level were positively nonlinearly associated with the risk of multifocality, bilateral tumors, and extrathyroidal extension (p for overall < 0.001 and p for nonlinear < 0.05, all), but inversely nonlinearly associated with the risk of BRAF V600E mutation (p for overall < 0.001 and p for nonlinear < 0.001) in none-HT cohorts rather than HT cohorts. Interestingly, we also found a positive association between TGAb level and lymph node metastasis (p for overall < 0.05) as well as with more than 5 metastatic lymph nodes (p for overall < 0.001) whether in HT or none-HT cohorts (Figure S2 ).

Patients with PTC are frequently concomitant with autoimmune thyroiditis, particularly Hashimoto thyroiditis [ 12 , 13 , 14 ], sparking considerable interest in their relationship. Although the potential link between thyroid autoimmunity and the invasiveness or metastatic potential of PTC has been recognized [ 15 , 16 , 17 ], conclusive evidence delineating the impact of thyroid autoantibodies (mainly to thyroperoxidase and thyroglobulin) on this association remains sparse.

To this end, we conducted here a multicenter retrospective case-control study to elucidate the association between thyroid autoantibodies with clinicopathological characteristics of PTC. Our univariate analysis revealed noteworthy disparities in these features across different states of antibody presence within our patient cohort, subsequently confirmed by logistic regression after accounting for confounding factors which demonstrated an evident link between antibody status and aggressive characteristics exhibited by cases involving PTC, such as multifocality, bilateral tumors, and larger tumor size. Positive results for specific types were associated specifically, TGAb positivity correlated significantly as a risk factor for extrathyroidal extension and lymph node metastasis, whereas TPOAb positivity showed an inverse trend albeit statistically insignificant differences existed. This insight provides valuable resolution towards prior uncertainties surrounding autoimmune conditions alongside PTC [ 17 , 18 ], while reinforcing our understanding about how these antibodies contribute towards its pathogenesis. Interestingly, a lower incidence rate of BRAF V600E mutations was observed in PTC patients with positive autoimmune markers, this finding corroborates earlier studies indicating that autoimmune thyroiditis may pose a risk factor for PCT with wild type BRAF V600E mutation [ 19 , 20 ].

Furthermore, we conducted a detailed analysis of the linear and non-linear relationships between thyroid autoantibodies level. Our findings revealed a close correlation between thyroid autoantibody level and the risk of certain aggressive characteristics of PTC. In reality, a striking finding in our study was the contrasting clinicopathological features of TPOAb and TGAb in PTC. Specifically, elevated TGAb level were linked to an increased risk of aggressive characteristics in PTC, whereas elevated TPOAb level were associated with a lower risk of extrathyroidal extension and lymph node metastasis in PTC. These results remained consistent even after stratification by HT. This suggests that higher TPOAb level inhibit the invasion and metastasis of PTC, indicating their potential as therapeutic targets for this condition, which aligns with previous reports [ 21 , 22 , 23 ].

It is indeed important to acknowledge the limitations of this study. The researchers were unable to obtain outcome information for the participants, which precluded an investigation into the impact of thyroid autoantibodies status on the overall prognosis of PTC patients. Additionally, this study had limited samples from external research centers; therefore, further studies involving more participants from multiple centers are needed in the future.

The impact of thyroid autoantibodies on the clinicopathological characteristics of PTC is noteworthy. High level of TGAb were identified as an independent risk factor for aggressive characteristics of PTC, whereas high level of TPOAb were inversely associated with extrathyroidal extension and lymph node metastasis.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to participant information privacy but are available from the corresponding author on reasonable request.

Abbreviations

• Lymph node metastasis

Extrathyroidal extension

Hashimoto thyroiditis

• Papillary thyroid cancer

Anti-thyroid peroxidase antibody

Anti-thyroglobulin antibody

Both of TPOAb and TGAb

Thyroid stimulating hormone

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Acknowledgements

We wish to thank all the patients who participated in this study.

This work was supported by the National Natural Science Foundation of China (82371602 and 82300884); the Natural Science Foundation of Hunan Province (2023JJ40990); the Graduate Research and Innovation Projects of Hunan Province (CX20230361).

Author information

Hai-Long Tan and Zi-En Qin contributed equally to this work.

Authors and Affiliations

Division of Thyroid Surgery, General Surgery Department, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China

Hai-Long Tan, Zi-En Qin, Sai-li Duan, Neng Tang & Shi Chang

Department of Thyroid and Breast Surgery, LiXian People’s Hospital, No.682 Xinhe Road, Changde, 415500, Hunan, China

Department of Thyroid and Breast Surgery, The First Hospital of Changsha, No.311 Yingpan Road, Changsha, 410008, Hunan, China

Ya-Ling Jiang

Hunan Provincial Clinical Medical Research Centre for Thyroid Diseases, No.87 Xiangya Road, Changsha, 410008, Hunan, China

Hunan Engineering Research Center for Thyroid and Related Diseases Diagnosis and Treatment Technology, No.87 Xiangya Road, Changsha, 410008, Hunan, China

National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China

Neng Tang & Shi Chang

Furong Laboratory, No.87 Xiangya Road, Changsha, 410008, Hunan, China

National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, No.87 Xiangya Road, Changsha, 410008, Hunan, China

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Contributions

H.-L.T., N.T., and S.C. were involved in the study concepts and design, and manuscript editing and review. H.-L.T. and S.-L. D. performed data acquisition and statistical analyses. H.-L.T., Z.-E. Q., and Y.-L. J. were involved in quality control of data and algorithms. H.-L.T., and N. T. were involved in data analysis, and interpretation, and reviewed/edited the article. All authors read and approved the final manuscript.

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Correspondence to Neng Tang or Shi Chang .

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The Ethics Review Committee of Xiangya Hospital, Central South University approved the study (20211245) and waived the informed consent requirement because of the retrospective and anonymous nature of the study.

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Tan, HL., Qin, ZE., Duan, Sl. et al. Association of thyroid autoantibodies with aggressive characteristics of papillary thyroid cancer: a case-control study. World J Surg Onc 22 , 224 (2024). https://doi.org/10.1186/s12957-024-03501-7

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DOI : https://doi.org/10.1186/s12957-024-03501-7

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Non-Small Cell Lung Cancer in a Very Young Woman: A Case Report and Critical Review of the Literature

Valentina polo.

1 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

2 Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy

Giulia Zago

Stefano frega, fabio canova, laura bonanno, adolfo favaretto, laura bonaldi.

3 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy

Roberta Bertorelle

Pierfranco conte, giulia pasello.

Patient: Female, 19

Final Diagnosis: Lung adenocarcinoma

Symptoms: Chest pain

Medication: —

Clinical Procedure: Ct scan and pet-ct

Specialty: Oncology

Unusual clinical course

Background:

Lung cancer in young patients is quite uncommon; clinical presentation and outcome in this population compared to the older group are not yet well defined and data about this setting are mostly single-institutional retrospective analyses.

Case Report:

We report here a case of a very young woman with diagnosis of early-stage lung adenocarcinoma harboring EML4-ALK rearrangement; she underwent radical surgery and adjuvant chemotherapy according to the pathologic stage. Potential risk factors for lung cancer in our patient are discussed and clinico-pathologic features and outcomes of lung cancer in the young population compared to the elderly are reviewed through discussing studies with sample sizes larger than 100 patients.

Conclusions:

A wide clinical overview should be performed when lung cancer is diagnosed in a young patient. Large-population studies are required to define the molecular signature and clinical behavior of lung cancer in young patients.

According to the Surveillance, Epidemiology, and End Results Program (SEER) registry based on 2007–2011 new cases, lung cancer (LC) is more frequently diagnosed among people aged 65–74 with only 1.6% of all cases occurring in patients younger than 45 years [ 1 ]. Most published data about LC in young populations are single-institutional retrospective analyses and few report on very young patients specifically. Previous data suggest that LC in young adults may be an entity with distinct characteristics compared to LC in older patients; however, data are not always consistent among all series [ 2 – 11 ]. In addition, age limits ranging from 40 to 50 years have been variably chosen by different authors to define younger cohorts of patients. We report a case of a young woman with early-stage EML4-ALK rearranged lung adenocarcinoma who underwent surgery followed by adjuvant chemotherapy. We also consider possible susceptibility factors for LC in our patient and review the majority of clinical studies with a sample size larger than 100 patients, in order to highlight and discuss LC patterns in young versus old patients [ 2 – 11 ].

Case Report

In January 2014, a 19-year-old white, never-smoker woman experienced chest pain; a chest X-ray and a computed tomography (CT)-scan showed a cavitating right lung lesion in the upper lobe without enlargement of mediastinal lymph nodes ( Figure 1A ). A bronchoscopy was performed and the evaluation of cell block prepared from bronchial brushings led to the diagnosis of adenocarcinoma. A positron emission tomography/computerized tomography (PET/CT) scan excluded additional disease localizations ( Figure 1B ). In March 2014 the patient underwent right upper lobectomy with systematic lymphadenectomy by video-assisted thoracic surgery (VATS); a diagnosis of primary pulmonary adenocarcinoma with papillary predominant pattern was made. Immunohistochemistry showed that tumor cells were positive for TTF-1 and negative for p63; Ki67 was 70%. Molecular analysis showed no EGFR , KRAS , and BRAF gene mutations by Sanger’s direct sequencing, whereas fluorescent in situ hybridization (FISH) showed the presence of EML4-ALK rearrangement in 57% of cells ( Figure 2 ). The patient was then referred to our Institution in April 2014. Clinical examination showed Eastern Cooperative Oncology Group (ECOG) performance status 0, and no additional findings. As previous medical history, the patient referred a general discomfort occurring between May and October 2013, characterized by nausea, vomiting, diarrhea, and skin rash. Blood test results are reported in Table 1 . In November 2013, the patient underwent an esophagogastroduodenoscopy with multiple biopsies, leading to the diagnosis of celiac disease. A gluten-free diet induced symptoms regression. The cancer family history revealed that the patient’s father died of renal cell carcinoma in 2007. A genetic test on a blood sample did not show TP53 mutations and the constitutional karyotype was normal. According to the pathologic stage (pT2a N1, stage IIA), she received adjuvant chemotherapy with 4 cycles of cisplatin-pemetrexed from May to July 2014. Before starting chemotherapy, the patient underwent ovarian tissue cryopreservation and gonadotropin-releasing hormone analogue was administered during the adjuvant treatment. Because of persistence of elevated gamma-glutamyl-transpeptidase (GGT) and transaminases before and during chemotherapy, the patient had a specialist opinion, which resulted in the diagnosis of autoimmune hepatitis. Currently, the patient remains on oncological and hepatologic follow-up visits. At the last follow-up visit, in February 2015, a CT-scan showed no disease recurrence ( Figure 1C ).

Computed tomography (CT) scan at diagnosis and positron emission tomography and CT-scan (PET/CT) at diagnosis, before surgery ( A, B ). CT scan after surgery at last follow-up visit ( C ).

FISH analysis was performed with ALK dual-color break-apart probe labelled with SpectrumOrange (3’end) and SpectrumGreen (5’end) (Abbott Molecular). The predominant ALK-positive FISH pattern observed in the sample was isolated red signal.

Significant selection of blood tests performed before diagnosis of lung cancer.

Occurrence of LC in young adults is quite uncommon and is characterized by peculiar epidemiological, clinical, and prognostic features. To date, the pathogenesis of this disease in young people is still very unclear. None of the known risk factors for LC could explain the early onset of the malignancy and no specific genomic alteration has been detected in this subgroup of patients.

According to the SEER registry, the proportion of African-Americans, Asian, and Pacific Islanders was higher among younger than older patients [ 1 ]. This epidemiologic discrepancy may be due to differences in carcinogens exposure or to biologic differences such as inefficient cell cycle arrest and DNA damage accumulation or cytochrome polymorphisms [ 9 , 12 , 13 ]. Regarding the clinico-pathologic features of LC in the young population, most retrospective series with sample sizes of more than 100 patients ( Table 2 ) reported a higher proportion of women and adenocarcinoma in younger groups compared to older patients [ 3 , 4 , 6 – 11 ], but some cases of very young patients with squamous cell LC have also been reported in recent years [ 14 – 16 ]. Data on the proportion of asymptomatic patients at diagnosis in young and old groups are discordant. However, chest pain is definitively the most frequent symptom of younger patients in comparative analysis [ 6 , 8 ], such as in our patient. Finally, lower occurrence of early-stage disease in young people, described in most of the retrospective series, could be due to more aggressive disease or a delayed diagnosis due to a low degree of suspicion of cancer in young patients [ 4 , 9 – 11 ].

Studies comparing young lung cancer patients to older patients with sample size of more of 100 patients: data about clinico-pathologic features.

Our patient’s tumor sample tested positive for EML4-ALK rearrangement. To date, only a few studies have investigated molecular alterations in younger patients, with controversial results. Higher frequency of EML4-ALK rearrangement (11.6%) and EGFR mutation (20%) were shown in 53 non-small cell LC patients ≤50 years old compared with patients of all ages [ 17 ]. In contrast, Ye et al. showed no difference in terms of oncogenic mutations (P=0.396), but a higher prevalence of TP53 mutations (P<0.001) in 36 resected lung adenocarcinoma from patients younger than 40 years compared to their older counterparts [ 18 ]; similarly, Kim et al. did not find a statistically significant difference in EGFR and EML4-ALK status between young and old patients [ 19 ]. Further investigation is needed to address the issue of genetic derangements in young patients with LC.

Risk factors for the onset of LC specifically in young adults are still unknown. The increased frequency of adenocarcinoma and the long latency time between smoking exposure and cancer appearance suggest that LC among young people does not require as much carcinogen exposure, but rather genetic derangements. However, the smoking status is similar between younger and older patients in a few series collecting these data, with approximately 75–95% of young patients reporting smoking sometime. Whether the number of cigarettes smoked per day or the age at which smoking began lead to an early onset of LC is still unclear. These patients might have genetic susceptibility to develop LC or inherited sensitivity to smoking-related carcinogenesis. Recently, case-control studies have showed that gene mutations or polymorphisms involving xenobiotic metabolizing enzymes and DNA repair pathways are associated with increased risk of early-onset LC [ 20 – 23 ].

Our patient was a never-smoker female, and she did not report previous exposure to carcinogens; thus, when we investigated possible risk factors for LC, we focused on genetic, immunological, and/or infective predisposition. The hypothesis of a genetic component in the early onset of LC is also supported by a few series showing an increased family history among young patients. In a case-control study, the authors demonstrated the greatest contribution to LC risk (7-fold increase) among 40- to 59-year-old non-smoker subjects with a first-degree relative affected by LC [ 24 ]. Our patient did not report family history of LC among her first-degree relatives. Her father died because of a kidney cancer, which is not included in any genetic syndrome involving LC; moreover, germ-line mutations of TP53 gene or constitutional karyotype alterations were not observed. Hereditary LC syndromes are rare, and, while germline EGFR T790M mutation has been reported as a predisposing genetic feature, especially in non-smoker patients [ 25 ], no evidence of germline EML4-ALK rearrangement has been reported in LC.

The medical history of the patient included the diagnosis of celiac disease, which is associated with an increased risk of lymphoma. In a study from a large Swedish cohort, the authors found a neutral risk of LC in celiac disease, with a hazard ratio of 1.00 beyond the first year of follow-up after celiac diagnosis [ 26 ]. More recently, a large-population cohort study in Finland showed a decreased risk of LC among 32 439 celiac patients [ 27 ].

Additional significant findings in our case were the recent diagnosis of autoimmune hepatitis, anti-cytomegalovirus (CMV), immunoglobulin (Ig) G, and anti-Epstein-Barr virus (EBV) IgG and IgM positivity. Subsequent examinations excluded the positivity of CMV and EBV DNA and of all hepatitis viruses. The association between solid cancer and autoimmune systemic disease is uncommon and especially involves scleroderma and LC [ 28 ], even though increased risk for LC has also been reported in systemic lupus erythematosus (SLE) patients [ 29 ]. In a recent paper, a 4-fold risk of LC in patients with systemic sclerosis, discoid lupus erythematosus, and polymyositis/dermatomyositis has been described [ 30 ]. However, there are no data about a possible link between autoimmune hepatitis and risk of LC. Similarly, EBV and CMV infections seem to have a role in the pathogenesis of solid tumors, such as lymphoepithelioma-like carcinoma and glioblastoma, respectively, but no involvement in LC risk has been reported. Indeed, microRNA studies in LC did not support any role of EBV in LC [ 31 ]. To date, the only virus infections associated with LC are human immunodeficiency virus (HIV) and human papilloma virus (HPV) infections [ 32 , 33 ]. Thus, we have no data to support the hypothesis that LC risk in our patient had a genetic, immunological, or infective basis.

Data regarding clinical outcome of young LC patients have been presented in only a few retrospective studies [ 2 , 4 , 6 – 11 ] ( Table 3 ). According to Roviaro GC et al., no significant statistical differences were observed in terms of survival between patients younger or older than 45 years, in the whole population and according to type of treatment or disease [ 2 ]. This was also confirmed by another series in which the majority of examined patients were included in clinical trials, thus making the 2 groups well balanced in comorbidity patterns and treatment modalities [ 8 ]. On the other hand, other studies showed a longer survival in the young group, despite the higher frequency of advanced disease. This finding could be explained by the higher chance of receiving more aggressive treatments, including multimodality treatments and further lines of chemotherapy, due to the lower prevalence of comorbidities [ 4 , 6 , 7 , 9 – 11 ].

Studies comparing young lung cancer patients to older patients with sample size of more of 100 patients: data about patients’ outcome.

OS – overall survival; NA – not assessed; NS – not significant; NR – not reported.

In case of disease relapse, our patient could benefit from a first-generation ALK inhibitor, which has demonstrated remarkable clinical outcomes including better response rate and prolonged survival compared to standard chemotherapy [ 34 , 35 ]. However, despite an initial improvement, ALK -positive tumors inevitably develop several resistance mechanisms to the targeted drug, resulting in progression of the disease. Other strategies, including the development of new-generation ALK inhibitors, are currently under clinical evaluation to overcome the acquired resistance in these patients [ 36 ].

Conclusions

Despite a comprehensive review of the patient’s medical and family history, we did not identify any underlying risk factor for LC. Larger prospective studies are needed to define the molecular signature and clinical behavior of LC in young patients. To collect evidence of no-smoking related pathways involved in cancer risk, a wide clinical overview should be performed when LC diagnosis occurs in a young patient. Given the rarity of the disease in this setting, only an international multi-center study could address this issue.

Abbreviations:

References:

• Biomarker-Driven Lung Cancer
• HER2 Breast Cancer
• Chronic Lymphocytic Leukemia
• Small Cell Lung Cancer
• Renal Cell Carcinoma

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Case Presentation: A 64-Year-Old Woman With Ovarian Cancer

Ramez Eskander, MD, discusses the case of a 64-year-old woman diagnosed with ovarian cancer.

EP: 1 . Case Presentation: A 64-Year-Old Woman With Ovarian Cancer

Ep: 2 . role of molecular testing in advanced ovarian cancer, ep: 3 . frontline maintenance therapy in advanced ovarian cancer, ep: 4 . switch maintenance therapy in advanced ovarian cancer: the ariel3 trial, ep: 5 . parp inhibitors in advanced ovarian cancer: mechanism of action and tolerability, ep: 6 . considerations for selecting parp inhibitor maintenance therapy, ep: 7 . ovarian cancer: current status and future directions.

Ramez Eskander, MD : Hi, my name is Ramez Eskander. I’m a GYN [gynecologic] oncologist at the University of California San Diego. I’m an associate professor of gynecologic oncology, and I am also the lead in gynecologic malignancies for our precision immunotherapy clinic as well as our experimental therapeutics team. Today we’re going to be discussing a case of a 64-year-old woman who presented with progressive symptoms of abdominal bloating, low back pain, early satiety, and progressive fatigue. Importantly her past medical history was notable for a hysterectomy 5 years prior for benign indications, hypothyroidism as well as generalized anxiety, which were both appropriately managed medically. Physical examination at the time of her office visit showed diffuse lumbosacral pain with movement, but more importantly, abdominal tenderness and significant abdominal distension with a fluid wave consistent with ascites. She also had an unintentional 8-lb [3.6-kg] weight loss. Thankfully her performance status was preserved, and her ECOG performance status was 1.

In the context of her presenting symptoms, a work-up was performed that included a pelvic ultrasound confirming the presence of an approximately 5-cm complex left ovarian mass. This also prompted a CT scan of the chest, abdomen, and pelvis, and CT imaging confirmed the presence of a complex pelvic mass, but in conjunction was notable for abdominal ascites, an omental cake, as well as retroperitoneal and inguinal adenopathy, concerning for a metastatic gynecologic primary malignancy. To facilitate diagnosis, a therapeutic and diagnostic paracentesis was performed, and a biopsy of the omental lesion obtained. Cytology from the paracentesis confirmed a high-grade serous ovarian cancer, and the omental biopsy confirmed histologically the same findings. Appropriately the patient had germline genetic testing performed and was found to be BRCA1/2 wild type, meaning no germline mutation. Somatic testing of the tumor from the omental biopsy was additionally conducted, showing no evidence of a somatic BRCA1/2 mutation. And importantly homologous recombination deficiency testing was submitted, and the patient was found to be homologous recombination proficient, meaning no evidence of homologous recombination deficiency.

In the context of her disease distribution and in review of her imaging, she was counseled regarding options and underwent primary surgical cytoreduction, which included resection of all her visible disease, leaving her without any evidence of disease intraperitoneally at completion of the surgical procedure. She was then counseled regarding treatment management options and was treated with systemic chemotherapy using a combination of carboplatin and paclitaxel administered intravenously every 3 weeks, followed by maintenance bevacizumab, the antiangiogenic agent, to help improve progression-free survival.

Unfortunately, 1 year after completion of cytotoxic chemotherapy and while on maintenance bevacizumab, the patient was found to have an elevation in her CA-125 [cancer antigen 125]. Importantly, her CA-125 did normalize at completion of cytotoxic chemotherapy after surgery, but with elevation in her CA-125, radiographic imaging was obtained once again, which did confirm the presence of progressive retroperitoneal adenopathy suggestive of recurrent disease. Given the disease distribution, she was not deemed a good candidate for secondary surgery and was therefore counseled regarding resumption of systemic chemotherapy. Given platinum-sensitive disease recurrence, she was rechallenged with carboplatin and paclitaxel administered intravenously every 3 weeks for 6 cycles. She did have a partial response, although there did appear to be some predominantly enlarged lymph nodes despite completion of 6 cycles of therapy. At this juncture the patient was counseled once again about treatment options, and after extensive counseling elected to proceed with single-agent rucaparib as a switch maintenance strategy in this setting to try to improve her cancer outcomes.

This transcript has been edited for clarity.

Case: A 64-Year-Old Woman With Ovarian Cancer

Initial Presentation

• A 64-year-old woman presented with abdominal bloating, low back pain, early satiety and progressive fatigue
• PMH: hysterectomy 5 years ago for benign indication; hypothyroidism managed medically; generalized anxiety disorder managed medically
• PE: diffuse lumbosacral pain with movement; abdominal tenderness and significant abdominal distension with a fluid weight consistent with ascites; unintentional weight loss of 8 lbs

Clinical work-up

• Pelvic ultrasound showed a ~5-cm complex left ovarian mass
• Chest/abdomen/pelvis CT revealed a complex pelvic mass and was also notable for abdominal ascites, omental cake, and retroperitoneal and inguinal adenopathy
• Paracentesis (1200cc) cytology confirmed high-grade serous ovarian cancer
• Omental biopsy histology also confirmed high-grade serious ovarian cancer
• Germline molecular testing: BRCA1/2 wt
• Somatic testing: BRCA1/2 negative; HRD proficient
• CA-125, 360 U/mL
• Diagnosis: Stage III, high-grade serous epithelial ovarian cancer
• Carboplatin/paclitaxel q3 weeks for 6 cycles; CA-125 normalized; CR
• Bevacizumab maintenance
• Rechallenged with carboplatin/paclitaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes
• Rucaparib monotherapy maintenance

Pembrolizumab Improves Surgical Outcomes and Response in Advanced Ovarian Cancer

Findings from the phase 2 NeoPembrOV study supported the addition of pembrolizumab to neoadjuvant chemotherapy before surgery in high-grade serous ovarian cancer.

FDA Approves Second Dose of CAR T-Cell Therapy in Ovarian Cancer Trial

The FDA has approved an individual patient investigational new drug application, allowing for a second dose of a novel CAR T-cell therapy for a patient with recurrent ovarian cancer.

Nivolumab Shows Promising Efficacy in dMMR Uterine and Ovarian Cancers

A phase 2 trial demonstrated that nivolumab is effective and has a manageable safety profile in patients with mismatch repair deficiency uterine or ovarian cancers.

FDA Approves Tepylute in Breast and Ovarian Cancer

The FDA approved Tepylute, a ready-to-dilute formulation of an existing treatment for breast and ovarian adenocarcinoma.

FDA Fast Track for TUB-040: ADC Shows Promise in Treating Ovarian Cancer

A phase 1/2a study is investigating the novel antibody-drug conjugate for the treatment of ovarian and non–small cell lung cancers.

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Case-control study of the characteristics and risk factors of hot clot artefacts on 18F-FDG PET/CT

• Jacques Dzuko Kamga 1 ,
• Romain Floch 1 ,
• Kevin Kerleguer 1 ,
• David Bourhis 1 , 2 ,
• Romain Le Pennec 1 , 2 ,
• Simon Hennebicq 1 ,
• Pierre-Yves Salaün 1 , 2 &
• Ronan Abgral 1 , 2  

Cancer Imaging volume  24 , Article number:  114 ( 2024 ) Cite this article

Metrics details

Introduction

The pulmonary Hot Clot artifact (HCa) on 18F-FDG PET/CT is a poorly understood phenomenon, corresponding to the presence of a focal tracer uptake without anatomical lesion on combined CTscan. The hypothesis proposed in the literature is of microembolic origin. Our objectives were to determine the incidence of HCa, to analyze its characteristics and to identify associated factors.

All 18F-FDG PET/CT retrieved reports containing the keywords (artifact/vascular adhesion/no morphological abnormality) during the period June 2021–2023 at Brest University Hospital were reviewed for HCa. Each case was associated with 2 control patients (same daily work-list). The anatomical and metabolic characteristics of HCa were analyzed. Factors related to FDG preparation/administration, patient and vascular history were investigated. Case-control differences between variables were tested using Chi-2 test and OR (qualitative) or Student’s t-test (quantitative).

Of the 22,671 18F-FDG PET/CT performed over 2 years, 211 patients (0.94%) showed HCa. The focus was single in 97.6%, peripheral in 75.3%, and located independently in the right or left lung (51.1% vs. 48.9%). Mean ± SD values for SUVmax, SUVmean, MTV and TLG were 11.3 ± 16.5, 5.1 ± 5.0, 0.3 ± 0.3 ml and 1.5 ± 2.1 g respectively. The presence of vascular adhesion ( p  < 0.001), patient age ( p  = 0.002) and proximal venous access ( p  = 0.001) were statistically associated with the presence of HCa.

HCa is a real but rare phenomenon (incidence around 1%), mostly unique, intense, small in volume (< 1 ml), and associated with the presence of vascular FDG uptake, confirming the hypothesis of a microembolic origin due to probable vein wall trauma at the injection site.

18F-fluorodesoxyglucose positron emission tomography / computed tomography (18F-FDG PET/CT) is a functional imaging technique based on the study of glucose metabolism in cells. Although it is a whole-body scan, the analysis of the lungs remains fundamental in many contexts, not only in oncology. Indeed, FDG-PET/CT is now routinely recommended for the characterization of solid pulmonary nodules ≥ 8 mm and for the initial staging of non-small-cell lung cancer [ 1 ]. More recently, it can also be suggested for the management of infectious or inflammatory pathology, such as unknown chronic fever or sarcoidosis [ 2 ].

Numerous specific technical artifacts and potential pitfalls in the interpretation of PET/CT in the thoracic region, including normal variations in physiological uptake of 18F-FDG and benign conditions, have been well described [ 3 ]. Awareness of these pitfalls is crucial as they may lead to misinterpretation with consequences for patient management and therapeutic implications [ 4 ]. One cause of these false positives results, called “hot clot artefact” (HCa), is still poorly understood. HCa fulfils 3 criteria: (i) the presence of one or more focal pulmonary 18F-FDG uptake(s) without anatomical lesion on CT scan; (ii) the high level of visual and semi-quantitative metabolic activity of the foci; (iii) the disappearance or migration of foci on late or subsequent acquisition [ 4 , 5 , 6 ].

There is very little literature available on this subject, based mainly on the publication of several case reports, totaling approximately twenty cases (21 patients). Nevertheless, certain hypotheses have been proposed to explain this relatively rare phenomenon. Thus, pulmonary microvascular embolism due to clots formed at the 18F-FDG injection site as a result of the vascular lesion and the agglutinating nature of FDG is the most plausible mechanism, as some authors have reported para-venous injection, rapid injection or blood aspiration into the injector system [ 4 , 7 , 8 , 9 , 10 , 11 ].

Such as a background, our aims were to determine the incidence of hot clot artefact in a large case-control PET/CT study, to analyze its 18FDG uptake characteristics and to identify its potential associated factors.

Materials and methods

This is a single-center retrospective observational case control study conducted in the Nuclear Medicine Department of Brest University Hospital between June 2021 and June 2023. The study was conducted in accordance with the Declaration of Helsinki and was approved by the French Advisory Committee on Information Processing in Health Research (CCTIRS).

All patients who underwent a 18F-FDG PET/CT during the 2-year inclusion period were analysed, regardless of indication. First, examination reports available in the radiology information system (Xplore, EDL, Paris, France) were queried using an AI word recognition algorithm with the terms “artefact” and/or “vascular adhesion” and/or “no morphological abnormality”. All selected files were reviewed to authenticate HCa cases, defined as the presence of one or more focal pulmonary 18F-FDG uptake(s) without anatomical lesion on CT scan and disappearance of the focus or no appearance of pathological lesion on a subsequent scan. Finally, 2 control patients per case were included as those managed immediately before or after the selected case on the daily work list and using the same examination modality.

18F-FDG PET/CT procedure

All 18F-FDG PET/CT images were acquired on two digital Biograph Vision 600 PET/CT scanner systems (Siemens Healthineers, Knoxville, TN, USA) with the same technical settings.

Standard patient preparation included at least 4 h fasting and serum blood glucose level < 7 mmol/L prior to intravenous injection of approximately 3 MBq/kg (0.08 mCi/kg) of FDG by a nuclear medicine technologist (NMT) via a catheter or a permanent device (implantable chamber, PICC line or midline). After injection, patients remained in a quiet room for approximately 60 min before acquisition.

At first, CT scan was obtained just after injection of intravenous iodine contrast agent (1.5 mL/kg), unless contraindicated. The CT consisted in a 64-slice multidetector-row spiral scanner with the following parameters : 110 kVp tube voltage (automatic modulation carekV ® ); 80 refmAs effective tube current with automatic dose modulation (care4D ® ); 0.5 s rotation time; 19.2 mm total collimation width ; pitch 1, 512 matrix size, 0.98 × 0.98 mm pixels; 2 mm slices thickness.

Then, PET data were acquired in in the craniocaudal direction using a whole-body protocol (2 min per step) and were reconstructed using an iterative ordered subset expectation maximization (OSEM) algorithm (True X ® = point spread function (PSF) + time of flight (TOF) acquisition capabilities, 4 iterations, 5 subsets). Images were corrected for random coincidences, scatter and attenuation using the CT scan data and were smoothed with a Gaussian filter (full-width at half-maximum = 2 mm). The axial field of view was 263 mm and the overlap fraction was 49%. The reconstruction matrix was 440 × 440 voxels and the voxel size was 1.65 × 1.65 × 1.65 mm.

Image analysis

Hot clot artifacts (HCa) were visually characterized in terms of number (single or multiple) and location (right or left; lower lobe (LL) or middle lobe (ML) or upper lobe (UL), peripheral or intermediate or proximal).

Tracer uptake was determined using SUVs, calculated according to the following formula: SUV = tissue radioactivity concentration [kBq/mL] / [injected dose (kBq) / patient weight (g)]. Various PET parameters were analyzed for each HCa using MIM software (MIM Software Inc., Cleveland, United States): SUVmax and SUVmean, corresponding to the maximum and average values of SUV respectively; MTV (metabolic target volume), defined as the summed volume in millilitres (mL) measured using an image gradient-based method (PET EDGE™) [ 12 ]; TLB (total lesion burden) in grams (g), defined as MTV x SUVmean.

Data collection

A different set of data was collected for each case and control patient, including: (i) clinical characteristics [gender (M/F), age, weight, height, blood glucose level, active cancer defined as patient with a history of known cancer who had not achieved a complete response for at least 6 months at the time of the PET-CT (yes/no), anticoagulant treatment or antiplatelet drug (yes/no), and previous history of venous thrombosis or pulmonary embolism (yes/no)]; (ii) FDG administration [venous access (proximal/distal), permanent device (yes/no), NMT in charge, injected activity, time between 18F-FDG injection and image acquisition, iodinated contrast administration (yes/no)]; (iii) imaging procedure [PET machine (PET1/PET2), FDG vessel adhesion at injection site defined as venous linear uptake (yes/no), FDG extravasation into soft tissues (yes/no)].

Statistical analyses were performed using EpiInfo software version 7.2.6.0.

Descriptive statistics were used to characterize the cohort. Qualitative variables were presented as number (n) and percentage (%). The association between dichotomous categorical variables and the presence of the hot clot artifact was measured by the odd ratio (OR) with a 95% confidence interval (95%CI). Significant differences were assessed using chi-2 or Fisher exact test. Quantitative variables were expressed as mean ± standard deviation (SD) and compared in both case and control groups using Student t test. The level of significance was p  < 0.05.

Among the 22,671 18F-FDG PET/CT scans performed in our department between June 2021 and June 2023, 211 patients (98 M/113F, mean age ± SD 62.2 ± 15.4 years) had at least one pulmonary hot clot artefact, corresponding to an incidence of 0.94%. For further analysis of potential associated factors, 422 controls were selected, i.e. 2 per case.

The selection of case-control patients is described in the flowchart (Fig.  1 ).

Flowchart of case-control patients’ selection

Hot clot artifact description

HCa were single, double or quintuple in 206 (97.6%), 4 (1.9%) and 1 case (0.5%) respectively, and were located in the right lung 112 times (51.1%) (58 in UL, 19 in ML and 35 in LL) and in the left lung 107 times (48.9%) (68 in UL and 39 in LL). The focus was peripheral (less than 2 cm from the pleura or fissure), proximal (less than 2 cm from the hilum) or intermediate (others) in 165 (75.3%), 23 (10.5%) and 31 (14.2%) cases respectively (Fig.  2 ).

Presentation of 2 illustrative cases of HCa

a 54-year-old patient underwent 18F-FDG PET scan as part of the staging of a left lung neoplasm. The MIP image showed FDG avidity of the tumour (star), FDG vascular uptake in the elbow and right arm (dotted black arrow), lymph node uptake in the right subclavicular region (black arrow), and 5 lung foci (blue arrows), 3 peripheral sub-scissural foci in the middle lobe, 1 peripheral sub-pleural foci in the left upper lobe, and 1 peripheral sub-pleural foci in the right upper lobe) without anatomical lesions opposite, corresponding to a quintuple case of Hca.

a 60-year-old patient with oral squamous cell carcinoma underwent 18F-FDG PET scans for staging (top row) and follow-up (bottom row). Focal FDG uptake in the peripheral subpleural region of the left upper lobe (blue arrow) on PET (B) and fused PET-CT images (C) with no CT abnormalities (A) disappeared on the second scan, confirming a case of HCa.

The mean values ± SD [Range] of SUVmax, SUVmean, MTV and TLG were 11.3 ± 16.5 [0.9–142.0], 5.1 ± 5.0 [0.7–35.6], 0.3 ± 0.3 ml [0.1–1.5] and 1.5 ± 2.1 g [0.2–18.8], respectively. Only 3/217 MTV values (1.4%) were greater than 1 ml.

Associated factors

Clinical characteristics.

There was no significant difference in clinical characteristics between case and control patients (Table  1 ), except for age (mean ± SD 62.2 ± 15.4 vs. 65.9 ± 13.8, p  = 0.002).

FDG administration

Venous access (proximal vs. distal vs. permanent device) was associated with the occurence of HCa ( p  = 0.001). The distribution of case controls by FDG administration is shown in Table  2 .

Imaging analysis

There was no difference in FDG extravasation into soft tissues between case controls, in contrast to FDG venous linear uptake at injection site on images, which was more frequent in the HCa case group than in the control group (64.9% vs. 42.2%, respectively; OR = 2.56 95%CI 1.79–3.70, p  < 0.001) (Table  3 ).

Our results showed an incidence of pulmonary hot clot artifact (HCa) on 18F-FDG PET/CT of 0.94% (211/22671 scans for a total of 219 HCa) confirms the idea of a rare phenomenon. However, it has to be considered as a pitfall for physicians when interpreting images. Only Hany et al. found comparable results ( p  = 0.2 with X 2 statistical test), reporting an artifact in 3 patients out of 750 examinations carried out over a 9-months period, i.e. a frequency of 0.4% [ 7 ]. To the best of our knowledge, this is the largest series investigating the incidence of HCa, as the literature on this subject is sparse and mostly consists of case reports [ 4 , 5 , 7 , 8 , 9 , 10 , 11 , 13 ] (Table  4 ).

In our series, the HCa was almost exclusively single (206/211 = 97.6%). This finding is in accordance with the literature, as 19 of 21 (90.4%) published cases reported a single artifact. At most, we have showed an atypical example of a quintuple artifact in the same patient, as described by Ha et al. We found a balanced distribution of artifacts between the 2 lungs (51.1% versus 48.9%), redressing with a large population sample the predominance in the right lung (65%) extracted from the literature (12 patients, 17 artifacts). In our results, HCa were subpleural in approximately ¾ of the cases (75.3%), showing a tropism of the artifact for the peripheral region of the lung where the blood vessels are of smaller caliber and supporting the theory of a microscopic phenomenon an embolic origin of the artifact [ 4 , 7 , 8 , 9 , 11 ].

Regarding the metabolic characteristic of HCa, we found a high mean SUVmax 11.3 but with a large range [0.91 to 145], as calculated from data of 12 cases of literature (mean SUVmax ± SD = 40.6 ± 49.1 with a maximum of 185.1 and a minimum of 3.4) [ 4 , 8 , 10 , 11 , 13 ]. These findings demonstrate very high SUVmax values especially for possible lesion sizes below the spatial resolution of CT, as already suggested in several case report [ 4 , 9 , 13 ]. However, this very high variability of SUV parameters does not allow in current practice the use of a threshold to distinguish an artifact from a pathological lesion prior to its morphological expression. Nevertheless, its volume could be an interesting tool. Indeed, the mean MTV ± SD was 0.3 ± 0.3 ml in our series; and interestingly, 99% of them (216/219) presented a MTV lower than 1 ml. This again confirms that this artifact is a very low-volume phenomenon, such as micro-embolism. Therefore, a MTV value < 1 ml could be added as a new criterion for defining hot clot artifacts, avoiding repeat examinations (18F-FDG PET/CT or chest CT), thus limiting health care costs and improving patient management (consequences of misinterpretation, radiation exposure).

In our results, we found a significant statistical association between the presence of FDG vascular adhesion at the injection site (64.9% of cases vs. 42.2% of controls) and the presence of a hot clot artifact (OR = 2.56, 95%CI 1.79–3.70; p  < 0.0001). This correlation favors an embolic origin, as we imagine that the stasis of the radiopharmaceutical at the injection site probably reflects trauma to the vein wall, making it likely that a hot clot formed and migrated towards the lung. This hypothesis already been raised in the literature. In fact, Sánchez-Sánchez et al. observed the presence of 18F-FDG extravasation in 3 of their 4 reported patients [ 11 ]. In addition, Farsad et al. described a para-venous injection in the 4 cases they reported [ 10 ]. The migration or disappearance of the HCa on late or subsequent scans and the absence of clinical consequences for all the 21 cases published are consistent with this micro-embolic origin [ 4 , 5 , 7 , 8 , 9 , 10 , 11 , 13 ]. Moreover, regarding patient preparation, the venous proximal access was significantly higher in cases than in controls (94.3% of versus 84.4% of controls, p  = 0.0012). This result may seem paradoxical, as distal veins are thinner and more fragile, and therefore probably at risk of HCa. One explanation might be that the systematic use of small-caliber catheters for distal access in our routine would ultimately be less traumatic and protect against this risk. Retrospectively, we verified the association HCa/FDG vessel adhesion on PET was independent of this venous access type. In addition, there was no association between the nuclear medicine technologist (NMT) responsible for patient management and the presence of the hot clot artifact ( p  = 0.994). This does not suggest an isolated problem of competence in venipuncture procedure, which appears to be fairly homogeneous within our department. Injection-acquisition time interval and injected activity were not correlated with the presence of hot clot artifact. However, these two parameters varied very little (about 60 min for the delay and 3 MBq (0.08 mCi)/kg body weight for the injected activity), as we routinely used procedural guidelines for PET imaging [ 14 ]. We found no statistical association between the PET machine used for acquisition ( p  = 0.736) and the presence of a HCa, but the 2 systems were of the same model with the same technical settings. However, a machine effect remains unlikely as the cases reported in the literature were published over a wide time interval (2003 to 2020). Therefore, differences related to technological advances in PET imaging (PSF + TOF acquisition capabilities, digital technology, etc…) during this period cannot be involved [ 15 , 16 , 17 , 18 , 19 ]. Finally, there was no statistical association between the administration of iodinated contrast and the presence of the warm clot artifact ( p  = 0.1941), even though both agents were injected into the same venous access, making a pro-coagulant interaction between FDG and iodinated contrast agent unlikely.

We choose a 1:2 case-control design using the daily PET work list to rule out an obvious lack of correlation between HCa occurrence and radiopharmaceutical production (chemical purity, batch number, etc…) or time dependence (seasonal period, pm vs. am, etc…). Our results showed that controls were on average older than cases (65.9 versus 62.2 years; p  = 0.0021). At first sight, this may seem surprising, given that older people have a more fragile blood vessel system. On the contrary, one explanation could be that platelet function is better in younger people [ 20 , 21 ]. The mean age of cases reported in the literature was 55.3 years (17 patients) [ 4 , 5 , 7 , 8 , 9 , 11 , 13 ]. In addition, other clinical characteristics were comparable between the 2 groups notably in terms of gender ( p  = 0.910), as reported in the literature (21 patients, 52% female and 48% male) [ 4 , 5 , 7 , 8 , 9 , 10 , 11 , 13 ]. Finally, the presence of active cancer ( p  = 0.519), a history of deep vein thrombosis or pulmonary embolism ( p  = 0.818), anti-platelet drugs ( p  = 0.997) or anticoagulant treatment ( p  = 0.773) were not statistically associated with the presence of hot clot artifact. These factors were examined to identify potential circumstances associated with VTE that may or may not put patients at risk of thrombus formation.

This study had several limitations related to its single center retrospective nature, which is source of selection bias and limits external validity, even though we used a large case-control study design. Firstly, the word recognition query in the 22,671 reports may have slightly underestimated the incidence of artefacts if nuclear medicine physicians did not mention them. Secondly, it resulted in a missing data on the venous catheter caliber used to perfuse the patient, which prevented its inclusion in the analysis of protective and confounding factors for HCa occurrence. As mentioned above, we believe that the paradoxical statistical relationship between proximal (risk factor) and distal (protective factor) venous access could be explained by the use of small-caliber catheters distally to minimize vascular trauma. Thirdly, it also prevented us from studying the effect of injection type (manual versus automatic), as all our patients were injected with an automated system. Further prospective studies are needed to assess the effect of injection type and catheter size on the occurrence of artifacts. Finally, this study was limited to the specific case of FDG, whereas the problem of false-positives results may also concern other radiopharmaceuticals used in PET/CT. For example, Sgard B et al. in 2020 reported a case of pulmonary artifact on PET/CT with prostate-specific membrane antigen (PSMA) radioligands in the setting of biochemical recurrence of prostate adenocarcinoma. They associated this PSMA uptake with vascular malformation, which is different from a hot clot phenomenon [ 22 ].

Hot clot artefact is a real but rare phenomenon, occurring in about 1% of examinations and representing a pitfall in the interpretation of 18F-FDG PET scans. The results of our large case-control study suggest that this focal pulmonary tracer uptake is mostly unique, intense and small in volume (< 1 ml); often peripheral in location and associated with the presence of vascular adhesion on images. This supports the hypothesis of a micro embolic origin due to probable trauma to the vessel wall at injection site.

Data availability

No datasets were generated or analysed during the current study.

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Each author has contributed to the submitted work as follows: JDK, RA are the guarantors of the paper. JDK, PYS, RA designed the study JDK, DB realized statistics. JDK, RF, KK, SH, RA analyzed the data. JDK, RA drafted the manuscriptRLP, PYS revised the manuscript. All authors contributed in drawing up the manuscript. All authors declare having no conflict of interest.

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Dzuko Kamga, J., Floch, R., Kerleguer, K. et al. Case-control study of the characteristics and risk factors of hot clot artefacts on 18F-FDG PET/CT. Cancer Imaging 24 , 114 (2024). https://doi.org/10.1186/s40644-024-00760-1

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Received : 11 June 2024

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DOI : https://doi.org/10.1186/s40644-024-00760-1

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