Four synchronous primary malignancies in one patient

Overview

Multiple primary malignancy is defined as the occurrence of two or more primary malignancies in one patient. Although this is a rare situation, its occurrence has been increasing over the last decade. Patients with an oncological disease have up to a 20% higher risk of a new primary oncological disease compared to the general population. Depending on the time interval between the diagnosis of individual malignancies, we divide multiple cancer cases into synchronous and metachronous. The diagnosis of four synchronous malignancies is extremely rare. In our case report, we present a patient with caecal adenocarcinoma, hepatic flexure adenocarcinoma, clear cell carcinoma of the right kidney and pheochromocytoma of the right adrenal gland occurring synchronously.

Keywords:

colorectal cancer – Renal cell carcinoma – pheochromocytoma – multiple primary malignancies – quadruple adenocarcinoma

Introduction

The medical progress achieved in recent decades in the screening, diagnosis and treatment of oncological dis­eases has made it possible to perceive malignancies as treatable and potentially curable diseases. Patients who can be considered cured, or who survive for a long time thanks to treatment, make up an ever-increasing group. In this context, the diagnosis of any new type of malignant disease comes to the fore [1].

Patients with an oncological disease have a 20% higher risk of developing a new primary oncological disease compared to the general population. The second primary malignancy is the main cause of death in this group [2].

We define multiple primary malignancies (MPM) as the presence of two or more synchronous or metachronous malignancies that arise independently of each other in one or more organs. Synchronous cases are those when the time between the detection of the individual malignancies is less than 6 months. An important condition is the confirmation that the new malignancy is not a metastasis of the primary disease [3].

The incidence of multiple primary malignancies varies between 3 and 5%. Most of them are duplex malignancies, the occurrence of which is not rare. Triple and quadruple malignancies are extremely rare. The incidence of triplex malignancy is reported to be below 1%; for quadruple primary malignancy this figure is even lower than 0.1% [3,4]. Until 2022, to our best knowledge only 10 known cases of patients with quadruple primary malignancy have been published [5].

In this article, we report the rare case of a 63-year-old patient with four synchronous primary malignancies, who was treated at our department. The patient was diagnosed with and surgically treated for adenocarcinoma of the ­caecum, adenocarcinoma of the hepatic flexure, adenocarcinoma of the right kidney and pheochromocytoma of the right adrenal gland.

According to available literature, this is the first case report with the above-mentioned combination of carcinomas and a neuroendocrine tumour simultaneously. Our goal is to draw attention to the rarity of this condition, as well as to clarify the approach to the diagnosis and surgical management of this disease. This case report was processed in accordance with SCARE criteria [6].

Case report

A 63-year-old patient with no personal history of comorbidities and a negative family history of oncological diseases was diagnosed on an outpatient basis for clinical manifestations of anaemic syndrome. The most important risk factors for oncological diseases such as smoking and alcohol consumption were not observed in the presented patient. The patient underwent a gastrofibroscopic examination of the upper part of the gastrointestinal tract, where no organic changes were identified in the oesophagus, stomach or in the accessible part of the duodenum. Subsequently, a colonoscopic examination was performed, where two tumourous infiltrates were described, no other polyps were detected in the large intestine. The first lesion was located in the area of the hepatic flexure and had the character of an intraluminally growing stenotic tumour. The second tumour was located and filled the entire lumen of the caecum.

Multiphasic CT of the abdomen showed a circular stenotic tumour in the area of the caecum and hepatic flexure along with regional lymphadenopathy. In addition to this finding, a tumour with a size of 75 × 57 mm was described, located on the dorsum of the right kidney with close pressure on the liver capsule. A suspected metastasis measuring 17 × 13 mm was visible in the right adrenal gland (Fig. 1).

After a multidisciplinary evaluation by a surgeon, a urologist and an oncologist and after establishing the diagnosis and obtaining the patient’s informed consent, we primarily indicated surgical treatment in the scope of an extended right-sided hemicolectomy with right-sided nephrectomy and adrenalectomy using a laparoscopic approach.

During revision, in accordance with the preoperative imaging studies, a locally advanced caecal carcinoma with a diameter of 6 cm and a carcinoma of the hepatic flexure with a diameter of 4 cm with regional lymphadenopathy were identified. Lymphadenopathy was also present in the area of the superior mesenteric vein. We performed a laparoscopic right-sided hemicolectomy with complete mesocolic excision and the construction of a laterolateral isoperistaltic ileotransversoanastomosis (Fig. 2). In the next step, after opening the right retroperitoneum, we verified a large tumour in the area of the right kidney, which obscured the operative field. During dissection in the area of the hilum of the kidney, a iatrogenic lesion of the renal vein with laparoscopically untreatable bleeding occurred, forcing a conversion by subcostal laparotomy. After treating the bleeding, a right nephrectomy with right adrenalectomy was completed. Perioperatively, the patient was hemodynamically stable, with no signs of hypertension during manipulation with the right adrenal gland due to the definitive histolo­gical findings.

The postoperative course of the presented patient was uncomplicated. Postoperatively, blood loss was corrected using two transfused units of erythrocyte concentrate. During the entire hospitalization, the patient’s vital functions were stabilized; he was afebrile, verticalized from the 1^st postoperative day and gradually refed. The solitary kidney showed good function and sufficient diuresis. On the 6^th postoperative day, the patient was discharged into outpatient care in a good condition and on full oral intake. Due to the need for transfusion treatment, we evaluate the postoperative course of the presented patient as grade 2 according to the Clavien Dindo scoring system.

A histological examination of the caecal tumour identified a G3 adenocarcinoma with local invasion behind the muscularis propria (pT3). G3 adenocarcinoma with spread to the serosa (pT4) was confirmed from the tumour in the hepatic flexure. A total of 27 lymph nodes from the mesocolon were examined, of which 7 lymph nodes were from the D3 floor. Twelve mesocolic lymph nodes and 2 lymph nodes from area D3 were infiltrated by a tumour. An immunohistochemical analysis of MMR proteins and MSI status was performed from both tumours with the conclusion of MMR proficient carcinoma with microsatellite stability (Fig. 3). We subjected colorectal cancer samples to DNA molecular genetic analysis. A positive mutation status of the RAS genes and negative mutation status of the BRAF gene were detected in both samples. Clear cell carcinoma graded NG 3 was identified in the tumour sample from the right kidney (Fig. 4). Neuroendocrine neoplasia was identified in the adrenal tumour sample, namely pheochromocytoma with an immunohistochemical profile: synaptophysin +, chromogranin A +, INSM1 +, S100 +, EMA –, AE1/AE3 –. The tumour had a low Ki 67 proliferative activity of less than 1%, had no extension into the periadrenal fat connective tissue, and did not infiltrate the adrenal capsule (Fig. 4).

The patient was operated on in September 2023 and continues to receive treatment in our clinic for follow-up. Considering the definitive histology, adjuvant therapy is not indicated for adrenal and renal tumors. However, patient continued with the adjuvant protocol for colorectal carcinoma with dispensary.

Discussion

The term MPM was first used by Billroth in 1889. The first case description of a patient with more than two diagnosed malignant diseases dates back to 1932 and was written by Warren and Gates [7]. These authors also defined the diagnostic criteria, which basically apply to this day. The basic criterion is the histopathological confirmation of the malignancy of tumours, their unique pathological features, their occurrence in different organs or a different part of the same organ, and the exclusion of metastatic origin [8].

The prevalence of MPM is increasing due to improved surveillance and increased diagnostic sensitivity. Demandante et al. published the results of a retrospective analysis performed on 1,104,229 patients with malignancy diagnosed between 1966 and 2000; within this set, they noted the prevalence of MPM at the level of 0.73–11.7%. Synchronous MPMs are rarer, representing 18.4–25.3% of all MPMs. 2–12% of patients with two malignancies develop a third or fourth malignancy [9]. Bittorf et al. retrospectively evaluated a set of 52,398 patients and in this set at least two malignancies were detected in 3.8% of patients and at least three malignant tumours in 2.8% of patients. An interesting finding remains that patients with MPM demonstrated an improved 5-year survival rate compared with patients with corresponding solitary malignancies. It is not clear whether these patients have a hitherto unexplained mechanism of increased tumour resistance or whether these longer survival rates were simply necessary for the development of multiple cancers in the first place [10].

MPMs are most often diagnosed in the over 50 age group, while the incidence of all malignancies increases at this age. According to some studies, MPM is diagnosed more often in the male population, which is more exposed to known risk factors for carcinogenesis such as smoking and alcohol consumption [8,10]. Moreover, most of the detected triple and quadruple primary malignancies were metachronous rather than synchronous, in contrast to what we report on in our case.

In our case report, we present synchronously occurring adenocarcinoma of the caecum, adenocarcinoma of the hepatic flexure, clear cell carcinoma of the right kidney, and pheochromocytoma of the right adrenal gland. Colorectal cancer is the third most common malignancy worldwide and approximately 1.2 million cases are diagnosed annually [11]. Testori et al. analysed a set of 837 malignant colorectal tumours in 2015, while in this set there were 32 (3.8%) cases of carcinoma in multiple parts of the colon and in 11 patients from this set (1.3%) another extracolonic primary malignancy was present [11].

The increasing incidence of renal tumours over the last two decades can be explained by the increase in the number of imaging examinations of the abdominal cavity for other reasons, and the majority of incidentally identified tumours are small and asymptomatic. Currently, approximately 60% of kidney tumours are identified incidentally. The incidental occurrence of renal carcinoma and ipsilateral pheochromocytoma is rare, and the prevalence of pheochromocytoma in patients with an incidentally diagnosed adrenal tumour is even rarer, reaching 6.5% [12]. In men with clear cell carcinoma of the kidney, a second malignancy is also present in 26.6% of cases, most often lung carcinoma and carcinoma of the orofacial region [11]. The synchronous incidence of colorectal and renal cancer is reported in the available studies to range from 0.33% to 4.85% [13,14]. The location of the tumours is interesting, as all four tumours were located on the right side of the abdominal cavity.

The investigated mutational status of the RAS/BRAF oncogenes is important in clinical practice before targeted biological treatment, the essence of which is to block growth factor receptors. This results in the inhibition of signalling pathways that induce the tumour process. The presence of the RAS mutation indicates a lack of response to treatment with monoclonal anti-EGFR agents. Mutations in the BRAF gene represent a negative prognostic factor for survival in CRC patients [15].

Some MPMs are associated with cancer syndromes, which suggests that they arise on a genetic basis. These syndromes include hereditary retinoblastoma (retinoblastoma and osteosarcoma), multiple endocrine neoplasia type 2a (medullary thyroid carcinoma and pheochromocytoma), von Hippel-Lindau disease (retinal and central nervous system hemangioblastoma, renal carcinoma and pheochromocytoma), Lynch syndrome (colorectal carcinoma and endometrial tumours) and hereditary breast and ovarian cancer syndromes. In other cases, some types of malignancy occur together statistically more often, while the genetic basis of their simultaneous occurrence is unknown [16].

Our presented case does not match the formulas of any of the cancer syndromes described in literature. Given the presence of two tumours in the right side of the colon, Lynch syndrome could be considered. However, due to the patient‘s age, negative family history, histology of conventional adenocarcinomas, and immunohistochemical status of the tumours (MMR proficient and MSS), this syndrome can be ruled out. Because of multiple primary malignancies presented we advised to conduct further comprehensive genetic testing.

Therapeutic options for cases of MPM are usually limited. Currently, there is no universal protocol available for the treatment of MPM. Each case must be assessed strictly individually, ideally within a multidisciplinary panel. The decisive element is the type and stage of each malignancy, its response to the treatment under consideration and the general condition of the patient. Radical treatment is indicated in the case of a curable disease, a conservative approach is considered when radical treatment is not possible [17,18].

 

Conclusion

The presented case report presents the first known case of MPM consisting of three separate carcinomas and a neuroendocrine tumour. Considering the wide spectrum of ­causes that lead to the development of MPM, in the diagnosis and treatment of oncology patients we should not only think about recurrence or metastatic lesions arising from the primary disease, but also about the occurrence of new primary malignancies. Thanks to advances in treatment and improved survival rates in cancer patients, MPM represents a new medical challenge that needs to be addressed. By publishing this rare case of four primary malignancies, we want to draw attention to this issue and thus contribute to improving the diagnosis and treatment of cancer patients.

 

Acknowledgments

The authors of the case report would like to thank the patient for his willingness to cooperate and for his consent to share medical information for the purposes of the educational process and for the writing of publications.

 

Patient consent

The authors of the case study obtained a written consent from the patient to publish this case study and to use the medical information and visual aids.

 

Ethics commission

The approval of the ethics committee was not necessary as the article is a completely anonymized case study and no experiments were performed. A clear written consent was obtained from the patient regarding the photographs and information being published.

 

Conflict of interests

The authors declare that they have no conflict of interest related to the creation of this article, and that this article has not been published in any other journal with access to congress abstracts.