Adenocarcinoma of unknown primary with TP53 gene polymorphism: a rare case report with literature review

Abstract

Background

Cancer of unknown primary (CUP) is an orphan disease generally presented by undifferentiated and aggressive morphological phenotype. The treatment of CUP is solely dependent upon the origin of cancer. Despite extensive diagnostic testing, in most of the cases the primary site remains unidentifiable.

Case presentation

This case demonstrates a 75-year-old male patient, who initially presented with the complaints of swelling over right side of the neck since 2 months. A cervical lymph node biopsy was taken for immunohistochemistry, which revealed cytokeratin (CK) and CK7 markers to be positive. Computerized tomography (CT) of Thorax showed subcentimetric subpleural nodules in bilateral lungs fields, predominantly in lower lobes (metastatic in nature). A subsequent pulmoCORE 12 gene panel test was recommended, and patient was discharged with tablet gefitinib 250mg and capsule containing vitamins plus minerals. After one month, patient revisited with the pulmoCORE 12 gene test report which revealed polymorphism in TP53. A pathogenic variant of tumor protein p53 (TP53), i.e., p.Glu198Ter (amino acid alteration) and c.592G > T (coding) variant, was detected, which has 17.2% variant allele frequency. There are no treatment guidelines for TP53 mutation; therefore, the patient was treated with injection paclitaxel 70mg and carboplatin 100mg for 12 cycles along with palliative radiotherapy of 20 Gy for 5 fractions. The overall prognosis of patient was found to be favorable.

Conclusions

There is a need for development of comprehensive guidelines and new molecularly targeted therapies for treatment of CUP which can be tailored for each patient and achieve precise therapeutic outcome.

Background

Cancer of unknown primary (CUP) is a heterogeneous group of metastatic tumors with unidentified primary origin which account for 3–5% of all the cancer [1]. Nearly 80% of the patients are unfavorable subsets who display an aggressive form of tumor with uncertain metastatic pattern and chemoresistance. CUP tumors are restricted to a single site in 50% of cases, frequently appearing in the head and neck, lymph nodes, liver, peritoneum, lungs, bones, and brain [2]. Additionally, majority of the patients do not respond to chemotherapy and have poor prognosis with a median survival of 1 year, ranking CUP among the top 5 cancer-related mortalities [3]. The proposed mechanisms underlying CUP pathophysiology are chromosomal instability, frequently leading to angiogenesis activation, oncogene overexpression, hypoxia-related protein expression, and protein kinase B (PKB) or mitogen-activated protein kinase (MAPK) activation. The overriding aberrations in carcinogenic pathways directly influence the morphology and genetic evolution of the CUP tumor [4]. The most common type of mutations observed in CUP is tumor protein p53 (TP53), Kirsten Rat Sarcoma virus (KRAS), epidermal growth factor receptor (EGFR), neurogenic locus notch homolog protein (NOTCH1, NOTCH2), Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A), Breast Cancer Gene (BRCA1 and BRCA2) [5]. TP53 is a tumor suppressor gene that regulates cell cycle check points, DNA repair and apoptosis. The mutated TP53 causes loss of function necessary for tumor suppression and results in uncontrolled tumor growth [6]. It is overexpressed in 70% of CUP cases and TP53 mutations are reported in 26% of patients (exon 5 to 9 region) [7]. Despite advances in understanding the molecular and genetic landscape of CUP, significant gaps remain in the literature regarding the specific impact of TP53 mutations on the clinical outcomes of CUP patients. Furthermore, there are limited data on the efficacy of targeted therapies and the role of novel biomarkers in improving the prognosis and management of CUP with TP53 mutations. Through a comprehensive review of CUP case reports, our case aimed to provide an overview of the hurdles encountered in diagnosing and managing patients with cancer of unknown primary with TP53 mutations. Additionally, we identified gaps in the existing literature and proposed future research directions to address these challenges, highlighting the necessity to develop effective therapeutic strategies and improve patient outcomes.

Case presentation

Day 1 (24/4/23): A 75-year-old male patient visited our hospital with complaints of swelling on right side of his neck which was gradually increasing in size over the past 2 months, initially measuring 2 cm × 2 cm and later growing into 4 cm × 3 cm within a span of 10 days. Upon interviewing, the patient reported a history of cerebrovascular accident resulting in right medullary infarct 7 years ago. He is a known case of hypertension since 7 years, type 2 diabetes mellitus since 2 years and benign prostatic hyperplasia since 2 months. Thus, patient was on regular medications such as tablet amlodipine 5mg once daily (OD), tablet vildagliptin 50mg plus metformin 500mg OD, tablet tamsulosin 0.4mg plus dutasteride 0.5mg OD, aspirin 75mg plus atorvastatin 10mg OD.

On local examination, a firm non-mobile mass measuring 4 cm × 3 cm vertically oval with an ill-defined lateral border of 7cm was observed. It was fixed probably to sternocleidomastoid muscle. A soft tissue scan of neck revealed prominent multiple discrete hypoechoic lymph nodes on the right side at levels II, III and IV with loss of fatty hilum that needed further fine-needle aspiration cytology (FNAC) correlation. Day 2 (25/4/2023): Ultrasonography (USG)-guided FNAC showed (Sydney system of reporting lymph node cytology: category V) malignancy favoring metastatic adenocarcinoma. Day 4 (27/4/23): Subsequent, computed tomography (CT) of the Thorax, abdomen and pelvis (plain and contrast) scans showed subcentimetric subpleural nodules in bilateral lungs fields, bilateral simple renal cyst (Bosniak type I), duodenal lipoma in the region of junction between D2 and D3 and small left indirect inguinal hernia with omental fat. Day 5 (28/4/2023): The serum prostate-specific antigen (PSA) level and carcinoembryonic antigen (CEA) level were found to be 0.112 ng/ml and 4.28 ng/ml, respectively. Day 12 (5/5/2023): A cervical lymph node biopsy was performed and the immunohistochemistry (IHC) features were suggestive of poorly differentiated metastatic adenocarcinoma. Further, IHC markers such as CK and CK7 were reported to be positive suggesting the possible site of origin to be upper gastrointestinal or pancreatobiliary region (Fig. 1). Day 24 (17/5/23): Positron emission tomography-computed tomography (PET-CT) imaging revealed hypermetabolic metastatic cervical lymph nodes, hypermetabolic right paratracheal lymph nodes, prostate showed focal hypermetabolism just the left of midline, renal cortical cyst noted in upper pole of left kidney and L5-S1 Grade I spondylolisthesis with spondylolysis. Day 40 (2/6/2023): A pulmoCORE 12 gene panel test (Anaplastic lymphoma kinase (ALK), BRAF, EGFR, ERBB2, KRAS, MAP2K1, Mesenchymal Epithelial Transition (MET), Neuroblastoma RAS (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), rearranged during transfection (RET), ROS1, TP53 and Neurotrophic tyrosine receptor kinase (NTRK 1,2,3)) was ordered until then the patient was discharged with tablet gefitinib 250mg for 20days and capsule containing Vitamin-A plus vitamin-E plus vitamin-C plus minerals.

Fig. 1 [Images not available. See PDF.]

Immunohistochemistry of biopsy of cervical lymph node (CK/CK7: Positive; CK20, TTF1, CK5, CK6, P40, P63, LCA, S100, CD56, P16, PAX8, PSA, WT1, synaptophysin, and chromogranin: Negative)

Day 74 (6/7/2023): About after one month patient followed up with the report of pulmoCORE 12 gene panel tests which revealed a polymorphism in TP53 gene. A pathogenic variant (Tier 1) of TP53, i.e., p.Glu198Ter (amino acid alteration) and c.592G > T (coding) variant, was detected with variant allele frequency 17.2% which resulted into loss of function of TP53. However, no drugs are available (FDA approved, off-label suggestions or non-FDA approved) to target this particular variant and there are no established guidelines or treatment recommendation for TP53 mutations established till date. Therefore, the treating physician opted to follow the empirical therapy for adenocarcinoma according to NCCN (National Comprehensive Cancer Network) guidelines [8]. Day 80 (12/7/2023): The patient received weekly injections of paclitaxel (70 mg) and carboplatin (100 mg) for 12 cycles, followed by subcutaneous injection of filgrastim (300 mcg) the next day. Upon discharge, the patient was prescribed ondansetron (4 mg) thrice daily before meals, rabeprazole (20 mg) plus domperidone (30 mg) twice daily before meals for 7 days, vitamin B12 and B-complex supplements once daily for 10 days and levofloxacin (500 mg) once daily for 5 days after 1 week and instructed to follow up for next cycles on time. During the follow-up, the patient exhibited good tolerance to all 12 cycles of chemotherapy. Overall, the patient responded well to empirical chemotherapy, resulting in a favorable prognostic outcome. Day 176 (16/10/2023): Additionally, the patient underwent 5 fractions of palliative radiotherapy with a dose of 20 Gy which was associated with radiation induced minor side effects like neck pain and voice change.

Discussion

Carcinoma of unknown primary in the head and neck region involving cervical lymph node metastasis commonly presents with histological subtypes including adenocarcinoma and squamous cell carcinoma. In CUP, immunohistochemical studies using various markers such as cytokeratin (CK7 and CK20) are performed to determine the cell type and cell pathology which can aid in differential diagnosis based on positive and negative status [3, 9]. In our case only CK7 was positive while other markers (Fig. 1) were negative, this narrowed the differential diagnosis to upper gastrointestinal or pancreatobiliary region. Similarly, Farag et al. reported a case in which the histomorphologic and immunohistochemistry profile of a liver cancer with an unknown primary suggested a few possible sites of origin, such as adenocarcinoma of the pancreatobiliary system or the upper gastrointestinal tract, but could not determine the exact origin [9]. However, immunohistochemistry markers for unknown primary cancers are not uniformly specific or sensitive and often fail to provide exact origin of cancer.

In past decades, the rapid growth of genomics and molecular biology has facilitated identification of tissue of origin in CUP patients through molecular diagnosis and gene sequencing techniques, further allowing the healthcare provider to individualize and tailor the treatment [10–12]. Molecular techniques such as 125 gene panel analysis cancerSELECT [13], 90-gene expression analysis (CancerTypeID) [14, 15], tissue of origin test [16], Fluorescence in situ hybridization (FISH), Next-generation sequencing (NGS) [17] assay are available with high accuracy and can effectively aid in treatment planning [17]. Moreover, systemic therapies based on known primaries identified through gene expression profiling have demonstrated superior prognosis than non-specific or empirical CUP regimens [16, 17]. Sorscher et al. reported a case wherein mRNA gene expression profiling confirmed the origin of tumor as papillary renal cell carcinoma and the patient was treated with everolimus [18].

Additionally, if gene mutations are detected, a relevant targeted therapy can be selected to irradicate the tumor cells irrespective tumor origin [19]. For instance, a case report by Mitani et al. reported that initially their patient received paclitaxel and carboplatin therapy for CUP, but after detecting EGFR mutation (c.2573 T > G p.Leu858Arg) in their patient, the empirical therapy was changed to erlotinib (tyrosine kinase inhibitor). This reduced the tumor size and slowed down the disease progress [20]. Another case study by Jia et al. reported CUP with BRCA1 R71K mutation identified by next-generation sequencing (NGS) and treated with Olaparib [21]. Similarly, Pu et al. reported 4 case series of CUP where all patients benefited from 90 gene expression assay-guided targeted therapy [22]. However, few CUP cases with BRAF mutation have received chronic BRAF inhibitors, particularly vemurafenib and dabrafenib, but these have subsequently promoted malignant transformation of other precancerous BRAF wild-type cells through paradoxical MAPK pathway activation and can contribute to drug resistance. Clinicians should always consider a possibility for emergence of secondary malignancy in CUP patients when treating for mutations, especially with BRAF inhibitors [23, 24].

On comprehensive review of the cases on CUP, we identified that gene expression profiling not only allow the diagnosis of tumor of origin but also facilitate detection of genetic aberrations and most importantly guide the treatment (Table 1). Nearly, about 80% of patients with CUP have one or more genetic alterations and 50% of them can be treated with targeted therapies [25]. In the current case, 12 gene panel test identified TP53 mutation in our patient and was treated with platinum-based empirical therapy. Similarly, Chen et al. reported a case of head and neck adenocarcinoma of unknown primary presented with VEGFA gene amplification and TP53 mutation. But the tumor showed unsatisfactory response to empirical chemotherapy and was subsequently treated with sorafenib based on VEGFA gene amplification [26]. Another CUP case by Ni et al. involved mutations in PD-L1 gene and TP53 (exon 5) which was initially treated with capecitabine plus oxaliplatin regimen based on IHC results indicating a digestive origin of the tumor. However, rising levels of CEA and CA199 showed it was ineffective. Switching to paclitaxel and cisplatin led to a decline in these tumor markers, and immunotherapy with nivolumab was administered for PD-L1 mutation [27]. The NCCN guidelines and other reports have recommended platinum-based empirical chemotherapy for subjects with adenocarcinoma of unknown primary [8, 28]. However, it is unfortunate that there are currently no FDA-approved therapies specifically targeting TP53 mutations. This is particularly challenging because TP53 mutations not only lose their tumor-suppressive functions but also gain tumor-promoting properties, making them difficult to target effectively. To address these challenges, there is an urgent need for the development of highly selective drugs that can target TP53 mutations while minimizing off-target effects. Recently, development of synthetic lethality-based approaches targeting mutant TP53 represents a promising advancement in cancer therapy, paving the way for more effective and targeted cancer treatments [29]. We aimed to summarize an overview of diagnostic assessment and treatment selection in the form of an algorithm (Fig. 2). Additionally, existing guidelines provided by the European Society for Medical Oncology and Spanish recommendations are outdated, and even the relatively more recent guidelines from the National Comprehensive Cancer Network (NCCN) do not fully incorporate the latest advancements in molecular diagnostics and therapeutic approaches [4]. Comparing our case with similar reported cases highlights the variability in genetic mutations and responses to different therapies, underlining the necessity for personalized treatment strategies. This case report contributes to the existing knowledge by emphasizing the importance of comprehensive genetic profiling in guiding effective treatment and underscores the need for updated clinical guidelines to incorporate emerging molecular and therapeutic advancements.

Table 1. Summary of diagnostic approaches, identification of genetic polymorphism and management of cancer of unknown primary (CUP) cases

Author name	Age/gender	Diagnostic tests	Gene mutation	Final diagnosis	Treatment
Farag et al. [9]	43 years, male	Immunohistochemistry, Next-generation sequencing	ATP7B c.4232G > A p.R1411Q Missense variant, ERCC2 c.491A > G p.H164R Missense variant, CTNNA1 c.839A > G p.Y280C Missense variant, HIF1A c.1292C > T p.T431I Missense variant, RAD21 c.1349G > A p.R450H Missense variant, etc	Metastatic liver cancer of unknown primary origin (adenocarcinoma of pancreatobiliary systems or upper gastrointestinal tract)	6 cycles of paclitaxel
Bo Yu et al. [10]	61 years, female	Next-generation sequencing, 90 gene expression assays	ERBB2 copy number variation (CNV), amplification. CCND1 amplification and multiple gene mutations, including TP53 (37.59%) mutation, c.738G > A, p.M246I; SPRED1 (29.20%) mutation, etc	Adenocarcinoma of breast cancer origin	Surgical resection, 8 cycles of TCbHP regimen (Docetaxel + Carboplatin + Herceptin + Pertuzumab)
Cackowski et al. [11]	79 years, male	Whole-genome sequencing	N581I mutation in the BRAF gene	Double-Negative Prostate Cancer	Pembrolizumab, bicalutamide, docetaxel
Du et al. [12]	72 years, male	Immunohistochemistry, Next-generation sequencing	EGFR mutations	Bone metastases from cancer of unknown primary	Osimertinib
Singh et al. [13]	83 years, male	Immunohistochemistry, Cancer selects 125 Gene panel test	No mutations (PD-L1 staining positive)	Metastatic Carcinoma of an Unknown Primary to the Heart	Pembrolizumab
Saller et al. [14]	Case 1: 84 years, female	Case I: CancerTYPE ID test, Immunohistochemistry Case II: CancerTYPE ID test, Immunohistochemistry Case III: CancerTYPE ID test, Immunohistochemistry Case IV: CancerTYPE ID test, Immunohistochemistry	None	Case I: Well-differentiated (grade 2) neuroendocrine tumor originating from the lung Case II: small/large cell neuroendocrine carcinoma of lung Case III: small/large cell neuroendocrine carcinoma of lung Case IV: small/large cell neuroendocrine carcinoma of lung	Not mentioned
Nagasaka et al. [15]	Case I: 41 years, male Case II: 79 years, male	Case I: Immunohistochemistry, CancerTYPE ID test Case II: Immunohistochemistry, CancerTYPE ID test	None	Case I: Papillary renal cell carcinoma Case II: Papillary renal cell carcinoma	Case I: Pazopanib Case II; sunitinib
Chiang et al. [16]	70 years, male	Immunohistochemistry, gene expression profiling, Pathwork Tissue of Origin test	None	Cancer of breast cancer cell of origin	Local radiation therapy, carboplatin
Raskin et al. [17]	21 years, male	Immunohistochemistry, Break-apart Fluorescence in situ hybridization (FISH) EWSR1 assay	EWSR1 translocation (EWSR1ex7/ATF1ex5)	Gastrointestinal clear cell sarcoma	Surgical intervention
Sorscher et al. [18]	53 years, male	Immunohistochemistry, CancerTYPE ID test	None	Papillary renal cell carcinoma	Everolimus
Sun et al. [19]	61 years, male	Multiple gene sequencing	EGFR mutation in exon 18(G719A/G719C)	Lung adenocarcinoma with cervical lymph node metastasis	4 cycles of gemcitabine plus cisplatin
Mitani et al. [20]	52 years, female	Next-generation sequencing	EGFR mutation (c.2573 T > G p.Leu858Arg)	Cancer of unknown primary	Erlotinib
Jia et al. [21]	63 years, female	Next-generation sequencing	BRCA1 R71K mutation	Cancer of unknown primary	Olaparib
Pu et al. [22]	Case I: 45 years, female Case II: 59 years, male Case III: 53 years, male Case IV: 50 years, male	Case I: Immunohistochemistry, 90 gene expression assay Case II: Immunohistochemistry, 90 gene expression assay Case III: Immunohistochemistry, 90 gene expression assay Case IV: Immunohistochemistry, 90 gene expression assay	None	Case I: primary bronchial lung cancer Case II: primary renal cell carcinoma Case III: tonsil cancer Case IV: renal cancer	Case I: Surgical intervention Case II: radiotherapy Case III: paclitaxel and carboplatin Case IV: pazopanib
Blackmon et al. [23]	72 years, male	Next-generation sequencing	BRAFV600E mutation	Melanoma of unknown primary	Vemurafenib Ipilimumab Trametinib Pembrolizumab
Andrews et al. [24]	26 years, male	Next-generation sequencing	BRAFV600E mutation	Malignant melanoma of unknown primary	Not mentioned
Chen et al. [26]	59 years, Male	Next-generation sequencing	Amplification of VGFA gene and TP53 gene mutation (R209Kfs)	Head and neck adenocarcinoma of unknown primary	1 cycle of Paclitaxel and cisplatin, NGS guided: Sorafenib
Ni et al. [27]	36 years, Male	Immunohistochemistry (digestive tract metastasis), Immune-related gene testing	PD-L1 positivity (25%), mutation in TP53 at exon 5	Cancer of unknown primary of pelvis	1 cycle of capecitabine plus oxaliplatin, 6 cycles of paclitaxel and cisplatin, immunotherapy: nivolumab
Fischerova et al. [28]	29 years, female	Immunohistochemistry of mismatch repair protein	Deletion of EPCAM gene up to exon 1–8 of MSH2 gene	Primary retroperitoneal nodal endometrioid carcinoma with lynch syndrome	Paclitaxel and carboplatin

Fig. 2 [Images not available. See PDF.]

Diagnostic and treatment algorithm for cancer of unknown primary [8]

Conclusion

The heterogeneity observed in CUP cases, unreliable results from diverse clinical trials and limited access to modern diagnostic tools like next-generation sequencing pose a significant challenge in development of uniform diagnostic and treatment standards. Currently, the urgent necessity is rapid development of comprehensive guidelines and biologically targeted therapies, especially synthetic lethality approaches targeting TP53 mutations. Future efforts should focus on conducting meticulously planned clinical trials that incorporate molecular diagnostics, and developing advanced technologies that can accurately characterize the molecular profiles of CUP tumors. By addressing these challenges, we can move toward the development of more tailored and effective guidelines for the management of CUP, ultimately improving patient outcomes and quality of care.

Acknowledgements

We would like to acknowledge HOD, Department of Oncology, Justice KS Hegde Charitable Hospital, Mangalore, India, for his constant support.

Author contributions

[RKC and UVM] conceptualized the study; [RKC and PP] collected the data; [JS and VVS] helped in formal analysis; [RKC] was involved in writing—original draft; [VCS, RKC and PP] contributed to writing—review and editing; [VS and UVM] supervised the study. VVS holds the final responsibility of the manuscript. All authors read and approved the final manuscript.

Funding

No funds, grants or other support was received.

Availability of data and material

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent will be available on request.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

CUP

Cancer of unknown primary

CK

Cytokeratin

CT

Computerized tomography

TP53

Tumor protein p53

OD

Once daily

FNAC

Fine-needle aspiration cytology

IHC

Immunohistochemistry

MAPK

Mitogen-activated protein kinase

NCCN

National Comprehensive Cancer Network

NGS

Next-generation sequencing

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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