Modern Diagnostics in a Retroperitoneal Malignant Tumor of Uncertain Histogenesis: A Case Report and Review of the Literature

Abstract

Background: Cancers of unknown primary (CUP) are a heterogeneous group of malignancies in which metastatic disease is present, but the primary tumor cannot be identified, even after thorough evaluation. These tumors account for approximately 3%–5% of all cancers and often show aggressive behavior along with uncertainty in diagnosis. Large masses in the retroperitoneal area or pancreas that are hard to classify pose a significant challenge.

Case presentation: We present a 51-year-old man with a history of tobacco use who presented with severe left-sided abdominal pain, nausea, and vomiting. Imaging revealed a large irregular upper abdominal mass measuring approximately 16 cm with central necrosis and compression of adjacent structures, initially suspected to be of pancreatic origin. Additional findings included destructive lesions involving the right second rib and sternum, pulmonary nodules, and a breast-adjacent lesion. Multiple biopsies of the abdominal mass demonstrated a poorly differentiated malignant neoplasm with extensive necrosis; however, despite comprehensive immunohistochemical evaluation at a specialized pathology center, a definitive tumor lineage could not be established. Serum tumor markers, including alpha-fetoprotein, carbohydrate antigen (CA) 19-9, carcinoembryonic antigen, and CA27-29, were within normal limits. Bone biopsies were nondiagnostic. Given the persistent diagnostic uncertainty, molecular profiling and circulating tumor DNA analysis were pursued to further characterize the tumor and identify potential therapeutic targets; results were pending at the time of evaluation.

Conclusion: This case illustrates the diagnostic challenges posed by poorly differentiated cancers of unknown origin that present as large abdominal masses and are suspected to be metastatic.

Graphical abstract

Keywords

retroperitoneal tumor / uncertain histogenesis / molecular profiling / diagnostic pathology

Introduction

A considerable challenge in modern cancer treatment arises from poorly differentiated malignant tumors of unknown cell type. While there have been advances in pathology, immunochemical methods, and genetic testing, a subset of tumors still cannot be reliably assigned to a specific cell type or tissue of origin. In many cases, patients with these types of tumors present with advanced-stage disease and atypical clinical or imaging findings, which complicates diagnosis and treatment planning[1,2].

The diagnosis of poorly differentiated malignant tumors, or poorly differentiated tumors, relies primarily on morphologic evaluation of the tumor and on immunohistochemical staining to distinguish among epithelial, neuroendocrine, lymphoid, melanocytic, and mesenchymal lineages. However, some tumors are highly aggressive, exhibit minimal differentiation, and lack characteristic immunohistochemical markers of the cell type or tissue of origin, making definitive classification difficult even with a thorough evaluation[3,4].

There is increasing recognition of the role of next-generation sequencing (NGS) and circulating tumor DNA (ctDNA) testing in identifying actionable molecular alterations, thereby refining the diagnostic approach and informing the selection of the most appropriate treatment options[5,6].

Another group of tumors that cause significant difficulty in diagnosing is large, retroperitoneal or upper abdominal tumors because of their proximity to multiple organs and overlapping imaging findings. There is substantial overlap in the imaging characteristics of neoplasms arising from the pancreas, adrenal gland, retroperitoneum, and adjacent soft tissues, especially when these lesions exhibit extensive necrosis and rapid growth. Furthermore, poorly differentiated malignant tumors often lack the distinct morphologic and immunohistochemical features necessary for an accurate pathological diagnosis[7].

Recent advances in molecular oncology have expanded the diagnostic tools available for evaluating tumors with uncertain histogenesis. Comprehensive genomic profiling enables the identification of potentially actionable alterations, enhances understanding of tumor biology, and aids in refining the differential diagnosis when conventional methods yield inconclusive results[8]. As these technologies are increasingly incorporated into clinical practice, they present opportunities to improve diagnostic accuracy and to tailor therapeutic strategies for patients with diagnostically challenging malignancies.

This report describes a challenging case involving a large malignant tumor in the upper abdomen characterized by significant necrosis and an indeterminate origin. Radiographic imaging revealed suspicious lesions in the bone, breast, and lung, raising concern for metastatic disease; however, histologic confirmation was not obtained. Despite a comprehensive evaluation at a specialized center, the tumor’s lineage could not be definitively established, illustrating the diagnostic complexities of poorly differentiated cancers.

Case presentation

A 51-year-old man with a history of tobacco use presented with severe left-sided abdominal pain, nausea, and vomiting. He reported progressive abdominal pain for approximately one month following the discovery of an abdominal mass. Additional symptoms included poor oral intake, fatigue, and intermittent hematochezia.

Initial diagnostic evaluation: During a previous hospitalization in January 2026, contrast-enhanced computed tomography (CT) imaging (Figure 1) revealed a large, heterogeneous mass measuring approximately 16 cm in the left upper abdomen with central necrosis. The lesion caused inferior displacement of the left kidney. The mass was initially suspected to originate from the pancreatic tail, although adrenal and retroperitoneal origins were also considered.

Chest CT (Figure 2) imaging demonstrated destructive lesions involving the right second rib and sternal manubrium, as well as a retroareolar breast lesion. Positron emission tomography-computed tomography (PET/CT) imaging demonstrated hypermetabolic activity within the large abdominal mass, increased uptake in the right supraclavicular region, uptake in the retroareolar breast tissue, metabolic activity in the sternum and ribs, and multiple pulmonary nodules. These findings raised strong suspicion for metastatic disease; however, histological confirmation of metastases at these sites was not obtained. Subsequent biopsies of PET-avid osseous lesions were nondiagnostic due to insufficient tissue.

Histopathologic evaluation: Endoscopic ultrasound-guided fine-needle aspiration of the suspected pancreatic tail mass identified malignant cells, but the sample was insufficient for definitive classification (Figure 3).

A subsequent core biopsy of the abdominal mass revealed a poorly differentiated malignant neoplasm with extensive necrosis. Because of atypical morphologic and immunophenotypic features, the specimen was referred to Johns Hopkins Hospital for expert consultation.

Extensive immunohistochemical evaluation did not establish a definitive lineage of differentiation. The differential diagnosis included high-grade neuroendocrine carcinoma, acinar cell carcinoma, poorly differentiated adenocarcinoma, SMARCA-deficient carcinoma, metastatic melanoma, adrenal cortical carcinoma, and lymphoma. Immunohistochemical studies remained inconclusive. Notable findings included rare focal INSM1 positivity, negative synaptophysin, weak chromogranin staining, a Ki-67 proliferation index of approximately 90%, mutant-pattern p53 expression, and negative staining for SOX10, CD45, BCL10, and chymotrypsin (Table 1).

After expert review, the lesion was classified as a poorly differentiated malignant neoplasm of uncertain histogenesis (uncertain origin). Bone biopsies of the rib and sternum were attempted to confirm suspected metastatic disease, but were nondiagnostic because of insufficient tissue. Therefore, metastatic involvement of the PET-avid lesions remained presumed based on imaging findings rather than histologic confirmation. Serum tumor markers, including AFP, Carbohydrate Antigen (CA) 19-9, Carcinoembryonic Antigen, CA27-29, and β-hCG, were within normal limits.

Clinical Course: The patient continued to experience severe abdominal pain, which led to several visits to the emergency department. Given the unknown tumor origin and suspected metastatic disease, treatment options were discussed by a team of specialists. Despite a comprehensive immunohistochemical evaluation, the tumor origin remained unclear. Systemic staging with PET/CT imaging showed high metabolic activity in the abdominal mass and other suspicious lesions in the ribs, sternum, breast, and supraclavicular area. Biopsies of selected suspected metastatic sites were performed, but were not diagnostic due to insufficient tissue.

Possible management strategies included the following: palliative surgical resection of the abdominal mass, radiation therapy, empiric systemic therapy, and molecular profiling to identify actionable mutations. Given the large tumor burden and symptom-causing mass effect, palliative surgical removal was considered for symptom relief, although curative treatment was considered unlikely. ctDNA testing and NGS were performed to identify potential therapeutic targets, but the results were not yet available at the time of manuscript submission; therefore, they were not incorporated into clinical decision-making.

The sequential steps of this diagnostic approach are summarized schematically in Figure 4.

Discussion

This case highlights the considerable diagnostic challenges associated with poorly differentiated malignant neoplasms of uncertain histogenesis. These tumors frequently exhibit aggressive clinical behavior but lack sufficient morphological or immunophenotypic features to determine a definitive lineage of differentiation. Accurate classification is crucial in such cases, as therapeutic decisions increasingly rely on tumor type, molecular characteristics, and the identification of potential targetable alterations. Although advances in immunohistochemistry and molecular pathology have improved diagnostic capabilities, a subset of high-grade malignancies remains unclassifiable even after comprehensive evaluation[9].

In this case, histopathological analysis showed a rapidly growing malignant tumor with significant necrosis and a Ki-67 proliferation index near 90%, suggestive of aggressive tumor behavior. Despite thorough immunohistochemical testing, we could not establish a clear lineage differentiation. The differential diagnoses included high-grade neuroendocrine carcinoma, acinar cell carcinoma, poorly differentiated adenocarcinoma, adrenal cortical carcinoma, melanoma, and lymphoma.

High-grade neuroendocrine carcinoma was initially considered due to focal positivity for certain markers and high growth activity. However, the lack of synaptophysin and chromogranin expression suggests that it is not a definite neuroendocrine tumor. Neuroendocrine carcinomas typically show widespread expression of these markers and often exhibit specific morphological patterns, such as organoid nesting or rosette formation[10].

We also considered acinar cell carcinoma of the pancreas because of the tumor location and prominent nucleoli. However, the acinar differentiation markers such as BCL10 and chymotrypsin were negative, making this diagnosis unlikely. Acinar cell carcinomas usually show strong positivity for pancreatic enzyme markers and distinctive cytoplasmic granularity on histology[11].

The possibility of a poorly differentiated pancreatic adenocarcinoma was also assessed. However, only a few tumor cells expressed cytokeratin, and the tumor retained intact SMAD4 (DPC4) expression, which is often lost in pancreatic ductal adenocarcinoma. Additionally, the large tumor size and extensive necrosis were somewhat unusual for a typical pancreatic denocarcinoma[12].

We also considered retroperitoneal sarcoma, particularly undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Retroperitoneal sarcomas can present as large abdominal masses with necrosis that compress neighboring organs. However, the histopathological features and immunohistochemical profile in this case did not support a mesenchymal origin[13].

Metastatic melanoma was also a consideration due to the poorly differentiated appearance. However, melanocytic markers, including SOX10, were negative, ruling out this diagnosis. Similarly, we excluded lymphoma due to the absence of CD45 expression and lack of clonal lymphoid populations on flow cytometry.

This case represents a challenging subset of poorly differentiated malignancies in which both the lineage of differentiation and the site of origin remain uncertain despite extensive investigation. The dominant abdominal mass measured approximately 16 cm and could not be classified following comprehensive immunohistochemical analysis and expert review at a tertiary referral center. Furthermore, PET/CT imaging revealed multiple hypermetabolic lesions suggestive of disseminated disease; however, biopsies of suspected metastatic sites were nondiagnostic, precluding histologic confirmation. Collectively, these findings highlight the diagnostic limitations that may persist even after thorough contemporary pathologic and radiologic evaluation. Accordingly, we consider the most precise designation for this lesion to be a poorly differentiated malignant neoplasm of uncertain histogenesis, rather than a cancer of unknown primary, because neither the tissue of origin nor the metastatic status could be definitively determined.

As shown in Figure 5, the diagnostic complexity of this case involves several important factors. First, the tumor had aggressive biological features. It grew rapidly, exhibited extensive necrosis, and showed a high Ki-67 proliferation index of nearly 90%. This suggests highly active tumor biology. Second, traditional diagnostic tools, including comprehensive immunohistochemical panels and serum tumor markers, did not reveal a clear lineage of differentiation. The negative staining for epithelial, neuroendocrine, melanocytic, lymphoid, and adrenal markers made it difficult to determine the primary site of origin. Diagnostic challenges are increasingly recognized in cases of poorly differentiated malignancies with uncertain histogenesis, especially when conventional morphologic assessment and immunohistochemical studies do not establish a definitive lineage of differentiation[14].

Modern methods such as ctDNA analysis and NGS have become essential in these cases. They enable the identification of actionable genomic changes or molecular signatures indicative of tumor origin. As summarized in Figure 5, integrating tumor biology, diagnostic limitations, and new molecular technologies provides a framework for clinical decision-making in complex cancers with uncertain histogenesis.

NGS and ctDNA analysis can identify driver mutations, genomic changes, or tumor signatures that may indicate tissue of origin or reveal actionable therapeutic targets. Molecular profiling is playing an increasingly important role in evaluating poorly differentiated malignant neoplasms of uncertain origin. NGS and ctDNA analyses may identify actionable genomic alterations, uncover biologically relevant pathways, and in some cases provide evidence supporting a likely tissue of origin. These approaches have become valuable adjuncts when conventional histopathology and immunohistochemistry are inconclusive[8].

The management of poorly differentiated malignant neoplasms of uncertain histogenesis remains complex and frequently necessitates individualized, multidisciplinary decision-making. Therapeutic strategies are determined by factors such as disease distribution, symptom burden, patient performance status, and available molecular data. For selected patients presenting with bulky symptomatic disease, palliative surgical intervention may be appropriate to relieve mass effect and enhance quality of life, even in the absence of curative treatment options[15].

In this case, the patient suffered severe pain from the large abdominal tumor, leading to discussions about palliative resection. Although unlikely to be curative in the presence of metastatic disease, this approach may offer significant symptom relief and enhance the patient’s functional status. Imaging strongly suggested disseminated disease involving the ribs, sternum, breast, supraclavicular region, and lungs. However, definitive metastatic involvement at these sites could not be established because biopsies of suspected lesions were nondiagnostic. Despite this, the overall radiographic pattern was highly concerning for advanced systemic disease.

This case highlights the need for collaboration among medical oncology, surgical oncology, pathology, and radiation oncology. Managing complex cancers of unclear origin often requires a coordinated approach to optimize patient outcomes.

Conclusion

This case demonstrates the significant diagnostic and therapeutic challenges associated with poorly differentiated malignant neoplasms of uncertain histogenesis. Despite comprehensive imaging, histopathologic assessment, expert pathology consultation, and extensive immunohistochemical analysis, neither a definitive lineage of differentiation nor a tissue of origin was identified. The case emphasizes the limitations of current diagnostic modalities in certain highly aggressive malignancies and highlights the necessity of multidisciplinary collaboration among pathology, medical oncology, surgical oncology, and radiology. In these scenarios, molecular profiling and ctDNA analysis may offer additional diagnostic and therapeutic guidance when conventional methods yield inconclusive results.

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RIGHTS & PERMISSIONS

The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.