Malignancy in mirror image anatomy reveals situs inversus totalis as an anatomic modifier of oncologic care

Abstract

Background

Situs inversus totalis (SIT) is a rare congenital laterality anomaly characterized by complete mirror-image transposition of the thoracic and abdominal viscera. Although SIT is not a proven cancer-predisposition syndrome, cancer in this setting challenges the spatial assumptions that guide diagnosis, staging, surgery, radiotherapy, and surveillance.

Methods

We conducted a retrospective, single-center observational study of patients with radiologically confirmed SIT treated at our cancer center between July 2017 and December 2025. Patients with histologically confirmed malignancy were included. Clinical, pathological, imaging, treatment, and follow-up data were extracted from medical records. Overall survival (OS) was summarized descriptively; Kaplan-Meier analysis was used only to visualize survival and censoring patterns.

Results

Among 11 patients with SIT, 6 had histologically confirmed malignancies. Median age was 66.5 years (range, 47–76), and median follow-up was 47.5 months (range, 30–55). Tumors included hepatocellular carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, cervical adenocarcinoma, poorly differentiated abdominal adenocarcinoma, and follicular lymphoma transformed to high-grade B-cell lymphoma. Treatment included surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, transarterial chemoembolization, and autologous stem cell transplantation. 4 patients died, and 2 were alive at last contact. Pooled median OS was 50 months and was interpreted only descriptively. Across cases, outcomes reflected tumor type, stage, and molecular features, whereas SIT mainly affected lesion localization, laterality recognition, nodal or vascular mapping, operative orientation, and treatment planning.

Conclusions

Malignancy in SIT is best understood as cancer within a reversed anatomical coordinate system. Standard oncologic care remains feasible but requires explicit anatomical verification and multidisciplinary planning.

Introduction

Situs inversus totalis (SIT) is a rare congenital laterality anomaly characterized by complete mirror-image transposition of the thoracic and abdominal viscera [1–3]. In most individuals, SIT is clinically silent and is discovered incidentally during imaging, surgery, or evaluation for unrelated disease [4]. Its apparently benign natural history, however, becomes clinically relevant when cancer develops in a reversed anatomical environment [5, 6]. Although current evidence does not establish SIT as a cancer-predisposition syndrome, its mirror-image arrangement can challenge the anatomical assumptions that underlie contemporary oncologic diagnosis and treatment [7].

Cancer care depends on precise spatial interpretation [8, 9]. Lesions are localized, tumors are staged, biopsies are targeted, nodal stations are assigned, operations are planned, vascular territories are mapped, and radiotherapy fields are designed according to expected relationships among organs, vessels, lymphatic drainage, and laterality [10–12]. SIT can disrupt this familiar coordinate system [13]. The clinical relevance of SIT in oncology may therefore lie less in generating a different cancer than in altering the anatomical conditions under which otherwise standard cancer care is delivered [13, 14].

This distinction is important because the available literature remains fragmented. Malignancy occurring in patients with SIT has been reported across multiple organ systems, including thoracic [15, 16], gastrointestinal [17, 18], hepatobiliary [19, 20], pancreatic [21], urologic [22, 23], gynecologic [24, 25], and hematologic tumors [26, 27]. However, most published reports are single-patient descriptions, technically focused surgical reports, or small case series. These studies have demonstrated that treatment is feasible in mirror-image anatomy, but they have rarely addressed a broader oncologic question: whether SIT alters tumor biology, complicates the interpretation of disease, or primarily modifies the anatomical execution of cancer care. As a result, clinicians still lack an integrated framework for approaching malignancy in patients with SIT.

The practical implications are substantial. Failure to recognize or explicitly communicate mirror-image anatomy may introduce error at multiple points in the cancer pathway, including lesion localization, laterality assignment, nodal mapping, vascular interpretation, operative orientation, interventional access, and treatment planning [28]. These issues are particularly consequential in anatomy-sensitive malignancies such as lung cancer and hepatocellular carcinoma (HCC), in which oncologic safety depends on accurate bronchovascular anatomy, mediastinal nodal-station assignment, hepatic segmental localization, portal venous inflow, hepatic arterial supply, and hepatic venous drainage [29]. In such settings, SIT should not automatically prompt deviation from established oncologic principles; rather, it should trigger heightened anatomical vigilance, procedure-specific planning, and multidisciplinary coordination [30].

In this retrospective single-center observational study, we analyzed patients with SIT and histologically confirmed malignancies treated at our cancer center over an eight-and-a-half-year period. We aimed to characterize the clinicopathologic spectrum of malignancy occurring in patients with SIT, describe treatment delivery and descriptive follow-up status, and examine whether the primary relevance of SIT in oncology is biological or anatomical. Unlike most published reports that focus on single operations or single tumor types, this study integrates a real-world institutional cohort with a literature-based comparison to define recurring SIT-specific challenges across oncologic care. We used this cohort to examine the working premise that SIT functions less as a determinant of tumor biology than as an anatomical modifier of oncologic care.

Materials and methods

Study design, setting, and reporting standards

This retrospective, single-center observational study included patients with SIT who received care at the Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from July 2017 to December 2025. The study was designed as a descriptive clinical cohort study rather than a comparative survival analysis or prognostic modeling study. The data cutoff for follow-up was December 31, 2025. The study was conducted in accordance with the Declaration of Helsinki and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies [31]. The study protocol was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Because this was a retrospective study based on de-identified clinical data, the requirement for written informed consent was waived by the ethics committee.

Patient identification and eligibility criteria

All patients with SIT documented in the institutional clinical database during the study period were screened for eligibility. SIT was defined radiologically as complete mirror-image transposition of the thoracic and abdominal viscera. Patients were eligible for inclusion if they had a pathologically confirmed malignant tumor diagnosed during the study period. Patients were excluded if they had benign tumors, non-neoplastic conditions, or clinically suspected but histologically unconfirmed malignancies. As summarized in Figs. 1A, 11 patients with SIT were identified during the study period. After eligibility assessment, 5 patients were excluded because they did not have eligible malignant disease, including gastrointestinal stromal tumor, adrenal pheochromocytoma, esophageal papilloma, suspected renal infection, and benign prostatic hyperplasia. The final analytic cohort consisted of 6 patients with SIT and histologically confirmed malignancies. The anatomical distribution and tumor spectrum of the included malignancies are shown in Fig. 1B and included lung cancer (n = 2), hepatocellular carcinoma (HCC; n = 1), cervical cancer (n = 1), pelvic follicular lymphoma (FL; n = 1), and poorly differentiated adenocarcinoma of the abdominal cavity (n = 1).

Fig. 1.

Cohort assembly and tumor distribution in patients with situs inversus totalis. A Flow diagram of patient screening and cohort assembly. Of 11 patients with situs inversus totalis (SIT) identified in the institutional database between July 2017 and December 2025, 5 were excluded because they did not have histologically confirmed eligible malignancy. The final cohort included 6 patients with SIT and confirmed malignant tumors. B Anatomical schematic showing the distribution of malignancies within the mirror-image thoracoabdominal anatomy of SIT. Tumor sites included lung cancer (n = 2), hepatocellular carcinoma (n = 1), cervical cancer (n = 1), pelvic follicular lymphoma (n = 1), and poorly differentiated adenocarcinoma of the abdominal cavity (n = 1). This panel illustrates the spatial basis for SIT-specific challenges in lesion localization, laterality assignment, nodal or vascular mapping, and treatment planning

Data collection and quality control

Clinical, pathological, imaging, treatment, and follow-up data were extracted from the institutional electronic medical record system using a predefined data-collection form. Data extraction was checked for consistency by two investigators. Any discrepancies were resolved by review of the source records and discussion with a senior investigator. Variables of interest included age at cancer diagnosis, sex, primary tumor site, histological subtype, disease stage, treatment modality, number of systemic treatment lines, duration of follow-up, treatment response or remission status where available, and survival status at last contact. Follow-up status was ascertained from outpatient records, inpatient records, telephone follow-up, and the death registry.

Staging and clinical classification

Tumor stage was assigned according to tumor-specific contemporary staging systems. Solid tumors were staged according to the American Joint Committee on Cancer (AJCC) staging system, 8th edition, where applicable [32]. Cervical cancer was staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system [33]. FL and transformed high-grade B-cell lymphoma (HGBCL) were staged according to the Ann Arbor/Lugano staging system [34]. Treatment modalities were classified as surgery, radiotherapy (RT), chemotherapy (CT), immunotherapy (IO), targeted therapy (TT), transarterial chemoembolization (TACE), and autologous stem cell transplantation (ASCT), as appropriate. Treatment lines were determined from the chronological sequence of systemic antitumor therapy recorded in the medical record.

Anatomical and radiological assessment in SIT

Radiological reports and available cross-sectional imaging findings were descriptively reviewed to identify SIT-related anatomical issues relevant to oncologic care. Particular attention was given to lesion localization, laterality assignment, nodal mapping, vascular interpretation, procedural orientation, and treatment planning. For thoracic malignancies, SIT-related considerations included reversed thoracic laterality, hilar orientation, bronchovascular branching, mediastinal nodal-station assignment, and the implications of mirror-image anatomy for thoracoscopic or radiation-based treatment planning. For HCC, SIT-related considerations included mirror-image liver position, hepatic segmental localization, portal venous inflow, hepatic arterial supply, hepatic venous drainage, and the spatial relationship between the tumor and major vascular structures. These features were assessed descriptively to clarify how SIT modified the anatomical delivery of oncologic care.

Outcomes and follow-up definitions

The primary descriptive outcome was overall survival (OS), defined as the interval from the date of pathological diagnosis to death from any cause or last documented follow-up [35, 36]. Patients who were alive at last contact were censored on the date of last follow-up. Secondary descriptive outcomes included treatment feasibility, treatment trajectory, radiological characteristics, treatment response or remission status where applicable, and practical diagnostic or procedural issues related to mirror-image anatomy. Because the cohort included biologically distinct solid and hematologic malignancies, OS was used only to summarize the observed follow-up status of the included patients and was not intended to define an SIT-specific survival benchmark.

Bias, missing data, and study size

Several measures were used to reduce potential misclassification and reporting bias. Eligibility required pathological confirmation of malignancy, and SIT was defined radiologically rather than by clinical suspicion alone. Tumor stage was assigned using tumor-specific standard staging systems. Data were extracted with a predefined form and checked for consistency by two investigators. The study size was determined by the number of eligible patients with SIT and pathologically confirmed malignancy identified at the institution during the study period. No formal sample-size calculation was performed because the study was descriptive and SIT-associated malignancy is rare. No matched or unmatched control group was included, and no direct comparison with patients without SIT was performed. Missing data were not imputed. Variables unavailable in the medical record were treated as not available and were not used for inferential analysis. Because of the small cohort size and marked clinical heterogeneity, no adjustment for confounding was attempted.

Statistical analysis

All analyses were prespecified as descriptive. Continuous variables were summarized using the median and range when appropriate, particularly for follow-up time, to avoid overinterpretation of distributional estimates in this very small cohort. Categorical variables were summarized as counts and percentages. Individual patient-level characteristics were presented in tabular format to preserve clinical interpretability. The Kaplan-Meier (KM) method was used only to provide a descriptive visualization of observed OS and censoring patterns within the included cohort. The KM curve was not used for hypothesis testing, group comparison, survival prediction, or derivation of an SIT-specific prognostic estimate. No log-rank test, Cox proportional hazards model, subgroup analysis, multivariable model, or sensitivity analysis was performed because the cohort size was limited and the included malignancies were markedly heterogeneous with respect to tumor type, stage, biology, and treatment. Any pooled median OS derived from this cohort should be interpreted strictly as a descriptive summary of these 6 patients and not as a predictive or clinically actionable survival benchmark. In particular, because the cohort combined distinct hematologic and solid malignancies, including early-stage lung adenocarcinoma, advanced cervical adenocarcinoma, HCC, poorly differentiated adenocarcinoma, lung squamous cell carcinoma, and transformed FL/HGBCL, a pooled median OS has no valid clinical meaning as a shared SIT survival baseline. Statistical analyses and figure generation were performed using R software, version 4.6.1 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Cohort assembly and patient characteristics

Individual clinicopathologic characteristics, treatment modalities, systemic treatment lines, follow-up duration, and survival status are summarized in Table 1. The cohort comprised 4 men and 2 women, with a median age at cancer diagnosis of 66.5 years (range, 47–76 years). The tumor spectrum was heterogeneous and included HCC, lung SCC, lung ADC, cervical ADC, PD-ADC of the abdominal cavity, and FL transformed to HGBCL. Two patients had early-stage disease, corresponding to stage I or IB, whereas 4 patients had advanced-stage disease, corresponding to stage IIIC, IV, or IVB. Treatment was selected according to tumor type, disease stage, anatomical feasibility, and clinical context. Treatment modalities included surgery, RT, CT, IO, TT, TACE, and ASCT. During follow-up, 4 patients died and 2 remained alive at last contact. Cohort-level summary statistics are provided in Table 2. The median follow-up was 47.5 months (range, 30–55 months). Because of the small sample size and marked biological heterogeneity of the included solid and hematologic malignancies, follow-up outcomes were interpreted descriptively rather than inferentially. Overall, clinical presentation and treatment selection were primarily determined by tumor type and stage. By contrast, the recurring contribution of SIT was anatomical: mirror-image visceral arrangement affected lesion localization, laterality recognition, imaging interpretation, nodal or vascular mapping, procedural orientation, and treatment planning.

Table 1.

Clinicopathologic characteristics and outcomes of patients with SIT and malignancy

Case	Sex	Age	Site	Histology	Stage	Treatment	Lines	FU, mo	Outcome
1	M	53	Liver	HCC	I	TACE + segmentectomy + IO/TT	2	36	Dead
2	M	76	Lung	SCC	IIIC	RT + CT	3	30	Dead
3	F	65	Cervix	ADC	IVB	RT + CT + IO	3	50	Dead
4	M	68	Abd cavity	PD-ADC	IV	Surgery + RT + CT	2	51	Dead
5	M	70	Lung	ADC	IB	Surgery + TT	1	55	Alive
6	F	47	Pelvis	FL transformed to HGBCL	IV	Surgery + DA-R-EPOCH + ASCT	1	45	Alive

Abbreviations: ADC Adenocarcinoma, ASCT Autologous stem cell transplantation, CT Chemotherapy, DA-R-EPOCH Dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, FL Follicular lymphoma, FU Follow-up, HCC Hepatocellular carcinoma, HGBCL High-grade B-cell lymphoma, IO Immunotherapy, PD-ADC Poorly differentiated adenocarcinoma, RT Radiotherapy, SCC Squamous cell carcinoma, SIT Situs inversus totalis, TACE Transarterial chemoembolization, TT targeted therapy

Table 2.

Detailed cohort summary statistics

Variable	Value
n	6
Sex, M/F	4/2
Age, median (range), y	66.5 (47–76)
Follow-up, median (range), mo	47.5 (30–55)
Stage I/IB, n (%)	2 (33.3)
Stage IIIC/IV/IVB, n (%)	4 (66.7)
Deaths during follow-up, n (%)	4 (66.7)
Alive at last contact, n (%)	2 (33.3)

Disease stage was assigned according to tumor-specific staging systems

Anatomy-sensitive resection and postoperative surveillance in patients with SIT

Two surgically treated cases further illustrated how SIT modified the anatomical delivery of standard oncologic care without changing the underlying tumor-specific treatment principles. The first was a patient with lung ADC who underwent thoracoscopic wedge resection, and the second was a patient with HCC who underwent laparoscopic segmental liver resection. In the lung ADC case, preoperative imaging demonstrated complete visceral transposition with dextrocardia and mirror-image thoracic anatomy. The morphologic left lung was located in the anatomic right hemithorax. A 19 mm × 16 mm nodule was identified in the inferior lingular segment of the left upper lobe. The lesion showed lobulation, irregular margins, and pleural traction, and was radiologically suspicious for malignancy. The preoperative CT images localized the lesion within the reversed thoracic coordinate system, supporting thoracoscopic wedge resection of the left upper lobe. At 3 months after surgery, follow-up CT showed expected postoperative changes in the left lung located in the anatomic right hemithorax, including linear and patchy parenchymal opacities at the operative site. No definite evidence of local recurrence was identified (Fig. 2A). In the HCC case, preoperative contrast-enhanced abdominal CT confirmed dextrocardia and complete visceral transposition. A large exophytic hepatic mass measuring approximately 9.6 cm × 8.6 cm × 7.9 cm was identified in hepatic segments 2 and 3. The lesion had a clear capsule, heterogeneous attenuation, partial fatty components, and arterial-phase enhancement of solid components, and compressed the splenic flexure of the colon. These imaging features were consistent with a malignant hepatic tumor. Because of SIT, preoperative interpretation required careful recognition of mirror-image liver position, hepatic segmental localization, and tumor-vessel relationships. At 3 months after laparoscopic segmental liver resection, follow-up contrast-enhanced CT showed expected postoperative changes in the left liver located in the anatomic right upper abdomen, with preserved remnant liver volume and no definite evidence of intrahepatic recurrence, abdominal metastasis, biliary dilatation, ascites, or enlarged hilar or retroperitoneal lymph nodes (Fig. 2B). Together, these two cases demonstrate that standard oncologic surgery was feasible in patients with SIT when guided by explicit anatomical verification. In both thoracic and hepatobiliary settings, the principal challenge was not deviation from established oncologic indications, but accurate translation of those indications into a reversed anatomical environment.

Fig. 2.

Anatomy-sensitive resection and postoperative surveillance in patients with situs inversus totalis (SIT). A Preoperative and 3-month postoperative CT images of thoracoscopic wedge resection for lung cancer in a patient with situs inversus totalis (SIT). Preoperative imaging demonstrated dextrocardia and complete thoracoabdominal transposition, with the morphologic left lung located in the anatomic right hemithorax. A 19 mm × 16 mm irregular nodule with lobulation and pleural traction was identified in the inferior lingular segment of the left upper lobe and was considered radiologically suspicious for malignancy. Three-month postoperative CT showed expected postsurgical linear and patchy changes at the operative site, without definite evidence of local recurrence. B Preoperative and 3-month postoperative contrast-enhanced CT images of laparoscopic segmental liver resection for hepatocellular carcinoma in a patient with SIT. Preoperative imaging showed a large exophytic hepatic mass in segments 2 and 3, measuring approximately 9.6 cm × 8.6 cm × 7.9 cm, with a capsule, heterogeneous attenuation, partial fatty components, and arterial-phase enhancement. Three-month postoperative imaging demonstrated expected resection-related changes in the left liver located in the anatomic right upper abdomen, with preserved remnant liver volume and no definite evidence of recurrence or metastasis

Treatment delivery and anatomy-sensitive planning

Standard tumor-directed treatment was deliverable across the cohort, including surgery, RT, CT, IO, TT, TACE, and ASCT. Treatment trajectories and follow-up status are shown in Fig. 3. The patient with HCC received TACE, segmentectomy, and subsequent IO/TT; the patient with stage IIIC lung SCC received RT and CT; the patient with stage IVB cervical ADC received RT, CT, and IO; the patient with PD-ADC of the abdominal cavity received surgery, RT, and CT; the patient with stage IB lung ADC underwent thoracoscopic resection followed by TT; and the patient with transformed FL/HGBCL received DA-R-EPOCH followed by ASCT. Anatomy-sensitive planning was most relevant in cases requiring resection, vascular mapping, or nodal assessment. In the HCC case, treatment planning incorporated review of mirror-image hepatic anatomy, including tumor-bearing segmental localization, arterial supply relevant to TACE, portal venous inflow, hepatic venous drainage, and the relationship between the lesion and major vascular structures. In the lung cancer cases, laterality confirmation and thoracic anatomical orientation were incorporated into lesion interpretation, thoracoscopic or radiation planning, and mediastinal or hilar nodal assessment. For cases requiring nodal evaluation, nodal stations or regional nodal basins were documented according to standard tumor-specific classification systems after explicit confirmation of mirror-image laterality on imaging. In thoracic malignancy, mediastinal and hilar nodal status was interpreted within the standard lung cancer staging framework, with left-right orientation verified against the reversed thoracic anatomy. In pelvic and abdominal malignancies, nodal localization was documented according to standard regional drainage basins, with laterality assigned relative to the patient’s actual mirrored anatomy rather than assumed conventional organ position.

Fig. 3.

Treatment trajectories and follow-up status of patients with situs inversus totalis and malignancy. Swimmer plot showing individual treatment courses, response milestones, and follow-up status for the 6 patients with situs inversus totalis (SIT) and histologically confirmed malignancy. Each horizontal bar represents 1 patient, and the x axis indicates months since pathological diagnosis. Bar colors denote disease stage at diagnosis: stage I, stage III, and stage IV. Symbols indicate clinically documented response or status events, including complete response, partial response, end of response, durable remission, and ongoing treatment or follow-up. The plot illustrates the heterogeneity of tumor stage, treatment duration, and clinical course across the cohort, while showing that tumor-directed treatment was deliverable in patients with mirror-image anatomy

Descriptive survival visualization and mirror-image anatomical impact

A KM curve was generated only as a descriptive visualization of observed OS and censoring patterns in this small heterogeneous cohort (Fig. 4). No statistical comparison, hypothesis testing, or survival inference was performed. The pooled median OS was 50 months; however, given the limited sample size and the marked heterogeneity of tumor type, stage, treatment, and expected disease course, this value should not be interpreted as a prognostic estimate, clinical benchmark, or SIT-specific survival baseline. During follow-up, 4 patients died and 2 remained alive at last contact. Overall, clinical outcomes were broadly aligned with tumor-specific disease stage and biological behavior rather than with a shared SIT-related oncologic pattern. The recurring impact of SIT was anatomical rather than biological, involving lesion localization, laterality recognition, imaging interpretation, nodal or vascular mapping, procedural orientation, and treatment planning. These considerations were most clinically relevant in thoracic and hepatobiliary malignancies, where bronchovascular orientation, mediastinal nodal-station assignment, hepatic segmental localization, and vascular inflow or outflow assessment were central to safe treatment delivery.

Fig. 4.

Descriptive survival visualization and mirror-image anatomical impact. Kaplan–Meier curve showing observed overall survival and censoring patterns in the final cohort of 6 patients with situs inversus totalis (SIT) and histologically confirmed malignancies. Time was calculated from the date of pathological diagnosis to death from any cause or last documented follow-up. Tick marks indicate censored observations. The dashed horizontal and vertical lines indicate the mathematically derived median overall survival of 50 months

Representative case 1: transformed follicular lymphoma

A 47-year-old woman presented with abdominal pain and distension in July 2021. Initial imaging demonstrated SIT, with dextrocardia and complete mirror-image transposition of the thoracoabdominal viscera (Fig. 5A). Coronal CT further confirmed the reversed thoracoabdominal anatomy and provided an overview of the mirrored visceral arrangement (Fig. 5B). Axial abdominal CT showed reversed upper abdominal organ orientation (Fig. 5C) and abdominal lymph-node involvement, with the representative enlarged nodal lesion indicated by the red arrow (Fig. 5D). Surgical resection of the pelvic-abdominal lesion was performed. Intraoperative frozen-section analysis suggested HGBCL involving the right adnexal region. Definitive histopathological examination demonstrated FL with focal marginal-zone differentiation, predominantly grade 1–2 with a minor grade 3 A component. Representative hematoxylin and eosin (H&E)-stained sections showed diffuse lymphoid tumor infiltration at low magnification (Fig. 5E) and corresponding tumor morphology at higher magnification (Fig. 5F). Tumor cells were positive for CD20, CD10, BCL2, and BCL6, and the Ki-67 proliferation index ranged from 15% to 60%. Fluorescence in situ hybridization identified C-MYC and BCL2 rearrangements. Subsequent ¹⁸F-FDG PET/CT demonstrated hypermetabolic lymphadenopathy and splenomegaly, and bone marrow biopsy confirmed marrow involvement. Nodal disease was interpreted according to standard lymphoma staging principles, with anatomical localization verified in the context of mirror-image anatomy. The final diagnosis was FL transformed to HGBCL, Ann Arbor stage IV. The patient received 6 cycles of DA-R-EPOCH, and interim PET/CT after 4 cycles demonstrated complete metabolic response with a Deauville score of 2. She subsequently underwent ASCT after BEAM conditioning and remained recurrence-free at last follow-up.

Fig. 5.

Representative imaging and histopathological findings in the patient with follicular lymphoma transformed to high-grade B-cell lymphoma. A Whole-body scout image showing dextrocardia and complete mirror-image visceral arrangement in a patient with situs inversus totalis (SIT). B Coronal computed tomography (CT) confirming reversed thoracoabdominal anatomy. C Axial abdominal CT showing mirror-image upper abdominal organ orientation. D Axial CT showing abdominal lymph-node involvement, with the representative lesion indicated by the red arrow. E, F Representative hematoxylin and eosin-stained sections of the resected pelvic-abdominal lesion, showing diffuse lymphoid tumor infiltration at low magnification (original magnification, 40×) (E) and corresponding tumor morphology at higher magnification (original magnification, 100×) (F). Green scale bars are shown in the histopathological panels

Representative case 2: EGFR-mutant lung adenocarcinoma

A 70-year-old man was incidentally found to have a pulmonary nodule during routine evaluation. Whole-body ¹⁸F-FDG PET demonstrated focal thoracic radiotracer uptake without evidence of widespread distant disease (Fig. 6A). Fused axial PET/CT localized the hypermetabolic lesion to the morphologic left upper lobe, which was located in the anatomic right hemithorax because of SIT, with the lesion indicated by the red arrow (Fig. 6B). Axial PET confirmed focal metabolic activity in the same pulmonary lesion, with a maximum standardized uptake value of 6.1, supporting a radiological suspicion of primary lung malignancy (Fig. 6C). Before surgery, lesion laterality, bronchovascular orientation, hilar anatomy, and the reversed thoracic coordinate system were explicitly reviewed. The patient subsequently underwent thoracoscopic wedge resection of the left upper lobe with pleural adhesion lysis. Histopathological examination demonstrated invasive lung ADC with mixed acinar and papillary architecture (Fig. 6D) and visceral pleural invasion (Fig. 6E). Resection margins were negative. Immunohistochemistry showed TTF-1 positivity and P40 negativity, and molecular analysis identified an EGFR L858R mutation. The final pathological stage was pT2N0M0. Mediastinal and hilar nodal status was interpreted within the standard lung cancer staging framework after confirmation of mirror-image thoracic anatomy. Postoperative almonertinib was administered, and the patient remained recurrence-free at last follow-up.

Fig. 6.

Representative PET/CT and histopathological findings in the patient with EGFR-mutant lung adenocarcinoma. A Whole-body ¹⁸F-FDG PET showing focal thoracic radiotracer uptake. B Fused axial PET/CT localizing the hypermetabolic pulmonary lesion to the morphologic left upper lobe, located in the anatomic right hemithorax in the setting of situs inversus totalis(SIT); the lesion is indicated by the red arrow. C Axial PET confirming focal metabolic activity in the corresponding pulmonary lesion. D, E Representative hematoxylin and eosin-stained sections of the resected lesion, showing invasive lung adenocarcinoma with mixed acinar and papillary architecture (D) and visceral pleural invasion (E). Green scale bars are shown in the histopathological panels; original magnification is 100× for both (D) and (E)

Discussion

The principal contribution of this study is not the estimation of prognosis in a rare cohort, but the reframing of SIT as an anatomical modifier of cancer care. In this retrospective cohort, malignancies occurring in patients with SIT were clinically and biologically heterogeneous, spanning thoracic, hepatobiliary, gynecologic, abdominal, and hematologic tumors. Their presentation, treatment selection, and follow-up status were mainly determined by tumor type, stage, molecular features, and disease-specific treatment principles. In contrast, the recurring influence of SIT was anatomical: mirror-image visceral arrangement affected lesion localization, laterality recognition, imaging interpretation, nodal or vascular mapping, procedural orientation, and treatment planning.

This distinction is important when interpreting malignancy in the setting of SIT. The coexistence of SIT and cancer should not be taken as evidence of causality or as proof that SIT represents a cancer-predisposition syndrome [37]. Patients with SIT may develop common malignancies for the same age-related, environmental, viral, genetic, molecular, or stochastic reasons as patients with conventional anatomy [38]. Thus, in this article, malignancy in SIT is used as a descriptive term to denote cancer occurring in a patient with SIT, rather than implying that SIT directly promotes malignant transformation. This cautious interpretation is consistent with the current evidence base, which remains dominated by case reports, small case series, and literature reviews rather than population-level or mechanistic studies.

The available literature supports this practical framing. As summarized in Table 3, reported malignancies in patients with SIT include lung cancer [15, 39, 40], HCC [20, 41], gastric cancer [38], colorectal cancer [42, 43], pancreatic cancer [44], gallbladder carcinoma [45], renal cell carcinoma [46], gynecologic cancer [25], lymphoma [26], and other mixed tumor contexts [47, 48]. Across these reports, the consistent theme is not a reproducible SIT-specific tumor phenotype or survival pattern, but the need to adapt the anatomical execution of otherwise standard oncologic care [48]. Thoracic reports emphasize reversed hilar anatomy, bronchovascular branching, mediastinal nodal stations, and operative orientation [15]; HCC reports emphasize mirror-image liver position, hepatic segmental anatomy, portal venous inflow, hepatic arterial supply, and liver-directed therapy [41]; and gastrointestinal, pancreatic, urologic, and gynecologic reports similarly highlight vascular variants, lymphadenectomy, port placement, and laterality verification. The present cohort extends this case-based literature by integrating multiple tumor types within a single institutional experience and by proposing a unified clinical framework: SIT modifies how cancer care is delivered anatomically, rather than defining a separate oncologic disease category [48].

Table 3.

Representative literature on malignancy in situs inversus totalis (SIT) and comparison with the present cohort

Reference	Tumor context	Evidence base	Treatment focus	SIT-specific issue	Main outcome
Wojcik et al., 2013 [15]	Lung cancer	Review of 21 SIT-lung cancer cases	Staging, surgery, systemic/local therapy	Reversed thoracic, hilar, and mediastinal anatomy	Lung cancer management is feasible but anatomy-sensitive; no SIT-specific survival baseline can be inferred.
Celik et al., 2021 [39]; Wojcik et al., 2023 [40]	Resectable NSCLC	Modern thoracic surgical cases	VATS lobectomy/segmentectomy with nodal dissection	Mirror-image bronchovascular branching and nodal stations	Supports meticulous laterality confirmation and nodal-station assignment before anatomical resection.
Li et al., 2022 [41]; Patel et al., 2012 [20]	Hepatocellular carcinoma	Nine-case series plus literature review; additional case review	TACE, hepatectomy, radiotherapy, multimodal therapy	Mirror-image liver, segmental anatomy, portal/hepatic arterial mapping	Directly supports careful anatomical planning for HCC resection or transarterial therapy in SIT.
Sun et al., 2023 [38]	Gastric adenocarcinoma	Review of 47 articles / 49 SIT-gastric cancer patients	Gastrectomy, laparoscopic/robotic surgery, D2 lymphadenectomy	Reversed upper abdominal anatomy and vascular variants	Curative oncologic surgery is feasible with preoperative imaging and vascular mapping.
Chen et al., 202042]; Su et al., 2025 [43]	Colorectal cancer	Case reports with literature review	Laparoscopic radical colorectal resection	Reversed colonic position, mesenteric vessels, and port orientation	SIT mainly changes technical execution and spatial orientation rather than tumor biology.
Maruyama et al., 2010 [44]	Pancreatic cancer	Two SIT-pancreatic cancer cases	Pancreaticoduodenectomy / distal pancreatectomy with lymphadenectomy	Transposed pancreas and major vessels	Complex pancreatic surgery is feasible when MDCT, 3D reconstruction, and angiography define anatomy.
Zhang et al., 2022 [45]	Gallbladder carcinoma	Rare SIT case with hepatic artery variation	Imaging-based surgical planning	Mirror anatomy plus common hepatic artery variation	Highlights the need to identify vascular variants before hepatobiliary oncologic surgery.
Oake and Drachenberg, 2017 [46]	Renal cell carcinoma	Case report and review identifying 9 RCC cases in situs inversus	Nephrectomy / kidney-directed surgery	Reversed renal position and renal hilar vasculature	Safe urologic oncology surgery requires explicit preoperative recognition of mirror-image anatomy.
Ustunyurt and Cift, 2014 [25]	Endometrial cancer	Case report of staging surgery in SIT	Hysterectomy, salpingo-oophorectomy, lymphadenectomy	Reversed pelvic and para-aortic nodal orientation	Supports explicit laterality verification during gynecologic nodal staging.
Murakami et al., 2003 [26]; Tanwar et al., 2019 [47]	Hematologic and mixed malignancies	Case reports including gastric lymphoma and mixed cancers	Disease-specific systemic/local therapy	Staging and localization require mirror-anatomy awareness	Consistent with the present lymphoma case: treatment course appears disease-specific, while SIT affects localization.
Valenzuela-Fuenzalida et al., 2024 [48]	Abdominopelvic cancers in SIT	Systematic review addressing cancer types in SIT	Descriptive literature synthesis	Rare co-occurrence versus causality	Supports cautious wording: current evidence does not establish SIT as a cancer-predisposition syndrome.
Present cohort	Mixed malignancies	Retrospective single-center cohort: 6 malignancies among 11 SIT patients	Surgery, RT, CT, IO, TT, TACE, ASCT	Lesion localization, laterality recognition, imaging interpretation, nodal/vascular mapping	Extends prior case-based literature by framing SIT as an anatomical modifier of oncologic care.

Abbreviations: ADC Adenocarcinoma, ASCT Autologous stem cell transplantation, CT Chemotherapy, FL Follicular lymphoma, HCC Hepatocellular carcinoma, HGBCL High-grade B-cell lymphoma, IO Immunotherapy, MDCT Multidetector computed tomography, NSCLC Non-small-cell lung cancer, RCC Renal cell carcinoma, RT Radiotherapy, SIT Stus inversus totalis, TACE Transarterial chemoembolization, TT Targeted therapy, VATS video-assisted thoracoscopic surgery

In the EGFR-mutant lung adenocarcinoma case, preoperative imaging localized a suspicious lesion in the morphologic left upper lobe, which was positioned in the anatomic right hemithorax because of SIT. Thoracoscopic wedge resection was feasible after explicit confirmation of lesion laterality, bronchovascular orientation, hilar anatomy, and operative geometry, and postoperative surveillance showed expected local surgical changes without definite recurrence. In the HCC case, enhanced CT demonstrated a large exophytic tumor in hepatic segments 2 and 3, but interpretation required recognition of the mirrored hepatic position and segmental orientation. Liver-directed treatment, including TACE and segmentectomy, was delivered within this reversed anatomical coordinate system, and early postoperative imaging showed preserved remnant liver volume without definite recurrence or metastasis. These cases show that SIT does not necessarily alter the oncologic indication for treatment, but it changes the anatomical pathway through which treatment must be safely implemented [41, 49].

The lymphoma case provides a complementary perspective. In contrast to lung cancer and HCC, where resection, vascular mapping, and anatomical orientation were central, the transformed FL/HGBCL case was driven primarily by disease biology, immunophenotype, cytogenetics, PET/CT-based staging, and systemic treatment response [40, 50]. The patient achieved complete metabolic response after DA-R-EPOCH and remained recurrence-free after ASCT. This observation supports the broader conclusion that SIT does not impose a shared biological behavior across malignancies. Instead, its clinical relevance depends on how strongly a given tumor type relies on spatial localization, operative planning, vascular mapping, nodal assignment, or radiation-field design [51].

SIT does not alter the core disease-specific principles of oncology, including staging, indication selection, margin control, lymph-node evaluation, systemic therapy, radiotherapy, targeted therapy, or response assessment [52]. Rather, it alters the anatomical execution of these principles [51]. Standard tumor-specific guidelines remain applicable, but they must be implemented through the patient’s actual anatomy [52]. Imaging should be reviewed with deliberate attention to reversed laterality; vascular territories and organ segments should be mapped according to the true anatomical configuration; operative access and port placement should account for mirror-image orientation; interventional routes should be planned according to actual vascular geometry; and radiation fields should be designed without assuming conventional organ position [51]. In practical terms, SIT should not prompt deviation from guideline-concordant oncology, but should trigger a higher standard of anatomical verification and multidisciplinary planning.

Nodal assessment is an especially important example. When nodal evaluation is required, nodal stations or regional nodal basins should be interpreted using standard tumor-specific systems only after explicit confirmation of mirror-image laterality on imaging [53]. For thoracic malignancy, mediastinal and hilar nodal status should be assessed within the conventional lung cancer staging framework while recognizing that right-left thoracic orientation is reversed [53]. For abdominal and pelvic malignancies, regional nodal basins should be documented relative to the patient’s actual mirrored organ position and expected lymphatic drainage rather than assumed conventional anatomy [25]. This approach preserves standard oncologic staging while reducing the risk of laterality-related misclassification.

The biological relationship between laterality disorders and malignancy remains unresolved [48]. Left-right patterning is governed by embryologic, ciliary, and molecular programs, and SIT may occur in association with motile-cilia disorders such as primary ciliary dyskinesia or Kartagener syndrome [54]. In theory, ciliary dysfunction, impaired mucociliary clearance, chronic inflammation, or altered developmental signaling could influence cancer risk in selected contexts [55]. However, these mechanisms remain biologically plausible but clinically unproven. Current evidence does not show that SIT itself produces a consistent malignant phenotype, tumor spectrum, treatment-response pattern, or prognosis [48]. In this cohort, disease behavior was more consistent with tumor-specific biology, stage, and molecular features than with a shared SIT-driven oncologic pattern.

The survival findings must therefore be interpreted with particular caution. The KM curve was retained only as a descriptive visualization of observed follow-up and censoring patterns. The pooled median OS should not be interpreted as a prognostic estimate, clinically actionable benchmark, or SIT-specific survival baseline. This limitation is fundamental because the cohort included only 6 patients and combined biologically distinct solid and hematologic malignancies with different stages, treatments, and natural histories. No direct comparison with patients without SIT was performed, and no survival inference can be drawn from these data.

This study has several strengths. It reports a real-world institutional cohort of patients with radiologically confirmed SIT and histologically confirmed malignancy; provides patient-level clinical, treatment, imaging, pathological, molecular, and follow-up information across multiple tumor types; incorporates perioperative imaging and imaging-pathology correlation; and integrates cohort observations with a literature-based comparison. Together, these elements support a practical framework for rare-anatomy oncology: cancer in patients with SIT should be treated according to its biology and stage, but delivered according to the patient’s actual anatomy.

Several limitations should be acknowledged. This was a retrospective single-center study with a necessarily small sample size, reflecting the rarity of SIT with histologically confirmed malignancy. The included cancers were highly heterogeneous, precluding tumor-specific inference and making pooled survival estimates clinically uninformative. The study did not include a control group without SIT and was not designed to test whether SIT alters cancer incidence, tumor biology, treatment response, or prognosis. In addition, the available literature summarized in this study remains largely case-based and may be subject to publication bias, as surgically complex or anatomically unusual cases are more likely to be reported.

Future studies should address these limitations through multicenter prospective registries or collaborative rare-anatomy oncology databases. Such studies should systematically record SIT subtype, associated ciliary or laterality disorders, tumor type, stage, molecular profile, imaging features, vascular anatomy, nodal-station assignment, operative or interventional modifications, radiation-planning considerations, treatment complications, and long-term outcomes. Until such evidence is available, the most defensible clinical approach is to apply standard tumor-specific principles while enforcing rigorous anatomical verification at every step of diagnosis, staging, and treatment delivery.

Conclusions

In conclusion, the oncologic significance of SIT lies primarily in anatomy rather than in demonstrably altered tumor biology. Malignancies in patients with SIT appear to follow tumor-specific clinical patterns, whereas the dominant challenge is the safe and accurate delivery of cancer care within a reversed visceral landscape. SIT should therefore be recognized as an anatomical modifier of oncologic care: standard principles should be preserved, but treatment must be planned and delivered according to the patient’s actual anatomy (Fig. 7).

Fig. 7.

Graphical abstract summarizing malignancy in patients with situs inversus totalis and the role of mirror-image anatomy in oncologic care. (1) Eleven patients with SIT were screened, and 6 patients with histologically confirmed malignancy were included. (2) The cohort had a median age of 66.5 years and a median follow-up of 47.5 months; 4 patients died and 2 were alive at last contact. (3) The tumor spectrum included lung cancer, HCC, cervical cancer, abdominal ADC, and lymphoma within the setting of complete visceral mirror-image transposition. (4) Two surgically treated cases, lung ADC and HCC, illustrate anatomy-sensitive resection in mirror-image thoracoabdominal anatomy. (5) SIT-related planning focused on lesion mapping, laterality verification, nodal and vascular mapping, procedure planning, and imaging surveillance. (6) Standard tumor-directed treatment remained deliverable, including surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy. SIT therefore modifies the anatomical delivery of oncologic care rather than defining a distinct cancer phenotype

Abbreviations

ADC

Adenocarcinoma

AJCC

American Joint Committee on Cancer

ASCT

Autologous stem cell transplantation

BEAM

Carmustine, etoposide, cytarabine, and melphalan

CT

Computed tomography

DA-R-EPOCH

Dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin

EGFR

Epidermal growth factor receptor

FIGO

International Federation of Gynecology and Obstetrics

FL

Follicular lymphoma

FU

Follow-up

H&E

Hematoxylin and eosin

HCC

Hepatocellular carcinoma

HGBCL

High-grade B-cell lymphoma

IO

Immunotherapy

KM

Kaplan-Meier

MDCT

Multidetector computed tomography

NSCLC

Non-small-cell lung cancer

OS

Overall survival

PD-ADC

Poorly differentiated adenocarcinoma

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

RCC

Renal cell carcinoma

RT

Radiotherapy

SCC

Squamous cell carcinoma

SIT

Situs inversus totalis

STROBE

Strengthening the Reporting of Observational Studies in Epidemiology

TACE

Transarterial chemoembolization

TT

Targeted therapy

VATS

Video-assisted thoracoscopic surgery

Authors’ contributions

ZL, GW, and KH contributed equally to this work. SZ and GX conceived and supervised the study. ZL, GW, KH, YW, TiZ, JiC, YX, QT, BY, JaC, XY, and SZ collected and curated the clinical data. SZ performed the statistical analyses and prepared and refined the figures. ZL, GW, KH, and YW drafted the manuscript. SZ reviewed the full manuscript, and SZ and GX critically revised it for important intellectual content. All authors read and approved the final manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81402197, 81600482, and 82570789), the Natural Science Foundation of Hubei Province (Nos. 2019CFB501, 2020CFB600, and 2024 AFB663), the China Postdoctoral Science Foundation (Nos. 2018M632875 and 2019T120671), and the China Scholarship Council (CSC) (No. 202306160006).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The requirement for written informed consent was waived because of the retrospective design and use of de-identified data.

Consent for publication

All authors have read and approved the final version of the manuscript and consent to its publication. Furthermore, the authors confirm that they have obtained all necessary permissions for the publication of any third-party material included in the manuscript. The research and its findings are original, and the authors provide their consent for the publication of the manuscript in its current form.

Competing interests

The authors declare no competing interests.