Metastatic Hepatocellular Carcinoma To The Nasal Cavity And Sinus: A Potential Diagnostic Challenge And The Detection Of Programmed Death Ligand-1 Expression

DOI: https://doi.org/10.21203/rs.3.rs-1807397/v1

Abstract

Purpose

Hepatocellular carcinoma that metastasizes to the sinonasal cavity is very rare. So far, there are limited reports related to this kind of rare condition within the literature. We are committed to concluding the clinicopathological characteristics and prognosis of these special patients.

Materials and methods

we retrospectively analyzed 12 patients suffered from nasal metastatic hepatocellular carcinoma from 2010 to 2021 at Fudan University Eye Ear Nose and Throat Hospital(FDUEENT). The clinical characteristics ,pathological morphology and immunohistochemistry, follow-up induration and prognosis analysis of these patients were investigated.

Results

There were 11 males and 1 female included in our study. And the metastatic sites mainly include nasal cavity, nasopharynx, sphenoid sinus and maxillary sinus. In the light microscope, the tumor cells mainly showed diffuse distribution around obvious blood vessels. Immunohistochemical analysis showed that at least one of the specific epithelial markers (hepatocyte paraffin-1, alpha-fetoprotein, glypican-3, arginase-1) was expressed in tumor cells. And the expression of programmed death ligand-1 was detected in one case which might provide a potent therapeutic target. The available follow-up information of six cases indicated that sinonasal metastases usually arise several years after developing liver cancer. However, their survival time since developing sinonasal metastasis was less than 9 months.

Conclusions

In summary, hepatocellular metastasis to sinonasal cavity remains very rare and the outcome of such patients was dismal. However, the definite early diagnosis coupled with aggressive treatment might play an important role in improving prognosis.

Introduction

The sinonasal tract can be involved extensive neoplasia, with morphological diversity equivalent to what can be seen throughout most parts of the body. And squamous cell carcinoma is the most common malignance, followed by undifferentiated carcinoma(1). The sinonasal secondary tumor is very scarce and renal cell carcinoma accounts for the majority of secondary sinonasal cancers(2).

Liver cancer, which mainly includes hepatocellular carcinoma(HCC, comprising 75%-85% cases), has ranked as the sixth most frequently diagnosed cancer and the fourth major cause of cancer death worldwide in 2018(3). Indeed, the prognosis of advanced HCC patients remains poor with 5-year survival rate of 18% and the occurrence of metastasis was leading lethal cause (4) (5).

The most frequent extrahepatic metastases from primary hepatocellular carcinoma was lungs, followed by lymph nodes, bones, and adrenal glands(6). Metastasis of hepatocellular carcinoma to the nasal cavity is extremely rare. We report a series of 12 cases of hepatocellular carcinoma metastasized to nasal cavity. Although metastasis spread to nasal cavity is infrequent, it was a question which deserved serious consideration in the differential diagnosis of nasal tumors. As fall as we know, this is the largest series of cases presenting such a mode of metastasis. Finally, we make the differential diagnosis of primary nasal carcinomas with the emphasis on the adjuvant immunohistochemical staining.

Materials And Methods

The material consisted of 12 cases which came from the pathology archives of Fudan University Eye Ear Nose and Throat Hospital(FDUEENT). Data was extract regarding demographics, laboratory results, time course of disease and metastasis, and the cancer treatment. In pathology, paraffin blocks and slides were available for histological and immunohistochemical analysis. Immunohistochemistry staining was performed using 4-um-thick whole slide sections. Descriptive statistical method was used to summarize the FDUEENT cohort. Overall survival (OS) was calculated by Kaplan-Meier methods.

Results

Clinical data

The group of patients included 11 males and 1 female(Table 1). Their age ranged from 44 to 70 years ,with a median age of 61 years. The nasal carcinoma was the first manifestation of liver cancer only in one case who has a ten year history of chronic hepatitis and liver cirrhosis. Metastatic sites were inconsistent, such as pharyngeal recess, sphenoid sinus, nasopharynx, nasal septum, skull base, maxillary sinus were observed in our study.

Table 1

the clinical pathological characteristics of the patients and tumors

Characteristics

Case number (n = 12)

Age

44–70(mean : 58.3 ± 9.2)

Sex

 

Male

11

Female

1

symptoms

 

Headache

2

Facial numbness

2

Epistaxis

3

Sinonasal metastatic sites

 

Nasopharynx

2

Nasal subcutaneous

1

Nasal cavity

7

Paranasal sinus

 

Sphenoid sinus

1

Maxillary sinus

1

Nasal CT and MRI scans provided some hints about the malignant nature of the lesion, such as bone erosion and remodeling. Nasal endoscopy conduces to the diagnosis of abnormal nasal mucosa in relative position(Fig. 1).

Histopathological features

Nasal lesions were usually small specimens by endoscopic biopsy. These tumors revealed diffused arrangement or constituted a single round nodule with nested or tubular structure (Fig. 2 ). In the light microscope, the tumor cells mainly showed diffused distribution (7/12) around obvious blood vessels. And the tumor cells were round to oval in shape with lightly eosinophilic cytoplasm, oval nuclei and small distinct nucleoli. Cell membrane were not always clear(7/12), while cellular atypia obvious, mitotic figures visible. Tumor necrosis was observed in 3/12 cases. Microscopically, the boundary between tumor and surrounding soft tissue was district(7/12) and peripheral lymphocytes infiltration was observed in only one case.

Immunohistochemical analysis showed that at least one epithelial markers expressed in tumor cells and the expression of CK is lower than the normal epithelioid cells of nasopharyngeal tissue(Fig. 3). In 11 out of 12 cases, the origin of tumors was confirmed by at least 4 antibodies: hepatocyte paraffin-1(HepPar-1), a-Fetoprotein (AFP), glypican-3(GPC-3), Arginase-1(Arg-1). And HepPar-1 was positive in 8 cases while GPC-3 in 6 cases, AFP in one case, Arg-1 in one case. In addition, the vascular structure were clearly delineated by antibody CD34. High molecular weight keratin such as P63 and P40 was negatively expressed in tumor cells, as well as mesenchymal markers like vimentin. PD-L1 expression with TPS ≥ 1% was detected in 1(8.3%) of these cases, as the same results as the CPS.

Prognostic features

The information of primary carcinoma was almost not available except for 6 cases. We find time from primary HCC to secondary sinonasal cancers ranged from one half a year to eight years (Fig. 4.A). Median time about HCC metastasis to the nasal tract was 5.25 years and the average time was 6.00 years. And two of these patients received radiofrequency ablation and intervention therapies because of the specious location of the primary hepatocellular carcinoma, which makes surgical excision difficult. And the overall survival (OS) for these HCC patients was from 10 months to 105 months with the average time was 65.5 months. However, the survival time after nasal metastasis ranged from one month to nine months(Fig. 4.B) with the average time 4.5 months.

Discussion

The nasal cavity and sinus involvement by dissemination of hepatic malignancy is rare. In the literature, renal cell carcinoma(RCC) is the most common metastatic malignance of the sinonasal tract(7). So far studies evaluating metastatic hepatocellular carcinoma in the nose have been limited to case reports and small cohorts(811).However, accurate diagnosis in these cases is necessary, on count of the treatment of primary carcinoma of nasal-sinus differs from the cure of metastasis.

The symptoms of patients with nasal metastatic hepatocellular carcinoma were not specific, similar to that of primary sinonasal tumors. In our study, the most frequent symptom was epistaxis. It is consistent with the fact that HCC is usually vascular(12). And compared to tumors in paranasal sinus, nasal masses were more likely to cause bleeding. Numbness and pain in face and nose were common symptoms, it could be the result of the pressure on the nerve from tumor.

The histological diagnosis of primary and secondary sinonasal carcinomas can be challenging. Metastatic HCC to the sinonasal cavity must be distinguished from other tumors such as poorly differentiated squamous cell carcinoma, the non-intestinal type sinonasal adenocarcinoma, neuroendocrine neoplasm, acinic cell carcinoma and metastatic tumors such as lung adenocarcinoma, pancreatic islet cell tumor, and poorly differentiated adenocarcinoma from esophagus, stomach, and pancreas. Morphologically, sinonasal metastases tend to spare the submucosa, instead preferring to develop in the mucosa. Indispensably, immunohistochemical staining is required to establish the eventual diagnosis. Use of stains is especially vital in differentiating between primary sinonasal malignancies and metastatic carcinoma to the nasal cavity and sinus, as there exists significant histopathologic overlap between these entities. P63 and P40 stains positively in almost primary sinonasal squamous cell carcinoma which is the most common form in nasal cavity and paranasal tissues(13). The immune phenotype of the non-intestinal type sinonasal adenocarcinoma is characterized by positivity for cytokeratin 7(14). Positive DOG-1 staining would support primary acinic cell carcinoma(15). Neuroendocrine neoplasm always showed phenotypical expression of neuroendocrine markers such as CD56, synaptophysin and chromogranin(16). In addition, cytokeratin 7 almost negative in metastatic hepatocellular cells, which is different from other adenocarcinoma cells. Above all, it is important to acquire medical history in diagnosis of non-primary tumors. Necessarily, the detection of four biomarkers, hepPar-1, AFP, GPC3 and Arg-1, plays an vital part in diagnosis of metastatic hepatocellular carcinoma. Among these, HepPar-1 was the most sensitive marker with the positive rate as 75.00%(9/12). And GPC-3 was positive in 50%(6/12) cases. However, AFP as well as Arg-1 was not sensitive enough and the positive rate in tumors was 8.33%(1/12). tumor cells expressed at least one of the four indexes. HepPar-1 was proved to be the most helpful biomarker, whereas the AFP expression is not helpful in the tumor cells. In our cohorts, either HepPar-1 or GPC-3 was expressed in all 12 cases. It is effective to applicate these two immunohistochemical indexes synthetically. The detection of immunohistochemical strains and history taking would be required to make eventual diagnosis.

Hepatocellular carcinoma is a leading cause of cancer-related morbidity and mortality and it accounts for the second most cancer deaths in the world(17). Men are more likely to develop HCC worldwide than woman (18). In the Literature, the majority of reported cases of HCC metastatic to the sinonasal area have been in men (11). Likewise, the majority patients in our study were males. There are multiple therapeutic methods for HCC, such as surgical resections or liver transplantation, ablative electrochemical therapies, chemoembolization, radioembolization and so on(19). Even so, prognosis of HCC is drastically different with multiple determinants(20). Surgical resection is a potentially curative option for patients at an early stage, with three and five-year survival rates of 72% and 50% respectively(21). In this study, the five-year survival rate was 75.00%(3/4) in these four follow-up patients. And five patients with related follow-up information all survive more than 3 years. However, patients with sinonasal metastasis had a dismal prognosis and they all died within one to nine months. Overall, the prognosis of patients with HCC with distant metastasis is poor, and the clinicopathologic characteristics and the survival of metastatic HCC varied according to various metastatic organs(22). Zhan et al. founded that lung metastasis has a worse prognosis than bone metastasis, and the average survival time of brain metastasis is shorter than bone or lung metastasis(23). Furthermore, the median survival of HCC with bone metastasis is only 1–2 months(24). On the other hand, there are different endings about virous extranasal cancers that metastasize to the sinonasal cavity. Chang’s study revealed patients who received surgical excision of nasal septal metastatic thyroid papillary carcinoma could have a good life(25). Overall survival rates are disappointing in our study may indicate that sinonasal metastasis of HCC is a factor for poor prognosis.

Recently ,the immune checkpoint inhibitors directed PD-1 (nivolumab and pembrolizumab) have provide novel treatment opportunities for patients with HCC(26). Related to the drug effect is the expression of PD-L1 on the tumor and its associated cells. And patients with tumor PD-L1\(\ge\)1% would get better treatment benefit than those PD-L1 < 1%(27). However, significant heterogeneity was founded in the tumor expression of PD-L1 across primary and secondary HCC samples(28). Juan et al. reported a case with positive membranous staining for PD-L1 in metastatic tumor cells and tumor infiltrating lymphocytes(29). In our study, we founded the positivity of PD-L1 in these metastatic tumors was 8.3%(1/12). Regretfully, the PD-L1 expression of the primary HCC samples status was unknown because HCC slides were not available from other hospitals. Nevertheless these findings indicated a potential immunotherapy opportunities for advanced patients. Recently, research shows PD-L1 positive patients with HCC were more likely to suffer from aggressive clinicopathologic features than PD-L1 negative patients(30). We are not able to obtain the same results as to the sinonasal metastases.

There are several limitations in our study. It is difficult to get complete data and verification because this is a retrospective study. Also, the limited number of cases for such a rare condition, may prevent meaningful statistical analysis.

Conclusions

The goal of this work was to describe clinicopathological characteristics of patients with HCC metastatic to nasal tract. And the 12 cases discussed here make this the largest published cohort of patients with sinonasal HCC metastases. Moving forward, it will be important to describe not only the clinical and pathological characteristics of the patients but also the indication of potential treatment for the both primary and the metastatic tumors .

Abbreviations

HepPar-1

hepatocyte paraffin-1

AFP

alpha-fetoprotein

Arg-1

arginase-1

GPC-3

glypican-3

HCC

hepatocellular carcinoma

PD-L1

programmed death ligand-1

Declarations

Ethics approval and consent to participate

Ethical approval and consent for this study was obtained from the Clinical Research Ethics Committee of Eye and ENT Hospital of Fudan University.

Consent for publication

Consent has been taken from the institution and the patients. All the authors have approved the publication of this manuscript.

Competing Interests

The authors declare that they have no competing interests.

Author contributions

Min Ye wrote the main manuscript text, Chunyan Hu collected data, Cuncun Yuan prepared figures 1-4,Changwen Zhai and Lan Lin conceived and designed the analysis. All authors reviewed the manuscript.

Funding

None.

Availability of data and materials

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

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