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Aims Methods and Results Conclusion The diagnosis of intranodal thyroid inclusions (ITIs) is controversial. We aim to investigate their clinicopathologic features and utilize immunohistochemistry (IHC) to support the diagnosis.Forty‐one cases of incidentally found ITIs between 2019 and 2023 were categorized into three groups, namely, Group A: thyroidectomy due to papillary thyroid carcinoma (PTC) with regional lymph node dissection (n = 33), Group B: thyroidectomy due to benign thyroid disease with incidental perithyroid lymph node sampling (n = 4), and Group C: surgery due to other head and neck cancers with lateral neck lymph node dissection (n = 4). The overall incidence of ITIs was 4.17% (33/792) in Group A and 0.76% (4/524) in Group C. All ITIs sufficient for study were negative for BRAF VE1 IHC. HBME‐1 and galectin‐3 IHC were also negative in all analysed cases. Although various degrees of nuclear changes were present in ITIs, classical PTC nuclear features, i.e. pseudoinclusions, nuclear grooves, and chromatin alterations, were less commonly seen (0%, 29.3%, and 51.2%, respectively) than in metastatic PTC (90%, 95%, and 95%, respectively) (all P < 0.001). Interestingly, 77.3% (17/22) of cases with lymph node metastasis in Group A had coexistence of ITIs and metastasis in the same lymph node. During follow‐up, two cases in Group A had PTC recurrence without accompanying ITIs, while none in Group B or C had recurrent thyroid lesions.We propose key diagnostic features for ITIs incorporating morphology and BRAF VE1, HBME‐1, and galectin‐3 IHC. The distinction between ITIs and metastatic PTC can be clinically relevant. [ABSTRACT FROM AUTHOR]

The tumor-draining lymph nodes (tdLN) are the initial site of metastases and are the prime site for generating robust antitumor responses. In this study, we explored the efficacy of a universal immune activator (ImmAct) targeted to the tdLN. This approach can be viewed as an attempt to turn a cold, unresponsive tdLN into a hot, responsive site. The adjuvant antitumor efficacy of our novel intranodal injection was evaluated in an aggressive metastatic mammary carcinoma murine model. The cancer cells were inoculated subcutaneously in the lower quadrant of the mouse to provoke the tdLN (inguinal lymph node). The study encompasses a range of methodologies, including in vivo and in vitro assays and high-dimensional flow cytometry analysis. Our findings demonstrated that intranodal administration of ImmAct following the dissection of the primary tumor led to improved tumor-free survival and minimized weight loss. ImmAct led to both local and systemic alterations in the cellular and humoral immunity. Additionally, after ImmAct treatment, non-responders showed a higher rate of exhausted CD8+ T cells compared to responders. Indeed, our innovative approach surpassed the gold standard surgery of sentinel lymph node excision. Overall, intranodal administration of ImmAct yielded a robust antitumor immune response, offering protection against micrometastases and relapse. [ABSTRACT FROM AUTHOR]

The tumor-draining lymph nodes (tdLN) are the initial site of metastases and are the prime site for generating robust antitumor responses. In this study, we explored the efficacy of a universal immune activator (ImmAct) targeted to the tdLN. This approach can be viewed as an attempt to turn a cold, unresponsive tdLN into a hot, responsive site. The adjuvant antitumor efficacy of our novel intranodal injection was evaluated in an aggressive metastatic mammary carcinoma murine model. The cancer cells were inoculated subcutaneously in the lower quadrant of the mouse to provoke the tdLN (inguinal lymph node). The study encompasses a range of methodologies, including in vivo and in vitro assays and high-dimensional flow cytometry analysis. Our findings demonstrated that intranodal administration of ImmAct following the dissection of the primary tumor led to improved tumor-free survival and minimized weight loss. ImmAct led to both local and systemic alterations in the cellular and humoral immunity. Additionally, after ImmAct treatment, non-responders showed a higher rate of exhausted CD8+ T cells compared to responders. Indeed, our innovative approach surpassed the gold standard surgery of sentinel lymph node excision. Overall, intranodal administration of ImmAct yielded a robust antitumor immune response, offering protection against micrometastases and relapse.

In patients with thyroid nodules, if the cervical lymph nodes gradually enlarge, a histological confirmation is required to rule out malignancy. Here is a case of benign intranodal thyroid tissue with cystic changes resembling lymph node metastasis of a papillary thyroid carcinoma. A 47-year-old man received ethanol sclerotherapy because of repeated enlargement of the thyroid gland 2 years prior to presentation. Subsequently, the patient underwent abscess removal from the deep neck and partial lobectomy of the attached left thyroid gland. Two months before the visit, extensive cervical lymphadenopathy was detected on ultrasonography (US) and computed tomography (CT). Total thyroidectomy and cervical lymph node dissection were performed to differentiate between metastatic papillary carcinoma of the thyroid gland and benign thyroid inclusions. Microscopic examination revealed multiple variable-sized nodules of benign thyroid follicles with cystic changes in both thyroid glands and bilateral cervical lymph nodes. An occult papillary microcarcinoma strongly positive for HBME-1 was also observed in the left thyroid lobe. However, the benign intranodal thyroid tissue was negative in both the real-time PCR-based BRAF V600E mutation test and HBME-1 immunohistochemical stain. Similarly, benign intranodal thyroid tissue can be enlarged by multiple cystic changes in a large number of lymph nodes along the neck node chain. For the differentiation of metastatic thyroid papillary carcinoma, real-time PCR-based BRAF V600E mutation test and HBME-1 immunohistochemical staining in addition to histological examination are helpful. [ABSTRACT FROM AUTHOR]

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular tumor with indolent biology, characterized by reciprocal t(1;3)(p36.6;q25) with resultant WWTR1 :: CAMTA1 gene fusion in the vast majority of cases, regardless of anatomic location. Only a small subset, exhibiting well formed vasoformative features will contain YAP1::TFE3 gene fusion. Primary intranodal EHE is exquisitely rare. We report a case in a 54-year-old male with persistent left groin mass with discomfort for nine months. A CT of the abdomen and pelvis showed a minimally enlarged left inguinal lymph node measuring 2.8 cm with no other masses or lymphadenopathy. PET/CT and MRI imaging of the abdomen showed no evidence of disease elsewhere. Sections showed an epithelioid vasoformative neoplasm, centrally necrotic and involving a lymph node. The cells were arranged in anastomosing cords with intracytoplasmic lumens, resembling "signet ring cells". By immunohistochemistry, the tumor cells were positive for vimentin, CD31, CD34, ERG and CAMTA1; and negative for AE1/3, CAM 5.2, KRT7, KRT20, desmin, actin, HMB-45 and S-100. Ki-67 proliferation index was estimated at <1%. Molecular studies including next generation sequencing (NGS) revealed the presence of WWTR1 :: CAMTA1 gene fusion, and fluorescence in situ hybridization for CAMTA1 (1p36.23) and WWTR1 (3p25.1) showed fusion signals, diagnostic of EHE. We highlight a rare occurrence of EHE in a lymph node exhibiting morphologic mimicry with metastatic carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: In the field of cancer therapy, lymph nodes are important not only as targets for metastases resection but also as prudent target organs for cancer immunotherapy. Lymph nodes comprise a complete structure for the accumulation of a large number of T cells and their distribution throughout the body after antigen presentation and activation of dendritic cells. This review highlights current topics on the importance of lymph node structure in antitumor immunotherapy and intranodal-antigen-presenting mature dendritic cell vaccine therapy. We also discuss the rationale behind intranodal injection methods and their applications in neoantigen vaccine therapy, a new cancer immunotherapy. Hundreds of lymph nodes (LNs) are scattered throughout the body. Although each LN is small, it represents a complete immune organ that contains almost all types of immunocompetent and stromal cells functioning as scaffolds. In this review, we highlight the importance of LNs in cancer immunotherapy. First, we review recent reports on structural and functional properties of LNs as sites for antitumor immunity and discuss their therapeutic utility in tumor immunotherapy. Second, we discuss the rationale and background of ultrasound (US)-guided intranodal injection methods. In addition, we review intranodal administration therapy of tumor-specific-antigen-pulsed matured dendritic cells (DCs), including neoantigen-pulsed vaccines. [ABSTRACT FROM AUTHOR]

In patients with thyroid nodules, if the cervical lymph nodes gradually enlarge, a histological confirmation is required to rule out malignancy. Here is a case of benign intranodal thyroid tissue with cystic changes resembling lymph node metastasis of a papillary thyroid carcinoma. A 47-year-old man received ethanol sclerotherapy because of repeated enlargement of the thyroid gland 2 years prior to presentation. Subsequently, the patient underwent abscess removal from the deep neck and partial lobectomy of the attached left thyroid gland. Two months before the visit, extensive cervical lymphadenopathy was detected on ultrasonography (US) and computed tomography (CT). Total thyroidectomy and cervical lymph node dissection were performed to differentiate between metastatic papillary carcinoma of the thyroid gland and benign thyroid inclusions. Microscopic examination revealed multiple variable-sized nodules of benign thyroid follicles with cystic changes in both thyroid glands and bilateral cervical lymph nodes. An occult papillary microcarcinoma strongly positive for HBME-1 was also observed in the left thyroid lobe. However, the benign intranodal thyroid tissue was negative in both the real-time PCR-based BRAF V600E mutation test and HBME-1 immunohistochemical stain. Similarly, benign intranodal thyroid tissue can be enlarged by multiple cystic changes in a large number of lymph nodes along the neck node chain. For the differentiation of metastatic thyroid papillary carcinoma, real-time PCR-based BRAF V600E mutation test and HBME-1 immunohistochemical staining in addition to histological examination are helpful.

There is growing interest in the use of contrast-enhanced ultrasound (CEUS) in diagnostic and interventional radiology. CEUS applications in interventional radiology are performed with intravascular or intracavitary administration of microbubble-based US contrast agents to allow for real-time evaluation of their distribution within the vascular bed or in body cavities, respectively, providing additional information beyond gray-scale US alone. The most common interventional-radiology-related CEUS applications in children have been extrapolated from those in adults, and they include the use of CEUS to guide lesion biopsy and to confirm drain placement in pleural effusions and intra-abdominal fluid collections. Other applications are emerging in interventional radiology for use in adults and children, including CEUS to optimize sclerotherapy of vascular malformations, to guide arthrography, and for lymphatic interventions. In this review article we present a wide range of interventional-radiology-related CEUS applications, emphasizing the current and potential uses in children. We highlight the technical parameters of the CEUS examination and discuss the main imaging findings. [ABSTRACT FROM AUTHOR]

Abstract Background Current human influenza vaccines lack the adaptability to match the mutational rate of the virus and therefore require annual revisions. Because of extensive manufacturing times and the possibility that antigenic alterations occur during viral vaccine strain production, an inherent risk exists for antigenic mismatch between the new influenza vaccine and circulating viruses. Targeting more conserved antigens such as nucleoprotein (NP) could provide a more sustainable vaccination strategy by inducing long term and heterosubtypic protection against influenza. We previously demonstrated that intranodal mRNA injection can induce potent antigen-specific T-cell responses. In this study, we investigated whether intranodal administration of mRNA encoding NP can induce T-cell responses capable of protecting against a heterologous influenza virus challenge. Methods BALB/c mice were immunized in the inguinal lymph nodes with different vaccination regimens of mRNA encoding NP. Immune responses were compared with NP DNA vaccination via IFN-γ ELISPOT and in vivo cytotoxicity. For survival experiments, mice were prime-boost vaccinated with 17 µg NP mRNA and infected with 1LD50 of H1N1 influenza virus 8 weeks after boost. Weight was monitored and viral titers, cytokines and immune cell populations in the bronchoalveolar lavage, and IFN-γ responses in the spleen were analyzed. Results Our results demonstrate that NP mRNA induces superior systemic T-cell responses against NP compared to classical DNA vaccination. These responses were sustained for several weeks even at low vaccine doses. Upon challenge infection, vaccination with NP mRNA resulted in reduced lung viral titers and improved recovery from infection. Finally, we show that vaccination with NP mRNA affects the immune response in infected lungs by lowering immune cell infiltration while increasing the fraction of T cells, monocytes and MHC II+ alveolar macrophages within immune infiltrates. This change was associated with altered levels of both pro- and anti-inflammatory cytokines. Conclusions These findings suggest that intranodal vaccination with NP mRNA induces cross-strain immunity against influenza, but also highlight a paradox of influenza immunity, whereby robust immune responses can provide protection, but can also transiently exacerbate symptoms during infection.

INTRODUCTION: Schwannomas—Schwann cells–originating tumors—may develop in many locations. However, primary schwannomas arising within lymph nodes are extremely rare, with only a few cases described to this date in the English literature. For the intranodal location, most of the cases are described in the abdominal cavity. In these cases, clinicians may consider and check for familial disorders, such as neurofibromatosis type 2 (NF2) and schwannomatosis also called neurofibromatosis type 3. Schwannomas are benign neoplasms. Histologically, differential diagnosis for spindle-cell lesions in lymph nodes is important and must be done carefully, mainly because they may be attributable to metastatic disease. We report a case of a primary schwannoma arising in a cervical lymph node. BACKGROUND: Primary schwannomas arising within lymph nodes are extremely rare, with only a few cases reported. Since they are benign neoplasms, the differential diagnosis with other intranodal spindle cell lesions, mostly malignant, is important. METHODS: An asymptomatic 69-year-old woman, previously submitted to left hemithyroidectomy for a benign folicular nodule, underwent thyroidectomy totalization following the identification of a large thyroid nodule in routine evaluation. RESULTS: Gross and microscopic examination and ancillary studies were consistent with the diagnosis of intranodal schwannoma. The patient had acquired bilateral hypoacusia. Therefore, type 2 neurofibromatosis was considered and vestibular schwannomas ruled out. CONCLUSION: Herein, we present the second case of a primary schwannoma in a cervical lymph node reported so far. The relevance of the differential diagnosis is highlighted. [ABSTRACT FROM AUTHOR]

Postoperative chylothorax is a well-known rare complication of thoracic surgery. It is a serious complication that is fatal in cases of inadequate treatment. The authors present 2 cases of postoperative chylothorax that were successfully treated by performing pedal and/or intranodal lymphography. In one case, the patient underwent lymphography after previous unsuccessful surgical ligation of the thoracic duct. The presented case reports describe therapeutic importance of conventional lymphography as a minimally invasive treatment of the postoperative chylothorax.

Primary spindle cell lesions of lymph nodes, with the exception of Kaposi's sarcoma, are rare. Intranodal palisaded myofibroblastoma has been described as a spindle cell tumor with prominent amianthoid fibers, intralesional hemorrhage, and intracellular or extracellular inclusions. Another spindle cell lesion, intranodal leiomyoma, has been reported only occasionally. We report the case of a 6-year-old boy with a mass in the neck without other systemic complaints. Excision biopsy of the lymph node revealed a spindle cell tumor with lymph nodal tissue at the periphery. The tumor showed features of smooth muscle differentiation with focally high mitotic index. The classical features of myofibroblastoma were not present. A final pathologic diagnosis of intranodal leiomyoma was rendered. The child has been free of recurrence in the follow-up period. Intranodal leiomyoma is a rare primary spindle cell lesion of the lymph nodes and should be considered in the differential diagnosis of the same. [ABSTRACT FROM AUTHOR]

Background Percutaneous thoracic duct embolization (TDE) is a safe, effective, and minimally invasive option for treating chylothorax. A recent report demonstrated the feasibility of ultrasound-guided intranodal lymphangiography as an alternative to pedal lymphangiography for visualization of the thoracic duct, promising relative technical ease and decreased procedure time for TDE. Methods We report a case of postoperative bilateral chylothorax treated with ultrasound-guided intranodal lymphangiography followed by TDE. Results Intranodal lymphangiography resulted in rapid opacification of the abdominal lymphatics, permitting technically successful primary and secondary embolization procedures. Deployment of metallic coils and liquid embolic agents within the thoracic duct produced rapid clinical and radiographic improvement. Conclusion Intranodal lymphangiography is a reliable, reproducible, and less technically challenging alternative to pedal lymphangiography. © 2013 Wiley Periodicals, Inc. Head Neck 36: E21-E24, 2014 [ABSTRACT FROM AUTHOR]

The authors present a case of a patient with non-traumatic right-sided chylothorax which was successfully treated by thoracic duct embolization. The procedure was performed through the cisterna chyli which was visualised by intranodal lymphography. The coils and acrylic tissue glues were used for embolization. The patient has been followed for 5 months and is free of recurrence of chylothorax.

Intra-nodal palisaded myofibroblastoma (IPM) is a rare benign lymph node mesenchymal tumor. It presents as a slow growing, painless nodular mass confined mostly to the inguinal area. Histologically, it shows palisading spindle cells, hemorrhages, hemosiderin laden macrophages, and amianthoid fibers, almost totally replacing the lymph node. Recent genetic evidence supports viral etiology. A case of IPM occurring in a 25-year-old woman is presented and the differential diagnosis of this lesion is discussed. IPM occurs between 4th and 6th decade of life, male to female ratio is 2:1 and the inguinal region is the commonest location. Origin of this tumor is from myofibroblasts or smooth muscle fibers. Though benign, morphologically it can be confused with malignant tumors like Kaposi's sarcoma, melanoma, and leiomyosarcoma. Prognosis is excellent and surgical excision is the only needed treatment. There are no reports of malignant transformation though an occasional case has recurred. [ABSTRACT FROM AUTHOR]

Since the first description of an entirely intraductal epithelial proliferation of salivary gland by Chen in 1983 as an 'intraductal carcinoma', there have been several dozen reported cases with the same and various additional names including 'low-grade salivary duct carcinoma', 'low-grade cribriform cystadenocarcinoma' and 'carcinoma in situ' of salivary gland. These refer to a combination of nests and cysts of varying size formed by a cellular proliferation resembling atypical ductal hyperplasia or ductal carcinoma in situ of the breast. The lesions are generally entirely intraductal with low, intermediate or high-grade dysplasia. Occasional benign tumors of salivary gland, particularly Warthin tumor and rare salivary carcinomas may arise within an intraparotid lymph node. In addition, intraparotid lymph nodes are a routine location for metastatic disease. A case of a 59-year-old female with a parotid mass is described, which grossly had the appearance of a Warthin tumor. Microscopically, it was an entirely intranodal proliferation of cells with diffuse AE1/AE3 and S100 positivity. The nests and cysts were completely surrounded by a rim of non-neoplastic myoepithelial cells, which were positive for CK14, p63, SMA, MSA and calponin. The tumor cells were negative for these markers. The cells were only focally positive for AR and BRST-2. They showed negligible MIB-1 staining. This report describes, for the first time, an entirely intranodal location for a low-grade intraductal carcinoma (so-called low-grade cribriform cystadenocarcinoma). [ABSTRACT FROM AUTHOR]

Spindle cell lesions within lymph nodes generally raise concern for metastasis. We report the 1st intranodal hybrid schwannoma/perineurioma arising in an inguinal lymph node in a 13-year-old boy. Presentation comprised a painless, slowly enlarging mass in a patient with no clinical features of neurofibromatosis. [ABSTRACT FROM AUTHOR]

Vaccination with idiotype (Id) protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id- and keyhole limpet haemocyanin (KLH)-pulsed, CD40 ligand-matured DCs administered intranodally. Nine patients with smouldering or stable myeloma without treatment were enrolled and DC vaccines were administered at weekly intervals for a total of four doses. Following vaccination, all patients mounted Id-specific γ-interferon T-cell response. Interleukin-4 response was elicited in two, and skin delayed-type hypersensitivity reaction occurred in seven patients. More importantly, Id-specific cytotoxic T-cell responses were also detected in five patients. Most if not all patients mounted a positive T-cell response to KLH following vaccination. At 1-year follow-up, six of the nine patients had stable disease, while three patients had slowly progressive disease even during the vaccination period. At 5-year follow-up, four of the six patients continued with stable disease. No major side effects were noted. In summary, intranodal administration of Id-pulsed CD40 ligand-matured DCs was able to induce Id-specific T and B-cell responses in patients. Current efforts are geared towards breaking tumour-mediated immune suppression and improving clinical efficacy of this immunotherapy. [ABSTRACT FROM AUTHOR]

Background/aim: Neoantigens are tumor-specific antigens that emerge due to gene mutations in tumor cells, and are highly antigenic epitopes that escape central immune tolerance in the thymus, making cancer vaccine therapy a desirable option., Patients and Methods: Tumor neoantigens were predicted in 17 patients with advanced cancer. They were resistant to the standard treatment regime, and their synthetic peptides were pulsed to the patient's monocyte-derived dendritic cells (DCs), and administered to the patient's lymph nodes via ultrasound., Results: Some patients showed sustained tumor shrinkage after this treatment, while some did not respond, showing no ELISpot reaction. Although the number of mutations and the predicted neoantigen epitopes differed between patients, the clinical effect depended more on the presence or absence of an immune response after vaccination rather than the number of neoantigens., Conclusion: Intranodal neoantigen peptide-pulsed DC vaccine administration therapy has clinical and immunological efficacy and safety., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Schwannomas-Schwann cells-originating tumors-may develop in many locations. However, primary schwannomas arising within lymph nodes are extremely rare, with only a few cases described to this date in the English literature. For the intranodal location, most of the cases are described in the abdominal cavity. In these cases, clinicians may consider and check for familial disorders, such as neurofibromatosis type 2 (NF2) and schwannomatosis also called neurofibromatosis type 3. Schwannomas are benign neoplasms. Histologically, differential diagnosis for spindle-cell lesions in lymph nodes is important and must be done carefully, mainly because they may be attributable to metastatic disease. We report a case of a primary schwannoma arising in a cervical lymph node., Background: Primary schwannomas arising within lymph nodes are extremely rare, with only a few cases reported. Since they are benign neoplasms, the differential diagnosis with other intranodal spindle cell lesions, mostly malignant, is important., Methods: An asymptomatic 69-year-old woman, previously submitted to left hemithyroidectomy for a benign folicular nodule, underwent thyroidectomy totalization following the identification of a large thyroid nodule in routine evaluation., Results: Gross and microscopic examination and ancillary studies were consistent with the diagnosis of intranodal schwannoma. The patient had acquired bilateral hypoacusia. Therefore, type 2 neurofibromatosis was considered and vestibular schwannomas ruled out., Conclusion: Herein, we present the second case of a primary schwannoma in a cervical lymph node reported so far. The relevance of the differential diagnosis is highlighted., Competing Interests: Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recent advances in molecular biology have led to dramatic enhancement of the stability of in vitro transcribed (IVT) messenger RNA (mRNA) and improvement in its translational efficacy. Nowadays, mRNA-based vaccines represent a promising approach in the field of anticancer immunotherapy, gaining attention over the earlier-established bacteria-, virus-, or cell-based vaccination approaches. Here, we present the experimental procedures employed in our laboratory to induce anticancer immune responses in different murine tumor models using IVT mRNA encoding for immune activation signals and antigens of interest.