Abstract

Secondary neoplastic lesions in lymph nodes are predominantly metastases from solid tumors, whereas primary lymph node hemangiomas are exceptionally uncommon, with only 24 well-documented cases in the literature. Histologically, they are characterized by endothelial cells that may appear flattened or enlarged, with variable vascular density, and the presence of stromal elements. Notably, the concurrent presence of a primary hemangioma and a metastasis from breast cancer – the latter being the most prevalent secondary lesion in axillary lymph nodes – represents an unprecedented observation. The unique case presented herein underscores the exceptional rarity of primary lymph node hemangiomas and demonstrates for the first time their possible coexistence with breast cancer metastasis within the same axillary lymph node. In sharing and discussing this case study, we pay homage to Professor Juan Rosai, whose work in redefining rare and complex diagnoses continues to enlighten our understanding of lymph node vascular lesions.

Introduction

Hemangioma of the lymph node is an uncommon vascular tumor mostly observed as secondary lesions, arising from contiguous infiltration of an extranodal hemangioma ^{1, 2}. In comparison to their secondary counterparts, primary lymph node hemangiomas are even more exceptional occurrences, with only 24 cases documented in the literature since the first description by Gupta in 1964, as shown in Table I ^3,4-16. Their rarity bestows upon the diagnosis a remarkable complexity, underscored by the illustrative case presented by Goldstein and Bartal in 1985 ¹⁶. Initially designated as an intranodal hemangioendothelioma, this case underwent reclassification by Professor Juan Rosai and colleagues in 1994 ². This reevaluation followed their 1992 case series, which still stands as the only existing collection of lymph node hemangioma cases in the literature to date ¹³. Within this work, the authors also undertook the reclassification of a lymph node exhibiting “hypervascularity”, a finding initially reported by Lott and Davies in 1983 ¹⁷. This reclassified case marked a significant milestone, as it represents the first instance of a solitary lymph node hemangioma supported by sufficiently high-quality images.

Hemangiomas found within lymph nodes typically show well-defined borders and are concentrated around the hilum or medulla of the lymph node. The unaffected parenchyma of the lymph node remains intact and might display slight follicular hyperplasia. This type of lesion is composed of benign single-layered and flat endothelial cells, except in the case of epithelioid hemangiomas where the endothelial cells tend to be plump. The vascular channels within hemangiomas can either be empty or filled with blood, while their stroma might range from edematous to fibrotic. These tumors can be categorized as capillary, cavernous, or mixed ¹. Capillary-type neoplasms manifest as a cluster of small blood vessels, resembling a pyogenic granuloma or canonical granulation tissue. On the other hand, cavernous hemangiomas consist of larger, irregular spaces filled with erythrocytes and occasional partially organized thrombi. Endothelial cells of hemangiomas exhibit immunoreactivity for vascular markers like CD31, CD34, Wilms tumor 1 (WT1), ETS-related gene (ERG), Friend leukemia integration 1 (FLI1), and factor VIII-related antigen (aka von Willebrand Factor).

Previous observations of carcinoma coexisting within extranodal hemangiomas have been reported ¹⁸. However, a critical void in our current understanding revolves around the possible coexistence of hemangiomas and synchronous metastases from solid tumors within a single lymph node. This gap signifies an absence of comprehensive insights into the mechanisms, underlying factors, and potential interactions that underpin the concurrent presence of these two distinct entities within the same anatomical site. Here, we present a unique case of primary lymph node hemangioma identified in an axillary lymph node alongside synchronous metastasis from breast cancer.

Case report

A 47-year-old woman was diagnosed with moderately differentiated invasive breast cancer of non-special type (ductal) with clinically positive ipsilateral axillary lymph nodes. No neoadjuvant chemo/radiotherapy interventions were undertaken, and the patient underwent total mastectomy with lymphadenectomy. The tumor was situated in the superior-exterior quadrant of the left breast, measuring 9.5 cm in its largest dimension, and exhibited a hormone receptor (HR)+/HER2-negative phenotype.

Histopathological analysis of the axillary lymph nodes confirmed carcinoma metastasis in four level I lymph nodes and one level II lymph node. Interestingly, within the metastatic level II lymph node, a distinct, well-defined vascular proliferation was observed, measuring 0.4 cm in its largest dimension (Fig. 1). Morphologically, this lesion was characterized by an abundance of small-caliber, thin-walled capillaries that seamlessly replaced part of the lymph node parenchyma, echoing the morphology of capillary hemangioma. These vessels were lined by single-layered plump endothelial cells devoid of atypia. Immunohistochemical analysis revealed CD31 and CD34 positivity, while D2-40 was notably absent. The stromal composition of the periphery of the lesion was modestly fibrous with scarce neutrophilic infiltration. The metastatic deposits of breast cancer were constituted by multiple intraparenchymal and subcapsular foci, alongside a few metastatic emboli within subcapsular vessels (Fig. 1).

Discussion

To our knowledge, this is the first observation of two distinct neoplastic conditions of this nature (i.e. breast cancer metastasis and primary hemangioma) within the same lymph node. This finding raises several important considerations. Firstly, it further confirms the significance of thorough histopathological evaluation when assessing lymph nodes, particularly in the context of malignancies ^19,20. Furthermore, this case illustrates the importance of acknowledging the possibility of multiple concurrent neoplastic conditions from different lineages while examining lymph nodes. The relationship between primary lymph node hemangioma and metastatic breast cancer remains unclear, hinting that their co-occurrence might be a coincidence. This case stimulates discussions on the rarity of lymph node hemangioma and the importance of meticulously recording such cases in the literature to improve our knowledge on their histopathology. Notably, there exists a prior instance where Karaosmanoglu and co-authors reported encountering a hemangioma within an intrapancreatic lymph node ²¹. However, a thorough examination of the iconography presented in the manuscript favors the interpretation of the lesion as an arteriovenous malformation. As more instances of lymph node hemangiomas are documented and incorporated into the medical literature, a more complete comprehension and description of these lesions should naturally evolve.

Other important considerations are related to the comprehensive evaluation of lymph nodes, the rare coexistence of different neoplastic conditions, the uncertain relationship between primary lymph node hemangioma and breast cancer metastasis, and diagnostic complexities. An area that remains to be addressed revolves around the possible biological interplay between hemangiomas and metastatic solid tumors within a single lymph node. Attracting questions include the underlying mechanisms that facilitate such a juxtaposition, the potential interdependencies between these entities, and the broader implications for diagnostic accuracy in the clinical practice. One possible biological linkage could involve the tumor-associated inflammasome, which may activate angiogenesis-related pathways ²². In addition, oncogenes activation is known to trigger the ‘angiogenic switch’ through the upregulation of angiogenic growth factors ²³. In this context, the tumor necrosis factor-alpha (TNFα) and vascular endothelial growth factor-C (VEGF-C) might play a part ^19,24.

Epilogue

In our short journey through the fascinating field of lymph node hemangiomas and their diagnostic intricacies, we remain indebted to the pioneering contributions of Professor Juan Rosai to the topic of rare vascular proliferations and histopathology at large ^25,26. The importance of delineating these rare entities is not confined to a mere academic curiosity but it carries direct implications for our daily practice as pathologists. In this context, Juan Rosai’s Collection of Surgical Pathology Seminars is still an invaluable resource, which is freely available to the pathology community at . This comprehensive database of digital histological images, spanning decades of insights, is a testament to his enduring commitment to pathologists, pathology residents, and young medical students (Fig. 2).

ACKNOWLEDGMENTS

This work was partially supported by the Italian Ministry of Health with Ricerca Corrente 5×1000 funds. FP includes the project in the Italian Ministry of the University MUR Dipartimenti di Eccellenza 2023-2027 (l. 232/2016, art. 1, commi 314-337). FP and NF thank the Ministry of Health grant GR-2019-12368592. This study was approved by the European Institute of Oncology Scientific Advisory Board Ethics Committee under approval number #UID3474; written informed consent was obtained from patients for use of tissue samples. According to the European Union’s General Data Protection Regulation (GDPR), all information regarding the recruited patient was pseudoanonymized and therefore no personally identifiable information is disclosed. The final proofreading process for the grammar and syntax of the manuscript was performed using ChatGPT 4 and Grammarly v.6.8.263.

CONFLICTS OF INTEREST

The Authors declare no conflicts of interest.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

All authors have significantly contributed to the research, analysis, and writing of this manuscript. Each author has reviewed and approved the final version for publication.

ETHICAL CONSIDERATION

This case report is compliant with the local ethical guidelines.

History

Received: August 18, 2023

Accepted: February 14, 2024

Figures and tables

Figure 1.Primary solitary hemangioma and breast cancer metastasis coexist in a single axillary lymph node. Representative micrographs showing the thin-walled capillary hemangioma (star) occupying approximately 50% of the lymph node parenchyma along with multiple metastatic deposits from breast cancer (arrows) and neoplastic emboli inside of non-neoplastic lymph vessels, as also demonstrated by cytokeratin staining (A, hematoxylin and eosin, original magnification, 50x; and insets, hematoxylin, and eosin and original magnification, pan-cytokeratin, 200x). At the immunohistochemical analysis, the lesion was positive for both CD31 (B, original magnification, 50x) and CD34 (C, original magnification, 50x), while D2-40 (aka podoplanin) was negative (D, original magnification, 50x).

Figure 2.Captured moments of Juan Rosai (1940-2020) engaging with aspiring pathologists who participated in his weekly histological teaching sessions in Milan, Italy. The images feature three of the authors of this study (Nicola Fusco, Elena Guerini Rocco, and Fabio Pagni) during their tenure as pathology fellows, standing alongside the esteemed scholar. These photographs epitomize Juan Rosai’s dedication to nurturing the future generation of pathologists (Photographs taken in Milan, 2012 circa).

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