LCS is an extremely rare disease, with generally poor prognosis. Few data are available in literature, with only two larger studies available: one systematic review [1] and a retrospective registry-based report of data from Surveillance, Epidemiology, and End Results (SEER) and National Cancer Data Base (NCDB) databases [3] in USA. There is still a lack of evidence regarding the most appropriate treatment approach for LCS. Most of the treatment protocol employed remain empirical combination of surgery, radiotherapy and chemotherapy, with variable results.

Some data suggested an advantage in radiation in the case of locoregional limited stage disease, without bone marrow or liver/splenic disease involvement [3-5]. Also, surgical resection with clear margins was associated to improved overall survival (OS) in some analysis [1], but not in others [3]. Many different systemic chemotherapy regimens have been administered in LCS patients with advanced stage disease, failing in demonstrating significant impact on OS [3, 6-8].

The case we reported showed, at diagnosis, locoregional left supraclavicular and axillar node involvement, however, the bulky ulcerated axillar mass was not surgically removable and could not receive radiation treatment upfront, since it was extensively ulcerated. For these reasons, we decided to start treatment with chemotherapy with neo-adjuvant aim. After first CHOP cycle, without any satisfactory improvement, we decided to add etoposide, basing on few data available in literature which showed good results with etoposide-based chemotherapy (such as ESHAP (etoposide plus cytarabine plus carboplatin plus methylprednisolone) [7] or EPOCH (etoposide, cyclophosphamide, vincristine, doxorubicin and prednisone) [8]). In our patients as well, we confirmed the good impact on mass clinical response to etoposide-based chemotherapy regiment, even if he did not reach a complete remission of disease with chemotherapy alone, showing the substantial chemo refractory of LCS. However, we achieved our aim to obtain a surgically removable mass.

Only few experiences in literature [10-11] reported bone marrow transplant (BMT) as consolidation treatment. However, basing on this small number of cases, BMT seemed to be one of the most reliable treatment for advanced stage LCS. Our case was only locally advanced, however, since we had stem cell storage available and our patient was in good clinical condition, we decided to perform ASCT as first remission consolidation.

To go further we can say that, in the last decade, an improving knowledge of molecular pathophysiology of LCS has opened the way for new target therapy approaches.

Genomic analysis in individual case reports described the recurrence of a missense mutation (V600E) in BRAF, cyclin-dependent kinase inhibitor-2 (CDKN2A/B) deletion, missense mutations in TP53 gene, and mutations in the NOTCH1 gene [12-14]. A report demonstrated the successful use of dabrafenib, a BRAF inhibitor, in a patient with systemic disseminated LCS (harboring BRAFV600E mutation) with progressive disease during chemotherapy [14]. This case opened the door for the promising role of target therapy in LCS as well as in other rare hematologic malignancies, uncovering future directions of research in this rare disease, in which the lack of prospective clinical trials constitutes a real unmet clinical need.

Unluckily, our patient was tested for BRAF mutation but resulted negative.

Interestingly, at the staging of disease, the bone marrow histology showed invasion by concomitant smoldering multiple myeloma. This is the only case of concomitant LCS and plasmecells neoplasm reported in literature for our knowledge. However, it is important to notice that many cases of LS have been linked to previous hematological disease. Some cases were reported arising from previous Langerhans cells histiocytosis, [1]: one case nine years after B-cell acute lymphoblastic leukemia, demonstrating an identical immunoglobulin rearrangement [10]; two further cases developed by previous hairy cell leukemias, one evolving from follicular lymphoma, with the same immunoglobulin peak, while another from chronic lymphocytic leukemia, with identical loss of the 6q23 signal on FISH [15].

In our case we do not perform clonality analysis on multiple myeloma infiltrate. However, it’s an interesting example of the hematopoietic plasticity, suggesting how much is still unknown of this rare entity.

In conclusions, we report a case of local advanced LCS with left supraclavicular and axillar bulky mass, successfully managed, thanks to an accurate pathological diagnosis, with a multidisciplinary approach with chemotherapy, surgery and radiotherapy treatment, followed by ASCT consolidation. Further researches will be needed to determine a systemic therapy that is effective for these patients, which should be based on multidisciplinary management. We think it is important to encourage physicians to publish all cases of LCS in order to improve the actual knowledge and to compile additional data that will assist in developing optimal treatments regimens for this rare and challenging disease.

Disclosures

AC, RS, FG, AB, AR, SG, CC, ES, AB, DM, NM, MF, IC, MG, GFO, MM, DR: nothing to disclose

Author Contributions

AC, RS, DR: wrote the manuscript; FG, AB: provide images; AC, RS, FG, AB, AR, SG, CC, ES, AB, DM, NM, MF, IC, MG, GFO, MM, DR: all the author reviewed and approved the manuscript.