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Department of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, Avenida Blasco Ibáñez, Valencia, SpainDepartment of Pathology, University of Valencia, Avenida Blasco Ibáñez, Valencia, Spain
Department of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, Avenida Blasco Ibáñez, Valencia, SpainDepartment of Pathology, University of Valencia, Avenida Blasco Ibáñez, Valencia, Spain
Department of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, Avenida Blasco Ibáñez, Valencia, SpainDepartment of Pathology, University of Valencia, Avenida Blasco Ibáñez, Valencia, Spain
Department of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, Avenida Blasco Ibáñez, Valencia, SpainDepartment of Pathology, University of Valencia, Avenida Blasco Ibáñez, Valencia, Spain
Although originally considered a reactive process, the pathogenesis is currently debated and a neoplastic nature has been proposed based on the presence of somatic mutations in a significant number of cases.
We report the clinicopathological and genetic features of what seems to be the first case of life threatening acquired, multisystemic LCH with massive widespread visceral and bone involvement.
A 44-year-old woman with systemic lupus erythematosus (SLE) and antiphospholipid syndrome progressively developed numerous subcutaneous and skeletal muscle nodules, up to 30 mm in diameter, that on computed tomography (CT) were consistent with panniculitis, metastases or lymphoma. She also developed bilateral breast nodules that on mammography were consistent with malignancy. Subsequently, multiple erythematous cutaneous lesions preceded the development of numerous bright red papules and nodules, mostly on the trunk and some on the head, upper limbs and gingivae. No lesions were present on the lower limbs (Fig. 1A,B). A widespread extensive multisystemic involvement of bones (osteolytic lesions devoid of peripheral sclerosis) (Fig. 1C), breasts (bilateral), lungs (Fig. 1D), liver, gastrointestinal and spleen (Fig. 1E) developed, which on CT were initially consistent with metastases. The patient had no fever and all SARS-CoV-2 PCR tests were negative. She had marked peripheral thrombocytopenia (Kasabach–Merritt syndrome) which required platelet transfusions. Visceral and gastrointestinal haemorrhagic episodes were common and a splenectomy was performed.
Fig. 1Clinical and histopathological features. (A,B) Numerous cutaneous redish nodules. (C) Multiple large radiolucent nodules are present in pelvic bones. (D) Multiple bilateral breast and pulmonary nodules. (E) The liver and spleen are full of variably sized nodules. (F) Subcutaneous lesion with a lobulated and septated growth pattern. (G) A lobule with intermediate cellularity showing cuboidal endothelial cells surrounded by pericytic cells. (H) A continuous α-SMA-positive pericytic cell population surrounding the endothelium. (I) Warthin–Starry staining slides are devoid of bacilli.
Bacillary angiomatosis was the first clinical suspicion and the patient was initially treated for 2 months with doxycycline and rifampicin (the latter replaced afterward by azithromycin). There was no clinical response and lesions progressively increased in number. Subsequent PCR and serology for Bartonella spp. were negative. The patient was then treated with sirolimus and pazopanib, and later with doxorubicin, all with no response. Therefore, guided by the detection of MAP2K1 (MEK1) and NRAS mutations, therapy with MEK inhibitor trametinib was initiated. Although a good initial response was obtained and some cutaneous lesions shrank, turned pale and dried, the platelet counts continued to be very low and the patient died a few months later of multiorgan failure due to visceral haemorrhagic complications.
Seven biopsies were obtained: four excisional (three subcutaneous, one cutaneous and the splenectomy specimen) and two incisional (one from each breast). The most distinctive histopathological feature in all biopsied tumours (subcutaneous, cutaneous, breast and spleen) was the presence of a lobular growth pattern, with areas of high, intermediate and low cellularity (Fig. 1F–I and Fig. 2). In all, there were feeder vessels surrounded by small capillary lumina covered by flat or cuboidal endothelial cells (Fig. 1B,G and Fig. 2F) invariably and continuously surrounded by α-smooth muscle actin (α-SMA)-positive pericytic cells (Fig. 1H and Fig. 2D). Fibrous septa were commonly present between the lobules (Fig. 1F and Fig. 2A). Ki-67-positive cells were numerous (up to 25%) in cellular areas (Fig. 2C). No neutrophils, nuclear dust, necrosis or granular amorphous material were found. No bacilli were observed with Warthin–Starry staining (Fig. 1I). No human herpes virus 8 (HHV8) immunostaining was present. Few thrombi could be found in large vascular lumina in a subcutaneous lesion. Small foci of extramedullary haematopoiesis were found in a subcutaneous lesion and confirmed with glycophorin-C immunostaining.
Fig. 2(A–D) Breast and (E,F) spleen lesions. (A,B) A lobular growth pattern with centrally placed dilated feeder vessels and inconspicuous capillary lumina with no endothelial atypia. (C) Ki-67 immunostaining shows a significant proliferation index. (D) α-SMA-positive pericytic cells surround endothelial cells in all the capillary vessels. (E,F) Lobular capillary growth with high cellularity and small capillary lumina in the spleen.
By next generation sequencing (Ion Reporter, version 5.14; ThermoFisher Scientific, USA) one subcutaneous lesion had an NRAS pathogenic mutation. Another subcutaneous lesion had a MAP2K1 c.173A>C variant. Furthermore, the same MAP2K1 variant was found in a breast lesion (Table 1). This MAP2K1 variant has not previously been reported, although according to in silico prediction it is potentially pathogenic: SiFT 0.02 (0–0.05 deleterious); PolyPhen 0.459 (0.15–1 possibly damaging).
However, to the best of our knowledge, no acquired cases of disseminated LCH with an aggressive, life threatening, massive, multisystemic visceral involvement in adults have been reported in the literature. We report the clinicopathological and genetic features of just such a case that clinically was first highly suspicious for bacillary angiomatosis and then, once excluded, for malignancy.
Bacillary angiomatosis is characterised by multisystemic disseminated lobular capillary lesions.
This was the diagnosis initially considered by the clinicians despite the biopsies being devoid of any of its characteristic histological findings. The patient was treated for 2 months with doxycycline and rifampicin/azithromycin, after which this interpretation was abandoned due to negative PCR and serology for Bartonella spp. and for the lack of response to treatment.
Well-differentiated angiosarcoma with metastatic dissemination was disregarded from the outset due to the consistent lobular growth pattern, uniform continuous SMA immunostaining of pericytic cells invariably surrounding the endothelium throughout the lesions, presence of septated interlobular fibrosis and the absence of endothelial multilayering and nuclear atypia.
The capillary lobule is a hallmark of benign vascular lesions
Reactive angioendotheliomatosis (RAE) was our first tentative diagnosis in this case. It is commonly associated with underlying autoimmune disease (including antiphospholipid antibody syndrome), renal failure, liver failure, cryoglobulinaemia or lymphoproliferative disorders.
Therefore, the presence in our case of massive visceral and bone involvement argued against this diagnosis. In fact, there are no reports of widespread visceral involvement of RAE in the literature. Moreover, the monomorphic lobular pattern and interlobular fibrosis as well as the detection of NRAS and MAP2K1 somatic mutations strongly supported the diagnosis of LCH which has also been reported in association with antiphospholipid antibody syndrome.
congenital cases of multisystemic disseminated LCH represent a distinct disorder with multisystemic involvement of the skin, brain, viscera, muscles and bone, with serious morbidity due to haemorrhagic brain lesions. However, no genetic studies were performed in the biopsy samples.
Therefore, our findings of NRAS somatic mutation in one lesion and the same MAP2K1 variant in two lesions from our patient, are unique and pertain to a different clinical scenario: that of an acquired process in an adult with SLE and antiphospholipid antibody syndrome. Clinically, congenital disseminated LCH tends to regress spontaneously, although brain lesions may provoke intracranial hypertension and haemorrhages.
In addition to clinical outcomes, there are other differences between congenital LCH and our acquired case, such as the tendency of the former to involve the brain and, histologically, that pericytes are less conspicuous than endothelial cells.
and a MAP2K1 mutation has also recently been reported in one case of cutaneous solitary LCH. The genetic alterations give support to the neoplastic nature of these lesions. Moreover, they provide an explanation for the activation and upregulation of the MAP Kinase pathway which promotes aberrant angiogenesis with proliferation of endothelial cells and pericytes. Since several very effective RAS/RAF/MEK/ERK inhibitors are available, these may be an appropriate therapy for cases of aggressive multisystemic LCH. Indeed, trametinib, a MEK inhibitor widely used in patients with advanced melanoma, has also been tested to treat a variety of vascular lesions with encouraging results.
In conclusion, we describe a previously unrecognised, life threatening, acquired, aggressive, multisystemic, disseminated form of lobular capillary haemangioma with massive visceral and bone involvement. Recognition of this variant is mandatory for both pathologists and clinicians in order to provide an early, appropriate diagnosis with genetic characterisation to design an effective therapy and improve clinical outcome.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose
Acknowledgements
The authors wish to acknowledge Esther Alvarez and Maria José Gastaldo for their excellent assistance with the immunohistochemical and molecular biology techniques.
References
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Pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases.
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