Langerhans Cell Histiocytosis Associated With Renal Cell Carcinoma Is a Neoplastic Process

Abstract

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder composed of Langerhans cells admixed with reactive mononuclear and granulocytic cells, associated with prominent eosinophils. LCH is considered a neoplasm, driven in most cases by oncogenic RAS/RAF/MEK/ERK pathway mutations. The disease predominantly affects children. Urinary system involvement has rarely been reported in a multisystem disease setting. We describe 7 patients who presented with LCH occurring within (6 cases) or after (1 case) a resected clear cell (n=6) or clear cell papillary (n=1) renal cell carcinoma (RCC), identified prospectively in our routine and consultation files (2012 to 2019). The patients included 5 women and 2 men, with a median age of 54 years (range, 39 to 73 y), none with a history of LCH or LCH manifestations before the time of RCC diagnosis. The median size of the RCC was 3.5 cm (range, 1.8 to 8.3 cm). Treatment included partial (5 cases), or radical (2 cases) nephrectomy. All RCCs on gross examination showed at least focal cystic changes and were low grade (World Health Organization [WHO]/International Society of Urologic Pathologists [ISUP] grade 1 to 2). The LCH foci were detected as incidental histological finding within the resected RCC in all six cases and they were limited to few high-power fields (<2 mm2) in 5 of 6 cases, but in the sixth case, they occupied almost the entire clear cell papillary RCC (2 cm nodule). No LCH manifestations were detected in the normal kidney or in perinephric fat. The seventh patient developed LCH within inguinal deep soft tissue followed by systemic manifestations 6 years after clear cell RCC. Langerhans cell immunophenotype was supported by the reactivity for S-100, CD1a, and langerin and by the negative pankeratin. Successful pyrosequencing of microdissected LCH DNA revealed the V600E BRAF mutation in all 6 cases of LCH within RCC. To our knowledge, only 3 similar cases were published since 1980; the only case tested for BRAF mutation showed wild-type BRAF. This is the first study analyzing the morphologic and genetic features of a cohort of LCH associated with RCC. In our experience, these cases may be underrecognized in practice, or may erroneously be diagnosed as RCC dedifferentiation or high-grade sarcomatoid transformation. Finally, the detection of BRAF mutation further confirms that LCH in this setting is indeed a neoplasm, rather than a reactive lesion.

Langerhans cell histiocytosis and associated malignancies: A retrospective analysis of 270 patients

“…The knowledge on risk and occurrence of LCH-AM can have a major impact on therapy and overall patient management, depending on its nature. Unfortunately, to date, there are only single case reports or relatively small case series of AM in both pediatric and adult patients with LCH [10,15,16]. Here, we present a total of 270 patients diagnosed with LCH who developed a total of 285 AM, which is by far the largest case series reported to date.…”

International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults

“…), lymphomas, and solid organ malignancies (especially lung and thyroid cancer). [28][29][30][31][32] LCH of the thyroid gland can co-occur with papillary thyroid cancer harboring BRAF-V600E mutations. 30,33 LCH foci have also been found incidentally around resected specimens of renal cell carcinoma.…”

Granulomas associated with renal neoplasms: A multi‐institutional clinicopathological study of 111 cases

“…As such, careful scrutiny may be needed to identify peri-or intratumoral granulomas, which are often small in size (mean = 1.9 mm). Care should also be taken to avoid misclassifying a multinucleated tumour cell, megakaryocyte or Langerhans cell (uncommon but reported in RCC [17][18][19] ) as a multinucleated giant cell. In keeping with the histology of typical sarcoidosis, necrotising granulomas were only present in 18% (two of 11) of study cases with a known diagnosis of sarcoidosis (overall rate of necrotising granulomas was 14%).…”