Localised renal Langerhans cell histiocytosis coexisting with unilateral renal clear cell carcinoma

Abstract

Langerhans cell histiocytosis (LCH) is an uncommon group of disorders, which can be either localised or systemic, characterised by abnormal proliferation of monocytes, macrophages and dendritic cells. These disorders represent an aberrant response of myeloid progenitor cells. Bones are the most commonly affected organ but there can be involvement of the skin, lungs, liver and spleen. Renal involvement, however, is rare. LCH is the most commonly seen in children but certain rare forms such as Erdheim-Chester disease can be seen in adults. In this report, we present a case of clear cell renal adenocarcinoma (CCRC) admixed with LCH in a patient with history of smoking and presenting with abdominal pain and heamaturia. Imaging revealed left renal lesion and subsequently left renal nephrectomy was performed with tissue biopsy showing grade 3 clear cell renal cell carcinoma admixed with neoplastic LCH.

Background

Langerhans cell histiocytosis (LCH) is an uncommon group of disorders characterised by abnormal proliferation of monocytes, macrophages and dendritic cells. While multisystem involvement can be present, LCH is limited to one organ system in 55% of cases. Disease infiltration in the kidneys is rare. We present an unusual case of renal clear cell adenocarcinoma admixed with LCH in an asymptomatic 49-year-old man who underwent left renal partial nephrectomy with histology showing clear cell renal cell carcinoma admixed with ovoid cells showing folded nuclei. Clear cell renal carcinoma can rarely coexist with LCH. This correlation is not very well studied and some of the explanations include distinct cell-to-cell interactions and specific patterns of signalling molecule profiles that are produced in the lesion microenvironment as well as reactive process to the primary tumour.

Case presentation

A 49-year-old man presented to his primary care physician with persistent non-radiating upper abdominal pain of 3 days duration with nausea but no vomiting. The patient also had change in urine stream and gross haematuria. He denied any fever, chills, burning micturition, history of renal stones, nocturia, urgency or frequency. He had a smoking history of 45 pack-years. Medical history was significant for Chronic obstructive pulmonary disease and hypertension, surgical history was significant for laparoscopic cholecystectomy for gallstones.

The patient was haemodynamically stable with blood pressure of 124/85 mm Hg and pulse rate of 81 beats per minute. Physical examination showed an abdomen that was soft, non-tender and non-distended with no rebound tenderness, guarding or rigidity, or palpable mass. Back examination revealed no costovertebral angle tenderness to palpation or percussion. Additionally, there was no spinal tenderness to palpation or percussion. Rectal examination showed good anal sphincter tone with prostate size of 30 g which was smooth and symmetrical.

Investigations

Haematology and serum chemistry were unremarkable and kidney function was normal with creatinine of 1.00. Urinalysis showed +3 red blood cell(RBC) and white blood cell (WBC) but no nitrite.

CT of abdomen and pelvis was remarkable for mid to lower pole partially exophytic (typical radiographic appearance of clear cell renal adenocarcinoma (CCRC)) left renal lesion measuring 1.4×1.3×1.02 cm, with demonstration of thick progressive peripheral and internal septal enhancement and no evidence of extension into the renal hilum (figure 1). The renal artery and vein were patent with no evidence of hydronephrosis within either kidney. No lymphadenopathy was noted. No difference was noted in normal renal parenchyma between the affected side and the contralateral normal kidney on CT scan.

Figure 1.

CT abdomen pelvis showing outgrowth at the lower border of the left kidney (red arrow).

Cystoscopy was aborted since during the procedure scope could not be advanced due to suspected fossa navicular stricture. Later, the patient underwent meatal dilation with cystoscopy and robotic left partial nephrectomy with gross findings of yellowish, golden appearing tumour invading Gerota’s fascia. Histology of the pathological sample showed grade 3 clear cell renal cell carcinoma admixed with neoplastic LCH (figure 2). The LCH was confirmed by positive CD 1A, S100 and langerin (CD 207) (figures 3 and 4). The BRAF-VE-1 antibody was negative precluding BRAF mutation. However, cyclin D1, a downstream marker of mitogen-activated protein kinase was positive, consistent with neoplastic LCH. The histological sample was also reviewed by a national tertiary academic centre who reached a similar diagnosis. The final diagnosis was renal cell carcinoma, clear cell type with secondary involvement by LCH.

Figure 2.

Photomicrograph showing clear cell renal cell carcinoma admixed with ovoid cells showing folded nuclei (arrow). H&E×100.

Figure 3.

Photomicrograph showing immunostaining positivity for CD 1A. Suggestive of Langerhans cells ×100.

Figure 4.

Photomicrograph showing immunostaining positivity for CD 207 suggestive of Langerhans cells ×100.

Treatment

On further exploration, the patient had two skin nodules which had been ongoing for years. Shave biopsy was performed on these two lesions which showed compound melanocytic nevus and intradermal melanocytic nevus. Positron emission tomography–computed tomography (PET-CT) done afterwards was unremarkable. Clinically, the patient remained asymptomatic afterwards and was kept under surveillance without initiation of any further treatment.

Discussion

Langerhans histiocytosis is limited to one organ system in 55% of the cases while remainder presents with multisystem involvement. Histiocytes can invade almost any organ with most common being skin, lymph nodes, lungs, thymus, liver, spleen, bone marrow or central nervous system.¹ Although rare, infiltration of disease in kidneys has been reported.^2–4 Similar to the dermal Langerhans cells, those in LCH express the histiocyte markers CD1a, S100 and CD207 (langerin). CD207 is associated with cytoplasmic Birbeck granules. BRAF V600E mutations have been identified in the majority of patients with multisystem disease and those with more severe clinical presentation.⁵ Interestingly, in all cases (BRAF mutated or not), the downstream BRAF targets MEK and ERK were phosphorylated, suggesting a common mechanism of activation of the signal transduction pathway regardless of BRAF mutation status.⁶ Pathological findings also vary depending on the site of biopsy.⁷ As some forms behave in a relatively benign manner and are associated with an inflammatory cell. It has been proposed that LCH might be a reactive disease. However, its neoplastic nature is suggested by the fact that the proliferating cells in LCH are clonal and overexpress p53. Nonetheless, no recurrent genomic, genetic or epigenetic abnormalities have been identified. The association of LCH with a malignant neoplasm is rare and has been noted with mostly lymphomas and leukaemia with some cases occurring after chemotherapy or radiotherapy as a possible complication of treatment^{8 9} and in some cases of LCH as a secondary reactive process to lymphoma/leukaemia occurring concurrently at the time of diagnosis.¹⁰ This association is even rarer with solid tumours, with few of the cases reported with lung cancer,¹¹ retinoblastoma, neuroblastoma, hepatocellular carcinoma, Askin tumour and Ewing sarcoma. The underlying pathogenesis of LCH-tumour association remains poorly understood. However, it is tempting to speculate that patients with malignant conditions that precede or are concurrent with LCH development, as in the patient presented, might be explained by distinct cell-to-cell interactions and specific patterns of signalling molecule profiles that are produced in the lesion microenvironment.¹²

Through literature search we were able to find three previous reported cases of coexistence of LCH with a renal cell cancer. Two had similar presentation of CCRC with LCH in elderly patients with prior history of smoking just like our patient.^{13 14} Interestingly both these patients, like our patient was asymptomatic and had incidental finding of two coexisting tumours. The other case was a patient with a history of childhood LCH relapsed in multiple sites including bone and nasal cavity, with a focus of LCH also being observed with the renal adenocarcinoma diagnosed later in the life.¹⁵

However, a very recently published case series described seven additional cases of patients with LCH occurring within (six cases) or after (one case developed LCH after 6 years of renal cell carcinoma (RCC) diagnosis) and were treated with either partial (five cases) or radical(two cases) nephrectomy. No LCH manifestations were detected in normal kidney or perinephric fat. Pyrosequencing of microdissected LCH DNA revealed V600E BRAF mutation in all six cases of LCH within RCC therefor favouring neoplastic lesion as compared with a reactive lesion.¹⁶

Renal cell tumours produce a wide range of hormones and cytokine-like products.¹⁷ Cellular interactions in this setting might be, in part, responsible for mitogenic and chemotactic signals that could promote the recruitment and growth of LCH tissue, which is intimately associated with the concurrent malignant process. The gross cross-sectional finding of yellowish golden appearing solid tumour in our patient is typical for solitary CCRC and is due to high-lipid content. The fact that the histopathological examination of this patient revealed LCH tissue in close relationship with the solid tumour, along with lack of other stigmata of LCH disease, suggests that a focal renal LCH lesion might have developed as a reaction to the primary tumour. The contribution of extrinsic factors such as smoking cannot be excluded^{18 19} since cigarette smoking is a single, strong and dose dependent risk factor for development of both renal clear cell carcinoma and LCH, and this risk factor were also present in all reported patients. Another simple explanation could be an unrelated co-incidence of having two different tumours at the same site diagnosed at the same time. Histological variability of renal tumours should also raise the suspicion of Birt-Hogg-Dubé syndrome which was unlikely to be the case in this patient as he did not meet the diagnostic criteria.²⁰ It is worth mentioning that the presence of histiolytic disorders occurring along with CCRC can be misdiagnosed as CCRC with sarcomatoid features and needs to be differentiated.¹⁶ Patients with unifocal involvement of one organ system can be treated with single agent prednisone or combination of vinblastine and prednisone. Alternatively, a subset of patients may benefit from close observation with treatment on disease progression. BRAF V600E mutation occurs in 50%–70% of LCH cases and is indicative of a neoplastic process rather than a reactive one.²¹ In our patient and the other two similar cases,^{12 13} the BRAF V600E mutation was not present along with intimate and simultaneous association, favouring more towards a reactive process. However, cyclin D1 positivity in our case hints towards a neoplastic process. Another feature that argues against a reactive process is the absence of any inflammatory findings and no difference in normal renal parenchyma between the affected side and the contralateral normal kidney on radiographic imaging. In conclusion, further understanding of this coexistence needs to be investigated. No matter the reactive, coincidental or neoplastic aetiology, appropriate follow-up and treatment is recommended.

Learning points.

• Langerhans cell histiocytosis (LCH) can be either localised or systemic, with kidney involvement being very rare.

• LCH can very rarely coexist with renal clear cell carcinoma.

• LCH coexistence with other tumours is poorly understood and could be due to cellular reaction from neoplasm versus reactive versus coincidental.

• BRAF V600E mutation favours a neoplastic process rather than a reactive one.