Further workup that included a CT of the neck, chest, abdomen, and pelvis in addition to bone scan did not show any abnormalities. Nine months post-operatively the patient was completely asymptomatic and regained full power in the lower limbs. Contrasted lumbar spine MRI showed no recurrence.
We received the case as a consultation following an outside pathology diagnosis of Langerhans cell histiocytosis (eosinophilic granuloma). Histologic examination showed nerve tissue infiltrated by histiocytes with moderate to abundant eosinophilic to clear-foamy and variablyvacuolated cytoplasm. The nuclei ranged from oval in shape to grooved with irregular outlines (Figure 2A). They had fine chromatin with small nucleoli. Chronic lymphocytic cell infiltrates were seen in the background. Rare Toutontype multinucleated giant cells were found (Figure 2B) and rare mitotic figures were seen (1/10 HPFs). No necrosis was present. The histiocytes were positive for CD68 (Figure 3A) and negative for S100 protein, CD1a, and BRAF V600E immunostains. ALK-1 immunohistochemical stain showed diffuse positivity in the histiocytes (Figure 3B). Therefore, ALK-positive histiocytosis was suspected and confirmatory molecular testing for the presence of ALK gene translocation, which was performed at an outside facility, showed the presence of KIF5B-ALK gene fusion by RT-PCR, confirming the diagnosis.
The histiocytic infiltrate in the reported cases shared almost consistent histopathological and cytological features. For most cases, the histiocytes show abundant eosinophilic, glassy cytoplasm that may show fine vacuoles. Occasionally, histiocytes can show grayish foamy-to-fluffy cytoplasm [3] and can be multinucleated [2]. Typically, the nuclei are clefted or lobulated and show irregular folding in the nuclear membrane with fine chromatin and small nucleoli [2]. Although the nuclear features are usually typical, rare cases can have oval to round nuclei without foldings or grooves [2]. Occasionally, cells may show emperipolesis, phagocytosis of red blood cells or polymorphonuclear leukocytes [2]. Touton-type multinucleated giant cells can be seen. Some variation in the pattern of histiocytic infiltration has been reported in the form of spindling of the histiocytes with associated fibrosis and a storiform pattern [2,3]. When the liver is involved, the cells are present predominantly in the liver sinusoids with variable portal tract involvement [1-3]. The bone marrow can show focal, patchy or diffuse involvement [1-3].
By immunohistochemistry, the histiocytes are positive for histiocytic markers (Factor XIII, CD68, fascin and CD163) with variable expression of S100. They are consistently negative for CD1a and BRAF V600E [1-5]. The ALK-1 immunostain is uniquely positive in a cytoplasmic and/ or membranous pattern [1-5]. The ALK1 expression by immunohistochemistry corresponds to translocation involving the ALK gene, most commonly with KIF5B which was initially described by Chan et al [1]. This translocation can be detected with either fluorescent in situ hybridization using a split apart probe for ALK or by RT-PCR and next generation sequencing which identifies the fusion partner. Despite being the most common fusion partner, other genes have been reported beside KIF5B, including TPM3 [1,3] and COL1A2 [2]. Interestingly, the reported case with ALK-COL1A2 gene fusion showed the less common nuclear features of oval nuclei with distinct nucleoli and no irregularities or folds in the nuclear membrane [2].
In general, the constellation of clinical presentation and pattern of involvement, morphology, immunohistochemistry and molecular testing help in excluding the other main differential diagnoses [6,7]. The differential diagnosis includes other histiocytic disorders including Erdheim- Chester disease, Rosai-Dorfman disease, Langerhans cell histiocytosis, and localized or disseminated juvenile xanthogranuloma. A summarized detailed description of the clinical, pathological and molecular findings of these diseases is provided in Table I.
A benign localized subglottic histiocytic lesion harboring the KIF5B-ALK fusion that clinically mimicked subglottic infantile hemangioma was recently reported by Wolter et al. [8]. They described an infiltrate of histiocytic cells with a mildly vacuolated and a slightly eosinophilic cytoplasm with small round nuclei and no nucleoli. There was no emperipolesis nor phagocytosis and the histiocytes were mixed with spindle cells. No Touton-type multinucleated giant cells were seen. The histiocytes but not the spindle cells were positive for ALK1 immunostain in an interesting pattern not described before: a perinuclear or cytoplasmic dot-like pattern. Those features, despite being partially present in some of the reported cases [2,3], prompted them to call the condition juvenile xanthogranuloma variant, ALK positive with KIF5B-ALK gene fusion. Whether this condition truly represents a variant of juvenile xanthogranuloma or a continuation of the spectrum of ALK-positive histiocytosis is debatable, although we favor the latter.
To the best of our knowledge, our case is the first to involve the sensory nerve root in the filum terminale of an adult patient, thus expanding the clinical manifestation of this disease. It also shows a spectrum of nuclear features that ranged from the classically folded nuclei to the less common rounded and smooth contoured. Central nervous system involvement has been described as a localized disease involving the cavernous sinus [2], the cerebellar vermis and cerebral cortex [4], and as part of a systemic involvement [9]. All localized cases were in children (15, 7 and 10 year old, respectively) whereas the systemic case reported a 40-year-old male who presented with hepatic parenchymal involvement, peritoneal and omental lesions, osseous lesions, and scattered subcutaneous nodules along with a homogenous lesion in the cervical cord at the level C3 to C4 [9]. The reported symptoms for the localized cases included headache, vomiting and refractory seizures [4]. Our patient presented mainly with progressive lower limb weakness. The reported outcome for localized disease is good with no local recurrence after surgical resection. However, some cases such as the cavernous sinus case may not be amenable to surgical resection [2]. Interestingly, this patient showed excellent response to ALK-inhibitor therapy (crizotinib) with no disease after 6 months [2]. Response to ALK-1 inhibitors has also been reported in KIF5B-ALK1 histiocytosis identified in two adults with liver and skin involvement [10] and with the case who had CNS involvement with systemic disease [9].
In conclusion, we presented the case of a 27-year-old male who had ALK-positive histiocytosis involving the sensory nerve root in the filum terminale. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestation of this newly described entity. It also shows a spectrum of nuclear features in the same case ranging from the folded to the smooth-rounded nuclei. ALK-positive histiocytosis is characterized by expression of ALK1 by immunohistochemical stain and shows fusion of the ALK gene with different partners, most commonly KIF5B. An integrated histological, immunohistochemical and molecular approach is recommended during the workup of histiocytic proliferative disorders. Of particular importance is ALK1, which we propose to be performed on all cases, not only to detect this probably under-recognized entity but also because of the therapeutic benefit that may be obtained from the use of ALK inhibitor therapy especially in unresectable or systemic diseases.
ACKNOWLEDGMENT
The authors would like to thank Dr. Chang Kenneth from
the Department of Pathology and Laboratory Medicine
at KK Womens and Childrens Hospital in Singapore for
performing the RT-PCR to detect the KIF5B-ALK fusion.
CONFLICT of INTEREST
The authors declare no conflict of interest.
AUTHORSHIP CONTRIBUTIONS
Concept: OIJ, Design: OIJ, Data collection or processing:
DAJ, MH, MAH, Analysis or Interpretation: OIJ, MAH,
Literature search: OIJ, DAJ, Writing: OIJ, DAJ, MH,
Approval: OIJ, DAJ, MH, MAH.
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