Klin Padiatr 2016; 228(06/07): 341-343
DOI: 10.1055/s-0042-103328
Short Communication
© Georg Thieme Verlag KG Stuttgart · New York

How to Treat INI1 Negative Non-Rhabdoid Tumours in Adolescents: Following Genotype or Histological Phenotype?

Behandlung von INI1-negativen nicht-rhabdoiden Tumoren bei Jugendlichen: Entsprechend des Genotyps oder des histologischen Phänotyps?
F. Völker
,
I. Kühnle
,
J. Edler
,
H.-U. Schildhaus
,
C. Vokuhl
,
A. Mohr
,
C. Sahlmann
,
C. M. Kramm
Further Information

Publication History

Publication Date:
31 May 2016 (online)

Mutations in the tumour suppressor gene for integrase interactor 1 (INI1; synonyms: SMARCB1, hSNF5) leading to abolished expression of the corresponding protein are an oncogenetic hallmark in malignant rhabdoid tumours (MRT) in and outside the central nervous system (CNS). They have also been reported in other rare tumour entities such as epithelioid sarcoma (Sullivan LM, Mod Pathol 2013, 26: 385–392) and sinonasal carcinoma (Bishop JA, Am J Surg Pathol 2014, 38:1282–1289). In INI1 negative rhabdoid tumours of the CNS, i. e. atypical teratoid rhabdoid tumours (AT/RT), anthracycline-intensified chemotherapy regimens significantly improved survival (Chi SN et al., J Clin Oncol. 2009, 27: 385–389), and in MRT of the kidney anthracyclines also enhanced presurgical treatment reponse (Furtwängler R et al., Cancer Genet 2014, 207: 434–436). However, non-rhabdoid INI1 negative tumours are usually treated according to their histological phenotype independently of the presence or absence of anthracyclines in the underlying chemotherapy regimens. In the present case study, we question such a generalizing treatment decision and may suggest that in individual cases anthracycline-intensified chemotherapy regimens should also be used for INI1 negative non-rhabdoid tumors, independently of their underlying histology.

Our potential index patient is a 16 years old male who were diagnosed with an INI-1 negative carcinoma of the nasopharynx after a 1.7 years long history of neck pain, facial paraesthesia, torticollis, and increasing trismus. PET/CT (positron emission tomography-computed tomography) with 18F-fluorodeoxyglucose (18F-FDG) and MRI (magnetic resonance imaging) revealed a non-resectable 3.5×4×4 cm large mass in the sinonasal and oropharyngeal area with osseous infiltration of the clinoid, the left occipital condyle, the frontal arch of the atlas, and the base of dens ([Fig. 1]). Distant metastases were not found.

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Fig. 1 Axial MRI slice and corresponding fused 18F-FDG-PET/CT slices of patient 1 showing the T1-hyperintens mass in the nasopharyneal area and a weak enhancement in the PET/CT indicated by the arrows.

Histological evaluation of a biopsy sample turned out to be difficult and was referred to the German National Paediatric Tumor Reference Center in Kiel, Germany. Immunohistochemistry suggested loss of INI1 expression, and subsequent FISH analysis confirmed a corresponding deletion within the INI1 gene. However, differential diagnosis still remained difficult with the tumour cells showing epithelioid differentiation as well as rhabdoid features. These features did not prove sufficient to either confirm diagnosis of epithelioid sarcoma or MRT. Very strong immunoreaction for pancytokeratin and overall histological features rather suggested diagnosis of an INI1 negative nasopharynx carcinoma with similarities to the sinonasal carcinoma of the basaloid type ([Fig. 2]).

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Fig. 2 Histological and immunohistochochemical features of INI 1 negative nasopharynx carcinoma. a Tumour cells with epithelioid and rhabdoid differentiation (HE staining) and b Strong immunoreaction for pancytokeratin. c PAS negative cytoplasm. d Loss of INI 1 expression in tumour cells; scarce immunoreactive cells are most likely representing normal stroma cells.

Treatment was started according to the recommendation of the Nasopharynx Carcinoma Registry of the German Society of Paediatric Oncology and Haematology (NPC-2003-GPOH; Buehrlen M et al., Cancer 2012, 118: 4892–4900). Cisplatinum and 5-fluorouracil were administered. Since there was further tumour progression 3 weeks after the first cycle, local radiotherapy was brought forward and performed over 5 weeks up to a total dose of 70 Gy with simultaneous administration of cisplatinum during first and last week. Early response assessment 2 weeks after radiotherapy showed only stable tumour disease, thus, the patient decided in the awareness of a palliative situation to pause treatment for a few weeks to do some traveling. His general condition had meanwhile stabilized under intensified pain medication (oxycodone/naloxone, metamizol, gabapentin, amitryptilline) and nutrition via a percutaneous endoscopic gastrostomy (PEG) tube. However, 6 weeks after radiotherapy, there was a 50% regression in tumour volume. Since there was still significant proliferative activity within the tumour as suggested by 18F-FDG-PET/CT this unexpected late tumour response convinced the patient to try further chemotherapy. In the lack of a standard secondline treatment and given the loss of INI1 expression it was decided to apply an anthracycline-intensified chemotherapy which is usually used for AT/RT as recommended by the EU-RHAB registry (Seeringer A et al., Klin Padiatr 2014, 226: 143–148).

Within the so-called DOX cycle of the AT/TR chemotherapy, the patient received doxorubicin (37.5 mg/m2/d) on 2 consecutive days. DOX was followed in 2 weeks intervals, respectively, by ICE (ifosfamide, carboplatin, etoposide) and VCA (vincristine, cyclophosphamide, carboplatin). DOX, ICE, VCA were administered 3 times each.

Upon this chemotherapy approach, clinical condition markedly improved towards a nearly unrestricted quality of life with no major pain after stopping pain medication, reestablishment of swallowing and oral nutrition, and significantly reduced torticollis. MRI showed a stable tumour residual with increasing signs of intratumoural fibrosis. However, PET/CT could still detect some increased glucose uptake. Because of the latter findings, an anthracycline-containing oral maintenance therapy was started similar to the maintenance treatment recommendations of the German Soft Tissue Sarcoma Registry (SoTiSaR; Klingebiel T et al., Pediatr Blood Cancer 2008, 50: 739–745). Oral maintenance consisted of intermittent trofosfamide/idarubicin and trofosfamide/etoposide every 3 weeks for 6 months.

Our second patient is a 15 years old male who was diagnosed with an INI1 negative epithelioid sarcoma of the left ear and the adjacent external auditory meatus after a 2 years history of a painfully swollen secreting lesion in this region. During this period, the lesion was biopsied twice showing each time chronic inflammation without any signs of malignancy. Because of persistence with ongoing local symptoms, the lesion was resected once more. This time, histology showed an additional cellular hyperplasia which was diagnosed as an INI1-negative epithelioid sarcoma of the proximal-type ([Fig. 3]). Loss of INI1 expression was associated with a mutation in the INI1/SMARCB1 gene. Subsequent staging showed a 0.7×1.7×2 cm large mass within the left auditory external meatus and the left ear ([Fig. 4]). On MRI, there was also some suspicion for possible polytope pulmonary metastases.

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Fig. 3 Immunohistochemical findings in SMARCB1 negative epithelioid sarcoma (proximal type) with complete loss of SMARCB1/INI-1 expression.
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Fig. 4 Axial MRI and corresponding fused 18F-FDG-PET/CT slices of patient 2 showing the T1-hyperintens mass in the left ear and a strong enhancement in the PET/CT indicated by the arrows.

According to the SoTiSaR, the patient was assigned to the “Non-Rhabdomyosarcoma-like” high risk group because of the suspected lung metastases. Treatment recommendation included initial adjuvant chemotherapy with so-called VAIA III cycles consisting of 3 single courses: I2VAd/I2VA/I2VAd (I2VA: ifosfamide, vincristine, adriamycin/doxorubicine [40 mg/m2/d over 2 days]; I2VA: ifosfamide, vincristine, actinomycin D). After end of the fourth VAIA III cycle, the tumour showed stable appearance on MRI, and local therapy with complete (R0) tumour resection was subsequently performed. Additional lung surgery confirmed that the suspected pulmonary lesions had not represented pulmonary metastases. Although histology still revealed viable tumour cells risk stratification was subsequently downgraded to “low risk”, and follow up was started.

The present 2 cases may support our suggestion to follow for malignant non-rhabdoid INI1 negative tumours an anthracycline-intensified chemotherapy approach as for INI1 negative AT/RT. In some cases like in patient 1, this may imply that a treatment empirically chosen on basis of a similar histological phenotype may be overruled by a chemotherapy regimen which had been proven successful for a similar genotype. In other cases, however, treatment for the histological phenotype may also be considered active for the underlying genotype as demonstrated in patient 2 where the histology driven chemotherapy regimen was even more anthracycline-intensified as the suggested genotype-driven treatment in patient 1.

As previously discussed, there might be a new family of INI1 deficient neoplasia (Agaimy A, Adv Anat Pathol 2014, 21: 394–410). However, the clinical picture and courses of these tumours appear more diverse than the present 2 case reports may suggest, and not all INI negative tumours may finally need the suggested anthracycline-intensified chemotherapy regimens. Future research will have to further classify INI1-negative tumours to identify the potential individual requirement for anthracycline-intensified chemotherapy regimens like in our patient 1.

The common loss of INI1 expression in rhabdoid and non-rhabdoid tumours will also open new therapeutic doors by developing targeted therapy strategies which may help to consolidate an initial treatment response to conventional radiochemotherapy. First clinical trials, e. g. employing EZH2 (enhancer of zeste homolog 2) inhibitors (EPZ6438/Tazemetostat; NCT02601950) for adults with relapsed INI1 negative malignancies are currently recruiting.