A 79-year old woman was hospitalized on April 25, 2018, at which time she had progressive dyspnea over the past 5 weeks, productive cough, poor appetite, and weight loss of 5 kg over the last 6 months currently weighing 81 kg. Her medical history included an invasive ductal breast cancer pT1cN0M0 G2 ER 90%, PR 20% 20 years ago treated with lumpectomy, radiotherapy, and tamoxifen until 2004, and an undifferentiated cancer of the right parotid pT1 (17 mm) pN2 (1/2 positive in level I, 1/11 positive in level II, no extranodal extensions) pM0 diagnosed 2008 and treated with a total parotidectomy achieving R0 margins and a selective neck dissection levels II-IV followed by radiotherapy.\nOn physical examination, the patient was in mild respiratory distress. The pulmonary exam revealed dullness to percussion, decreased fremitus, and decreased breathing sounds in up to two-thirds of the left lung field. Oxygen saturation was 92% with the patient breathing ambient air, and arterial blood gases showed partial respiratory insufficiency. A chest X-ray confirmed a left-sided pleural effusion, and thoracentesis removed 1.5 liters of turbid fluid. Biochemical analysis of the fluid established an exudative etiology. Atypical cells with immunocytochemical positivity for p40, cytokeratin 5, and p63 in the cytopathology specimen were primarily suggestive of a non-small cell lung cancer, and a CT scan of the thorax showed a mass (4.2 × 2.2 × 2.8 cm) in the right upper lobe and extensive cardiophrenic, mediastinal, and hilar lymphadenopathy as well as enlarged lymph nodes along the left arteria mammaria interna. An FDG PET/CT scan confirmed these findings, and the scan revealed a hypermetabolic activity in mesenteric lymph nodes and at the left pleura (). Thoracoscopy and biopsy of the parietal pleura were performed. Surprisingly, histopathological examination revealed a non-small cell carcinoma () expressing CD5 (), CD117 (), and p63 all indicating a carcinoma of thymic origin (). With no signs of a thymic pathology, the histopathological diagnosis of CASTLE was established, and as additional immunostainings for CD5 () and CD117 () in the specimen of the parotid cancer diagnosed 2008 were positive also, a rare case of a CASTLE tumor of the parotid healed at the primary and neck sites, but with late metastatic dissemination was diagnosed.\nAs CD117 was highly overexpressed in the tumor, exons 9, 11, 13, 14, and 17 of the C-KIT gene were analyzed after extraction of genomic DNA by PCR using specific primers, but no common mutation was found consistent with previous reports (, ). Anticancer immunity and potential response to immunotherapy were assessed by PD-L1 staining of the pleural tumor, which showed a high expression level of 60% ().\nThe patient underwent talc pleurodesis and left partial pleurectomy for recurrent pleural effusions. Systemically, disseminated metastatic disease was treated with the monoclonal PD-L1 inhibitor pembrolizumab at a dose 200 mg every 3 weeks. Four months after the start of immunotherapy a follow-up FDG PET/CT study showed a partial remission with a moderate morphologic reduction of the tumor load, but a markedly reduced metabolic activity at all tumor sites (). Pembrolizumab treatment continued at a dose of 200 mg IV every 3 weeks. The patient showed a mild skin rash treated with low dose prednisolone (20 mg with tapering) for 2 weeks. No other adverse events associated with pembrolizumab were observed, and the therapy was tolerated well. At the last follow-up, the patient was in good clinical condition and had gained 3 kg of weight. On March 28th, 2019, a second follow-up FDG PET/CT showed no residual pleural effusion (not shown) and a further regression of lesions in the right lung and lymph nodes. Residual focal FDG-Uptake was seen in the left pleura ().
Patient 1 was a 61-year-old female who presented with a 5-cm anterior neck mass with retrosternal extension. She was surgically treated with a right thyroid lobectomy at another institution. The lesion was interpreted to be a poorly differentiated papillary thyroid cancer. Postoperative treatment consisted of sequential and combined chemoradiotherapy. Local recurrence in the region of the right thyroid occurred 20 months later, and radiotherapy was performed to relieve symptoms. Six years later, the patient had local recurrence again and was referred to our institution for further treatment. After curative wide local excision and central neck dissection, postoperative radiotherapy was given to the thyroid bed and bilateral cervical lymph node areas (55 Gy/16 fractions). Histological re-evaluation of the recurrent tumor specimens revealed CASTLE (pT4bN1M0). A third local recurrence was diagnosed 1 year later, and concurrent chemotherapy (paclitaxel 210 mg/m2 and cisplatin 40 mg/m2) and radiotherapy (50.4 Gy /28 fractions) were applied. The patient died from acute respiratory distress 1 month after the initiation of treatment.