25 August 2021: Articles
Transition From Distinct Types of Mutation-Harboring Multifocal Lung Adenocarcinoma to Rhabdoid Tumor: A Longitudinal Follow-Up
Challenging differential diagnosis, Rare disease
Kensuke Setoguchi1ABCDEF, Shigehisa Yanagi1ABCDEFG*, Toshihiro Gi 2ADE, Hironobu Tsubouchi1AE, Kazuko Uto1ABCDEF, Takafumi Shigekusa 1ABE, Nobuhiro Matsumoto 1AE, Yuichiro Sato3AE, Masamitsu Nakazato1AEDOI: 10.12659/AJCR.932452
Am J Case Rep 2021; 22:e932452
Abstract
BACKGROUND: Rhabdoid tumor (RT) of the lung is a rare and aggressive malignancy. The origin of and the mutation responsible for RT are entirely unknown. The distinction between RT associated with subtypes of lung cancer and SMARCA4-deficient thoracic sarcomas is also unknown.
CASE REPORT: Three pulmonary subsolid nodules in the right S6, left S6, and left S8 were identified in a 78-year-old Japanese woman. At 3 and 9 months later, a chest CT showed unchanged sizes, but at 15 months the development of a 37-mm mass in the right S6 was observed. The patient’s systemic condition deteriorated rapidly, and she died 1 month later. An autopsy revealed that the mass consisted of 90% RT and 10% lung adenocarcinoma. There were another 2 adenocarcinoma lesions in the left lung. KRAS mutation analyses revealed the same KRAS mutation (G12D) in the adenocarcinoma and RT components in the identical mass and metastatic RT, indicating that all of these components had the same clonality. A different KRAS mutation in each of the 3 adenocarcinoma lesions was detected (right S6: G12D, left S6: A59G, left S8: G12C), indicating that the multiple adenocarcinoma lesions were truly multifocal lung adenocarcinoma. The adenocarcinoma and RT components retained SMARCA4 expression.
CONCLUSIONS: This is the first evidence of RT originating from multifocal lung adenocarcinoma. KRAS mutation is thought to be responsible for the RT’s emergence via the epithelial-mesenchymal transition. Patients with multiple subsolid nodules should be followed closely; aggressive surgical intervention should be considered given concerns about the evolution of this aggressive malignancy.
Keywords: SMARCA2 Protein, Human, Rhabdoid Tumor, KRAS Protein, Human, Adenocarcinoma of Lung, DNA Helicases, Follow-Up Studies, Mutation, Nuclear Proteins, Proto-Oncogene Proteins p21(ras), Transcription Factors
Background
Rhabdoid tumor (RT), a highly aggressive neoplasm, was first described in 1978 as a childhood-onset distinctive renal tumor [1]. Several cases of adult-onset RTs have been reported in the kidneys as well as extrarenal sites including the lungs [2,3]. In the 2004 World Health Organization (WHO) classification, large-cell carcinoma with rhabdoid phenotype (LCC-RP) was grouped as a variant type of large-cell carcinoma [4]. LCC-RP is defined as having malignant tumor cells comprised of ≥10% rhabdoid cells, which are characterized by abundant acidophilic cytoplasm, large nuclei, and conspicuous eosinophilic cytoplasmic globules [5]. LCC-RP is extremely rare, and it is an aggressive malignancy with a poor prognosis [5,6].
In the 2015 WHO classification, the rhabdoid phenotype was regarded as a cytologic feature rather than a specific histologic group, as it colocalizes with various histologic subtypes [7,8]. More recently, SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4)-deficient thoracic sarcomas (SMARCA4-DTSs) were proposed as a distinctive disease entity with rhabdoid morphology and highly aggressive malignancy [9]. To date, direct evidence of the cell lineage in which RTs arise from a specific subtype of lung cancer has not been obtained. The driver oncogene(s) responsible for the occurrence of RT in lung cancer are also not fully understood. Moreover, the distinction between RT associated with subtypes of lung cancer and SMARCA4-DTSs remains to be determined.
Here, we report a patient with RT arising from multifocal lung adenocarcinoma. The results of our longitudinal chest computed tomography (CT) and
Case Report
A 78-year-old Japanese woman presented with a 1-month history of dyspnea on effort. She had never smoked and had no history of alcohol use or dust exposure. She had a 32-year history of systemic lupus erythematosus, and she had been continuously treated with oral prednisolone (4 mg/day) and mizoribine (50 mg/day). She had undergone radical surgery for ascending colon cancer 4 years before her presentation. The chest CT at presentation demonstrated 3 subsolid nodules in her lung fields: an 11-mm subsolid nodule in the superior (S6) segment of the right lower lobe, a 9-mm subsolid nodule in the superior (S6) segment of the left lower lobe, and an 8-mm subsolid nodule in the anteromedial (S8) segment of the left lower lobe (Figure 1).
A transbronchial biopsy was performed for the lesion in the right S6 segment, but no definite diagnosis was made. The patient was then followed-up by chest CT assessments, and the chest CT examinations conducted 3 and 9 months later showed that the nodules had remained unchanged in size. However, a chest CT at 15 months demonstrated the development of a 37-mm mass lesion in the right S6 segment. A CT-guided needle biopsy was performed for the mass lesion at 16 months. The pathology assessment of the needle-biopsied specimen revealed that the mass lesion was composed of carcinoma cells with rhabdoid features, characterized by large cells with eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and large intracytoplasmic inclusions. The tumor cells were negative for
Immunohistochemistry results showed that the programmed death-1 ligand-1 tumor proportion score of the tissue sample was 50%. A chest CT examination revealed the rapid growth of the mass lesion (from 37 mm to 60 mm within 1 month) (Figure 1). The subsolid nodules in the left S6 and S8 segments were unchanged in size throughout the clinical course. At 17 months, the patient was hospitalized with fever, wet cough, bloody sputum, and appetite loss. Her systemic condition deteriorated rapidly, and her Eastern Cooperative Oncology Group performance status fell to 4. We therefore decided to manage her treatment as best supportive care. She died 1 month after being hospitalized.
The autopsy revealed that there was a 65-mm mass lesion in the right S6 segment with extensive hemorrhage and necrosis (Figure 2A). The mass consisted of 90% solid tumor with rhabdoid cells and 10% non-mucinous adenocarcinoma lesion with focal intracytoplasmic mucin (Figure 2B–2D). A continuum of changes from adenocarcinoma to the solid area with rhabdoid cells was observed, suggesting the process of epithelial-mesenchymal transition (EMT) (Figure 2E). The adeno-carcinoma lesion was positive for cytokeratin (CK) AE1/AE3 (a pan-cytokeratin marker), CAM5.2 (a pan-cytokeratin marker), CK7, and CK20 (Figure 3A, 3C, 3F, 3G). Mucin 5AC (MUC5AC) immunopositivity was detected in a small part of the adeno-carcinoma lesion (Figure 3H). The immunoreactivity for hepatocyte nuclear factor 4α (HNF4α) was scant (Figure 3I). Rhabdoid cells were positive for AE1/AE3, CAM5.2, and vimentin but negative for CK7, CK20, MUC5AC, and HNF4α (Figure 3B, 3D, 3E). Multiple metastatic foci of RT were observed in the pancreas, lungs, heart, gall bladder, and soft palate. There were another 2 adenocarcinoma lesions in the S6 and S8 segments of the left lower lobe (Figure 4A–4E). There was no evidence of the recurrence of the preexisting colon cancer.
To investigate whether the adenocarcinomas and RT had the same origin, we analyzed
The
We then investigated the involvement of
Discussion
Rhabdoid tumor of the lung is an extremely rare type of lung cancer characterized by a highly aggressive malignancy property. The origin of RT and its responsible driver oncogene remain unclear. This is the first case report identifying an RT that had originated from a multifocal adenocarcinoma in the lung. The longitudinal CT findings and the results of our
Several case studies have reported RTs in the lung that co-localized with various subgroups of differentiated lung cancer. Based on our literature search, as of March 20, 2021, 54 cases of RT in the lung have been described in 22 published articles (Table 1) [5,6,15–34]. Among these cases, 50 case reports noted the associated tumor types: adenocarcinoma (30%, 15 of the 50 cases), large-cell carcinoma (28%, 14 cases), poorly or undifferentiated tumor (10%, 5 cases), sarcomatoid carcinoma (8%, 4 cases), large-cell neuroendocrine carcinoma (6%, 3 cases), squamous cell carcinoma (4%, 2 cases), small cell carcinoma (4%, 2 cases), invasive mucinous adenocarcinoma (IMA, 2%, one case), and more. This is the first case report to describe a patient with RT associated with multifocal lung adenocarcinoma.
Since some of the adenocarcinoma cells contained intracytoplasmic mucin in our patient’s case, we initially considered IMA as a differential diagnosis of non-mucinous lung adenocarcinoma. However, several of the findings were different from the essential and desirable diagnostic criteria of IMA described in the most recent published WHO classification of thoracic tumors [35]. First, almost none of tumor cells in our patient’s case had abundant apical columnar cells with small basally oriented nuclei. Second, the immunopositivity of MUC5AC and HNF4α, which are markers of IMA, was scant in the present case. A recent study with a comprehensive genomic analysis demonstrated the clonal relationship of spatially separate IMA lesions: among 24 patients with 2 separate IMAs, tumors from all but 1 patient shared the same driver mutations [36]. In contrast, in the present study, each adenocarcinoma lesion possessed a different type of KRAS mutation. We thus concluded that all 3 of these adenocarcinomas were not IMAs, but rather were non-mucinous adenocarcinomas with intracytoplasmic mucin.
In our patient’s case, 4 findings indicated that the multifocal adenocarcinoma underwent a transition to RT. First, the histology showed the presence of the continuum of changes from adenocarcinoma to the solid area with rhabdoid cells, suggesting the EMT process. Second, the immunohistochemical study exhibited continuous changes of epithelial- and mesenchymal-marker expression between the adenocarcinoma and RT areas. Third, the
The EMT plays pivotal roles in cancer biology including tumor growth, invasion, dissemination, and metastasis [37]. Since EMT-suggestive findings were observed in the RT specimen in the lung in the present and previous cases [26,31], the EMT might be key to the dedifferentiation of parental cancer cells to rhabdoid cells in the lung. Regarding the mutation responsible for RT evolution, Dettmer et al showed the existence of the same
In 2015, Le Loarer and colleagues demonstrated that
Another important feature of our patient’s case was the rapid growth of the mass during the CT follow-up for the management of the multiple subsolid nodules of the lung. The 2017 Fleischner Society Guidelines recommend that incidental pulmonary nodules be managed as follows: in patients with multiple subsolid lesions ≥6 mm, a short-term follow-up CT at 3–6 months should be considered [45]. Our patient’s case emphasizes the necessity of considering aggressive surgical intervention (eg, multiple limited resections) in patients with multiple subsolid lesions in order to terminate the evolution of the RT.
Conclusions
We present the first case of a rhabdoid tumor arising from multifocal lung adenocarcinoma.
Figures
Figure 1.. Chest CT findings in the longitudinal follow-up. A chest CT on the patient’s initial visit demonstrated 3 subsolid nodules in the lung fields: a 9-mm subsolid nodule in the superior (S6) segment of the left lower lobe (upper left panel), an 8-mm subsolid nodule in the anteromedial (S8) segment of the left lower lobe (middle left panel), and an 11-mm subsolid nodule in the superior (S6) segment of the right lower lobe (lower left panel). The mass lesion in the right S6 segment had grown from 11 mm to 37 mm at 15 months. The mass in the right S6 segment grew from 37 mm to 60 mm within 1 month. The subsolid nodules in the left S6 and S8 segments were unchanged in size through the clinical course. Figure 2.. Autopsy findings of the right lower lobe of the lung. (A) Gross appearance. The tumor was well- to partly ill-demarcated and irregularly shaped with massive hemorrhage (arrowhead). (B–E) Histological examination of the right S6 mass specimens revealed an extensive necrotic area (* in B) with a component of the solid area with rhabdoid cells, characterized by large cells with eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and large paranuclear intracytoplasmic inclusions († in B, C). The tumor also had a component of non-mucinous adenocarcinoma with focal intracytoplasmic mucin (‡ in B, D). (E) A continuum of changes from adenocarcinoma (‡) to the solid area with rhabdoid cells (†). B: 15×; C: 400×; D, E: 200× magnification. Hematoxylin and eosin (H&E) stain. Figure 3.. Immunohistochemical findings of the tumor in the right lobe of the lung. The adenocarcinoma component was positive for AE1/AE3 (A), CAM 5.2 (C), CK7 (F), and CK20 (G). Little immunopositivity for MUC5AC (H) and HNF4α (I) was observed in the adenocarcinoma lesion. The component of rhabdoid cells was positive for AE1/AE3 (B), CAM 5.2 (D), and vimentin (E). Paranuclear intracytoplasmic inclusions were strongly positive for vimentin in some of the rhabdoid cells (E, arrowheads). A–I: 200× magn. Figure 4.. Autopsy findings of the left lower lobe of the lung. A: Gross appearance. The tumors located in the left S6 and left S8 segments are shown. Histological examination of the nodules in the left S6 (B, C) and left S8 (D, E) segments revealed adenocarcinoma lesion with focal intracytoplasmic mucin. B: 40×; C, E: 400×; D: 12.5× magn. H&E stain. Figure 5.. KRAS mutational analyses. The same KRAS mutation (G12D) was detected in both components of the rhabdoid tumor and the adenocarcinoma in the tumor of the right S6 segment as well as a metastatic rhabdoid tumor in the soft palate. The adenocarcinomas in the left S6 and left S8 segments possessed different types of KRAS mutation, i.e., A59G and G12C, respectively. Figure 6.. Immunohistochemical findings of SMARCA4 (BRG1, A–C). Both adenocarcinoma cells (B) and rhabdoid tumor cells (C) retained nuclear expression of SMARCA4. A: 100×; B, C: 200× magn.References:
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