Intrathoracic Rhabdoid Tumors Showing Rapid Progress in Patients with a History of Immune-suppressive Therapies for Hematological Diseases

Abstract

We herein report 2 autopsied cases of intrathoracic undifferentiated/rhabdoid neoplasms showing rapid progress in patients who received immunosuppressive therapies for hematological diseases (Case 1, a 72-year-old man who underwent hematological cell transplantation for aplastic anemia; Case 2, a 77-year-old man who received chemotherapy for multiple myeloma). Both patients experienced progressive pulmonary effusion and died after three months and two weeks of follow-up, respectively. Autopsy revealed rhabdoid neoplasms infiltrating the alveolar spaces in both cases. Nuclear immunoreactivity for SMARCB1/INI1 was lost in Case 2. Clinicians and pathologists should consider the possibility of rapidly progressive neoplasms, such as intrathoracic undifferentiated/rhabdoid neoplasm, as a differential diagnosis for pneumonia in possible immunosuppressive conditions.

Introduction

Intrathoracic undifferentiated/rhabdoid neoplasms with loss or alteration of the switch/sucrose-non-fermenting (SWI/SNF) complex, such as SMARCB1/INI1 and SMARCA4/BRG1, are highly aggressive and often underdiagnosed owing to their rarity, which leads to false diagnostic interpretations (1-11). The SWI/SNF complex is an ATP-dependent chromatin remodeling complex that plays an important role in DNA repair, transcription, and cell differentiation (12,13). Alterations in SWI/SNF complex subunits are commonly correlated with distinct pathological features, such as a discohesive epithelioid or rhabdoid phenotype, defined as the presence of eosinophilic cytoplasmic inclusions of aggregated intermediate filaments adjacent to the nucleus (12,13). A prototypical example is the inactivation of SMARCB1/INI1 in pediatric malignant rhabdoid tumors (MRTs) and epithelioid sarcomas (12,13). Rare SMARCB1-deficient tumors, which more commonly occur in adult patients than in children, include synovial sarcomas, epithelioid malignant peripheral nerve sheath tumors, and myoepithelial carcinomas (12,13).

SMARCA4-deficient undifferentiated tumors were recently included as a novel lung tumor subtype in the World Health organization (WHO) classification of thoracic tumors and are defined as malignant neoplasms with an undifferentiated or rhabdoid phenotype and SMARCA4 deficiency (8,9,11). This type of tumor typically affects smoking men with a wide age distribution and is associated with a short overall survival rate, regardless of disease stage (8,9,11). These tumors show molecular overlap with smoking-associated non-small-cell lung cancer (NSCLC) harboring driver alterations in STK11, KRAS, and/or KEAP1 (1,2,7,9,11). Therefore, this entity is now termed SMARCA4-deficient undifferentiated tumor, rather than sarcoma. Intrathoracic undifferentiated/rhabdoid neoplasms associated with SMARCB1/INI1 inactivation are exceedingly rare and tend to closely resemble histological and immune profile SMARCA4/BRG1-deficient undifferentiated tumors or nuclear protein of the testis (NUT) carcinomas (6,10). SMARCB1/INI1-deficient intrathoracic undifferentiated/rhabdoid tumors are also associated with smoking, men, and a poor prognosis (6).

In this case report, we describe two autopsied cases of thoracic undifferentiated/rhabdoid neoplasms showing rapid progression in patients with hematological disorders treated with umbilical cord stem cell transplantation or chemotherapy. Both cases had difficulties in the differential diagnosis of infectious diseases and recurrent hematological neoplasms. One patient was diagnosed with a SMARCB1/INI1-deficient intrathoracic undifferentiated/rhabdoid tumor, whereas SMARCB1/INI1 and SMARCA4/BRG1 were retained in another case.

These two cases suggest that the possibility of a rapidly progressive neoplasm, such as intrathoracic undifferentiated/rhabdoid neoplasm, should be considered as a differential diagnosis for pneumonia in possible immunosuppressive conditions.

Case Reports

Case 1

•Clinical findings

The patient (72-year-old man) was diagnosed with aplastic anemia and had undergone umbilical cord blood stem cell transplantation 9 months previously. He had bloody sputum, and a shadow in the right S2 was detected on imaging (chest radiography and chest computed tomography) (Fig. 1). He was a smoker (smoking pack-years, 36). Exertional dyspnea, bloody sputum, a slight fever, and pleural effusion worsened, and the patient was admitted to our university hospital. Arterial oxygen saturation (SaO₂) (r.a.) was 91%, and the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was 3 at admission. Infectious pneumonia was suspected based on the clinical course and imaging findings (Fig. 1). He received antibiotic treatment; however, he died because of pulmonary failure after three months of follow-up.

Figure 1.

Thoracic computed tomography images of Case 1. A) The image shows infiltrative shadows in the right upper and lower lobes (arrows) at the initial diagnosis. B) The image shows infiltrative shadows in the right lung and atelectasis at three weeks before death.

•Autopsy findings

▪Gross appearance (Fig. 2A): The right upper and middle lobes of the lung were swollen (right lung weight: 1,440 g) and filled with greyish-white tumors (12×10 cm) and marked hemorrhage on the cut surface. Small white nodules, up to 1 cm in diameter, were scattered on the pleura and diaphragm.

Figure 2.

Gross appearance, histologic features and metastatic sites of the tumor in Case 1. A) Soft greyish-white tumors with marked hemorrhage (asterisk: 12×10 cm) filling the right upper and middle lobes of the lung on the cut surface. Bar indicates 1 cm. B) Histological features of the tumors. Tumor cells show diffuse, loose, adhesive proliferation infiltrating the bronchial mucosal surface (arrows). Asterisk, tumor; arrowheads, bronchial cartilage. Hematoxylin and Eosin (H&E) staining, ×40 (original magnification). C) Higher magnification of the tumor shows proliferation of tumor cells with plump eosinophilic cytoplasm and eccentric nuclei in loosely cohesive arrangement compatible with characteristic features of rhabdoid tumors. H&E staining, ×400 (original magnification). D) Localization of the tumor and metastatic sites. Primary site (yellow), metastasis (orange), and lymph node metastasis (purple).

▪Histological findings (Fig. 2B, C): Hematoxylin and Eosin-stained sections showed diffuse, loosely adhesive proliferation of tumor cells invading the bronchiolar walls and focally exposed to the bronchial space (Fig. 2B). The tumor cells were large and showed rhabdoid features with a deviated nucleus and eosinophilic intracytoplasmic inclusion-like bodies (Fig. 2C). The tumor cells diffusely filled the alveolar space. There were no differentiated components, such as adenocarcinomas or squamous cell carcinomas.

Metastasis was found in the pleura, diaphragm, pericardium, bilateral adrenal glands (microscopic), liver (microscopic), and right pulmonary hilar lymph nodes (Fig. 2D).

Case 2

•Clinical findings

The patient (77-year-old man) was diagnosed as plasma cell myeloma and received chemotherapy and at the state of very good partial response. The patient was a previous smoker (smoking pack-years, 0.5). Two weeks before admission, the patient suffered from cough, sputum, and shadow in the right middle lobe of the lung, and swelling of the mediastinal lymph nodes was detected on imaging (Fig. 3). SaO₂ (r.a.) was 97%, and ECOG-PS was 2 at admission. Atypical cells were detected in the pleural effusion and were misdiagnosed as a recurrence of plasma cell myeloma. The patient received chemotherapy for plasma cell myeloma; however, pleural effusion (Fig. 3) and metabolic acidosis worsened, and he died of pulmonary failure after two weeks of follow-up.

Figure 3.

Thoracic images of Case 2. A) Chest X-ray image showing a nodular lesion in the right middle lobe (arrow) at the initial diagnosis. B) Computed tomography image showing a nodular lesion in the right middle lobe (arrow) at the initial diagnosis. C) Chest radiograph showing infiltrative shadows and pleural effusion in the right thorax on the day of death. D) The computed tomography image shows an increase in nodular lesions in the right middle lobe (arrow) and infiltrative shadows and pleural effusion in the right thorax (arrowheads) three days before death.

•Autopsy findings

▪Gross appearance (Fig. 4A): The right middle lobe of the lung was swollen (right lung weight: 720 g) and filled with greyish-white tumors (10×8 cm) with marked hemorrhage on the cut surface (Fig. 4A). White nodules up to 6.5 cm in diameter, were scattered on the pleura and diaphragm. A greyish-white tumor mass with hemorrhage was observed in the mediastinum around the bronchus, which involved the lymph nodes and invaded the esophagus and thyroid glands.

Figure 4.

Gross appearance, histologic features and metastatic sites of the tumor in Case 2. A) Soft greyish-white tumors with marked hemorrhage (asterisk; 10×8 cm) filling the right middle lobe of the lung on the cut surface. Bar indicates 1 cm. B) Histological features of the tumors. Tumor cells showing diffuse, loosely adhesive proliferation infiltrating the bronchial mucosal surface (arrows). Asterisk, tumor; arrowhead, bronchial cartilage. Hematoxylin and Eosin (H&E) staining, ×40 (original magnification). C) Higher magnification shows proliferation of tumor cells with plump eosinophilic cytoplasm and eccentric nuclei in a loosely cohesive arrangement compatible with characteristic features of rhabdoid tumors. H&E staining, ×400 (original magnification). D) Localization of the tumor and metastatic sites. Primary site (yellow), metastasis (orange), and lymph node metastasis (purple).

▪Histological findings (Fig. 4B, C): Hematoxylin and Eosin-stained sections showed a tumor composed of rhabdoid tumors diffusely filling alveolar spaces. The tumor cells were large and showed rhabdoid features with a deviated nucleus and eosinophilic intracytoplasmic inclusion-like bodies (Fig. 4C). Some of the tumor cells were spindle-shaped. Tumor cells invaded the bronchiolar walls and were focally exposed in the bronchial space (Fig. 4B). There were no differentiated components, such as adenocarcinomas or squamous cell carcinomas.

Metastasis was found in the pleura, diaphragm, bilateral lungs, thyroid, esophagus (direct invasion), and left adrenal gland (microscopic invasion). Lymph node metastasis was found in the cervical, right pulmonary, mediastinal, and right subclavicular lymph nodes.

•Immunohistochemical findings

Immunohistochemical staining was performed using primary antibodies (Supplementary material) and the Envision method (Dako, Carpinteria, USA), as described previously (14). Appropriate positive and negative controls were used. Table summarizes the immunohistochemical findings of the tumors in cases 1 and 2. Figure 5, 6 show representative immunohistochemical findings of the tumor cells in cases 1 and 2, respectively. The tumor cells in both cases showed almost the same immunoreactivity, except for SMARCB1/INI1 and PD-L1. The tumor cells were diffusely and strongly positive for AE1/AE3, CK7, EMA and Vimentin (Fig. 5A, B, 6A, B). Tumor cells in Case 2 showed loss of nuclear staining for SMARCB1/INI1, whereas tumor cells in Case 1 retained nuclear immunostaining for SMARCB1/INI1 (Fig. 5D, 6D). Immunoreactivities for other SWI/SNF complexes, such as SMARCA4/BRG1, SMARCA2/BRM, ARID1A, and PBRM1, were retained in tumor cells in both cases (Fig. 5E, F, 6E, F). Immunoreactivity for PD-L1 (clone 73-10) was observed in some tumor cells (tumor proportion score [TPS]=30%) in Case 1, whereas it was observed in only a few tumor cells (＜1%) in Case 2 (Fig. 5C, 6C). Immunoreactivity for TTF1, CD34, calretinin, synaptophysin, P53, and Sall4 was negative. Immunoreactivity for EZH2 was focal and weak in the tumor cells in both cases. Immunoreactivities for RB1, BAP1, MTAP, MLH1, and MSH2 were retained in the tumor cells in both cases.

Table.

Immunohistochemical Findings.

	Case 1	Case 2
Pan - CK AE 1/A E 3	+	+
CK 5/6	(-)	(-)
CK 7	+	+
CK 20	(-)	(-)
EMA	+	+
Vimentin	+	+
TTF 1	(-)	(-)
p 40	(-)	(-)
CD 34	(-)	(-)
C alretinin	(-)	(-)
Synaptoph ysin	(-)	(-)
SMARCA 2/B RM	+	+
SMARCA 4/B RG 1	+	+
SMAR CB 1/I NI 1	+	-, defect
ARID 1 A	+	+
PBRM 1	+	+
P 53	(-)	(-)
RB 1	+	+
BAP 1	+	+
MTAP	+	+
EZH 2	+, weak	+, weak
MLH 1	+	+
M SH 2	+	+
Sall 4	(-)	(-)
PD - L 1	+, 30%	-/+, <1%

CK: cytokeratin, EMA: epithelial membrane antigen, TTF-1: thyroid transcription factor-1, SMARCA: switch/sucrose-non-fermenting (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin, subfamily a, BRM: brahma, BRG1: BRM/SWI2-related gene 1, INI1: integrase interactor-1, ARID1A: AT-rich interactive domain-containing protein 1A, PBRM1: protein polybromo-1, BAP1: breast cancer 1-associated protein 1, MTAP: methylthioadenosine phosphorylase, EZH2: enhancer of zeste homolog 2, MLH1: MutL homolog 1, MSH2: MutS homolog 2, PD-L1: programmed death-ligand 1

Figure 5.

Tumor cell features with immunohistochemistry in Case 1. A) Tumor cells showing immunoreactivity for cytokeratin-AE1/AE3. Intracytoplasmic globular structures showed stronger positivity. B) Tumor cells show immunoreactivity for vimentin in the intracytoplasmic globular structures. C) Some tumor cells showed immunostaining for PD-L1 in the cell membrane and cytoplasm (arrows). D) Tumor cells showing retention of nuclear immunoreactivity for SMARCB1/INI1. E) Tumor cells showing retained nuclear immunoreactivity for SMARCA4/BRG1. F) Tumor cells showing nuclear retention of SMARCA2/BRM. ×400 (original magnification).

Figure 6.

Tumor cell features with immunohistochemistry in Case 2. A) Tumor cells showing immunoreactivity for cytokeratin-AE1/AE3. Intracytoplasmic globular structures showed stronger positivity. B) Tumor cells show immunoreactivity for vimentin in the intracytoplasmic globular structures. (C) Only a few PD-L1-positive tumor cells were observed. D) Tumor cells showing negative nuclear immunostaining for SMARCB1/INI1 (arrows), whereas endothelial cells and lymphocytes were positive as an internal positive control (arrowheads). E) Tumor cells showing retained nuclear immunoreactivity for SMARCA4/BRG1. F) Tumor cells showing nuclear retention of SMARCA2/BRM. ×400 (original magnification).

Discussion

In the present case report, we demonstrated two cases of intrathoracic undifferentiated/rhabdoid neoplasms showing rapid progression and a poor prognosis. These two cases showed similar clinicopathological findings; however, the status of loss/genetic alterations differed between the two cases. That is, one case was a SMARCB1/INI1-deficient tumor, whereas the status of loss/genetic alterations remained unknown in another case. Generally, undifferentiated/rhabdoid neoplasms are associated with deletions of the SWI/SNF complex, such as SMARCA4A/BRG1 and SMARCB1/INI1 (1-7). In addition, deletions of other subunits of the SWI/SNF complex, including SMARCC1/BAF155 or SMARCC2/BAF170, have been detected in some undifferentiated/rhabdoid tumors, including epithelioid sarcoma and breast carcinoma (15,16). SMARCA2/BRM was retained in the present cases; however, the status of SMARCC1/BAF155 and SMARCC2/BAF170 remained unknown. Therefore, deficiency of other subunits of the SWI/SNF complex may be present in cases with unknown loss/genetic alterations. The diagnosis as “rhabdoid neoplasm” was able to be made by histological features; however, there seem to be limitations for making a definite diagnosis without certain molecular features. Other differential diagnoses may include NSCLC with rhabdoid features, although disease entities and differential diagnoses may remain controversial. Further studies are required to clarify the key genetic alterations in unknown cases.

In Case 2 with SMARCB1/INI1-deficiency, the clinicopathological features were consistent with previously reported SMARCB1/INI1-deficient intrathoracic tumors (6,7,10). The patient was a man with a history of smoking, and the tumors showed rapid progression in this study. In a series of SMARCB1/INI1-deficient intrathoracic tumors reported by Haberecker et al. (6), 89% of the patients were men with a wide age distribution, and 75% of patients had a smoking history. The tumors presented as lung, pleura, thoracic wall, and/or mediastinal masses, and the tumor size ranged from 3.5 to 15.8 cm (mean, 7 cm). All patients died of progressive disease, and metastatic disease was detected in 56% of patients at presentation in their study (6). The tumors were stratified into morphological sub-groups: epithelioid, rhabdoid, mixed, and solid (6). Case 2 in this study may be subclassified as a mixed type (epithelioid and rhabdoid) according to their subgroups (6).

Interestingly, both intrathoracic undifferentiated/rhabdoid neoplasms in the present study arose in patients with hematological disorders treated with hematopoietic stem/progenitor cell transplantation (HCT) or chemotherapy. Secondary neoplasia is a well-known complication of HCT (17,18). Secondary neoplasia after HCT other than post-transplant lymphoproliferative disorders includes therapy-related myeloid neoplasms, donor-derived malignancy, and second solid neoplasms (SSNs) (18). The incidence of SSN is 2.2% at 10 years and 6.7% at 15 years (19). SSN after HCT has been demonstrated in the breast, thyroid, skin, liver, lung, and other organs. Little is known about the pathogenesis of SSN after HCT; however, the involvement of an interaction between cytotoxic treatment, genetic predisposition, environmental factors, viral infections, GVHD, and immunosuppression has been reported (18-20). Since it is plausible that both cases were in immunosuppressive states in this study, the tumors may have arisen as SSN in both cases (18-20). To our knowledge, SSN with undifferentiated or rhabdoid features have not been reported. Therefore, there may be no associations between the undifferentiated/rhabdoid features and histogenesis of SSN (18-20).

In summary, we presented two cases of intrathoracic undifferentiated/rhabdoid neoplasms showing rapid progression in patients with hematological abnormalities and possible immunosuppressive conditions. Clinicians and pathologists should consider the possibility of rapidly progressive neoplasms, such as intrathoracic undifferentiated/rhabdoid neoplasm, as a differential diagnosis for pneumonia in immune-suppressive situations.

The authors state that they have no Conflict of Interest (COI).

Supplementary Material

Supplementary table 1

Table 1. Primary antibodies used