Pseudomesotheliomatous Carcinoma of the Lung with Morphological Characteristics of Signet Ring Cell Carcinoma: An Autopsy Case Report

Abstract

A 50-year-old woman presented with left pleural effusion. A pleural fluid cell-block specimen and longitudinal lymph node needle biopsy suggested signet ring cell carcinoma (SRCC). Although computed tomography showed a consolidation shadow in the left lower lobe, a left lung biopsy could not be performed. Upper gastrointestinal endoscopy revealed no malignancies. We administered carboplatin, pemetrexed, ipilimumab, and nivolumab for lung cancer; however, she died due to progressive respiratory failure. Pathological autopsy revealed that the left pleura was thickened as in mesothelioma, based on which pseudomesotheliomatous carcinoma of the lung (PMCL) was diagnosed. PMCLs exhibiting an SRCC morphology are rare.

Introduction

Pseudomesotheliomatous carcinoma of the lung (PMCL), characterized histologically by diffuse invasion of the visceral and mural pleura and mesothelioma-like extension into the pleura, is a rare form of peripheral lung cancer that is different from malignant pleural mesotheliomas and presents a poor prognosis (1). Signet ring cell carcinoma (SRCC), a subtype of adenocarcinoma, occurs in various organs, including the gastrointestinal tract. However, primary SRCC of the lung, which shows gastrointestinal traits immunohistochemically, is rare, accounting for 0.14-1.9% of all lung cancers (2). PMCL exhibiting the morphology of SRCC is very rare, and only one such case has been previously reported (3).

We herein report a case of PMCL with the morphology of an SRCC.

Case Report

A 50-year-old woman with dry cough presented to a physician. One year prior, a complete medical check-up had shown no notable findings, and her medical history was unremarkable, with no history of smoking or exposure to asbestos. The patient had no family history of cancer. Chest radiography showed left pleural effusion, and blood test results revealed elevated CA19-9 levels. She was referred to our hospital due to a suspicion of malignancy and hospitalized for respiratory failure owing to increased left pleural effusion. Although she had been scheduled to undergo positron emission tomography-computed tomography (CT) at another hospital before admission, she had been unable to do so due to progressive respiratory failure.

On admission, physical examination findings were as follows: Eastern Cooperative Oncology Group performance status, 1; oxygen saturation, 95% (nasal cannula, 3 L/min); and respiratory rate, 24 breaths per min. Respiratory sounds were diminished in the left lung, and mild crackles were heard. Superficial lymph nodes were not palpable. Among serum tumor markers, CEA, CA19-9, CA125, CYFRA, and SLX levels were elevated to 6.8 ng/mL (reference interval: 0-5 ng/mL), 29,724 U/mL (0-37 U/mL), 144 U/mL (0-35 U/mL), 15.68 ng/mL (<3.5 ng/mL), and 106 U/mL (<38 U/mL), respectively (Table). Chest radiography on admission revealed left pleural effusion and reduced X-ray penetration in both lungs (Fig. 1A). Chest CT showed a shadow in the lower lobes of the left lung that could indicate either atelectasis or a nodule shadow (Fig. 1B); no lesions at other sites could be considered primary lesions based on contrast-enhanced whole-body CT. In addition, the mediastinal and hilar lymph nodes were enlarged (Fig. 1C), and a thrombus was observed in the inferior lobe of the right pulmonary artery.

Table.

Laboratory Data on Admission.

Hematology					Serology
WBC		8,200	/μL		CRP		9.09	mg/dL
Neu		78.6	%		KL-6		260.3	U/mL
Lym		13.4	%
Mon		4.7	%		Coagulation
Eos		2.2	%		D-dimer		24.8	μg/dL
Bas		1.1	%		PT-INR		1.16
RBC		3.50	×106/μL		APTT		26.4	s
Hb		10.4	g/dL
Hct		32.5	%		Tumor markers
PLT		25.1	×104/μL		CEA		6.8	ng/mL
					CA19-9		29,724	U/mL
Biochemistry					CA125		144	U/mL
TP		6.8	g/dL		CA15-3		17.3	U/mL
Alb		3.1	g/dL		CYFRA		15.68	ng/mL
AST		18	U/L		Pro-GRP		35.47	pg/mL
ALT		12	U/L		SLX		106	U/mL
LDH		372	U/L
ALP		82	U/L
BUN		17.2	mg/dL
Cr		0.70	mg/dL
Na		140	mmol/L
K		3.9	mmol/L
Cl		103	mmol/L

Alb: albumin, ALP: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, Bas: basophil, BUN: blood urea nitrogen, CA: carbohydrate antigen, CEA: carcinoembryonic antigen, Cr: creatinine, CRP: C-reactive protein, CYFRA: cytokeratin fragment, Eos: eosinophil, Hb: hemoglobin, Hct: hematocrit, KL-6: Krebs von den Lungen-6, LDH: lactate dehydrogenase, Lym: lymphocyte, Mon: monocyte, Neu: neutrophil, PLT: platelet, Pro-GRP: progastrin-releasing peptide, PT-INR: prothrombin time-international normalized ratio, RBC: red blood cell, SLX: sialyl-Lewis X antigen, TP: total protein, WBC: white blood cell

Figure 1.

Chest radiograph on admission showing left pleural effusion and decreased permeability of both lungs (A). Chest CT after pleural fluid drainage showing a consolidation shadow in the lower lobe of the left lung (B, arrowhead); however, contrast-enhanced whole-body CT showed no other lesions that could be considered primary lesions. The mediastinal and hilar lymph nodes are enlarged (C, arrows). CT: computed tomography

A pleural fluid cell-block specimen analysis showed atypical cell clusters with mucus in the cytoplasm mixed with reactive mesothelial cells and neutrophils (Fig. 2). Scattered images also showed ubiquity of the nuclei, corresponding to SRCC. An immunohistochemical examination revealed that the tumor cells were positive for CK7, CA19-9, and HGM; partially positive for MUC5AC; and negative for CK20, TTF-1, napsin A, ER, PgR, and p16, indicating the intratumoral spread of adenocarcinoma with a gastric phenotype.

Figure 2.

The pleural cell-block specimen showing a group of atypical cells with mucus in the cytoplasm. In addition, scattered images show the uneven distribution of nuclei, which correspond to findings compatible with signet ring cell carcinoma [A, Hematoxylin and Eosin (H&E) staining, low-power field; B, H&E staining, high-power field].

Based on findings from the pleural fluid cell-block specimen and tumor markers, gastrointestinal or gynecological cancer was suspected. However, upper gastrointestinal endoscopy, contrast-enhanced whole-body CT, and contrast-enhanced magnetic resonance imaging with uterine and ovarian scans did not show any lesions suspected to be primary lesions. An ultrasound bronchoscopy-guided needle biopsy of the subcarinal lymph node and an endometrial biopsy revealed a morphologic image of an SRCC with gastric-type morphology similar to the malignant cells in the pleural fluid. Lung biopsies of the consolidation in the left lower lobe and colonoscopy could not be performed because of worsening respiratory status.

As most lesions were located in the thoracic cavity and consolidation was observed in the lower lobe of the left lung, which could also correspond to a primary lesion, we decided to treat the patient for primary lung cancer. As there were not enough samples of mediastinal lymph node biopsy tissue to allow for genetic testing, we performed such testing on a cell-block specimen. The tumor was negative for the EGFR mutation, ALK fusion gene, ROS1 fusion gene, and BRAF V600E mutation and expressed programmed death ligand 1 (PD-L1) (22C3) with a tumor proportion score (TPS) between 1% and 24%. The 2022 Japanese Lung Cancer Society Guidelines recommend a regimen of platinum-based therapy plus an immune checkpoint inhibitor as the first-line treatment for advanced non-small-cell lung cancer for PD-L1 TPS 1-49% with a negative driver gene abnormality. The patient was administered carboplatin (area under the curve, 4), pemetrexed (400 mg/m²), ipilimumab (1 mg/kg), and nivolumab (360 mg); this regimen was selected because the patient presented with a pulmonary embolism, for which an angiogenesis inhibitor would be inappropriate, and because we expected a therapeutic effect from the addition of the anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody due to her relatively young age and rapid progression of the tumor. However, the general condition of the patient showed a deteriorating trend due to tumor progression, so chemotherapy was administered at a reduced dose. The patient was also treated with apixaban for pulmonary artery embolism. Unfortunately, the patient died from respiratory failure on day 37 after admission to our hospital. Autopsy was performed with the consent of her family.

An open chest examination revealed 600 mL of serous pleural effusion on the right side and 500 mL of hematogenous effusion on the left side. The left lung was firmly adhered to the chest wall and diaphragm. The left pleura was thickened as in mesothelioma, and tumor seeding was observed in the right visceral pleura (Fig. 3). The tumor consisted of a thickened pleura and diaphragm, with a mesothelioma-like extension invading the lung. However, no intrapulmonary lesions (possibly the primary site) were evident, despite obtaining multiple specimens from the lower lobe of the left lung at a site considered to represent atelectasis or a nodule.

Figure 3.

Macroscopic findings at autopsy. The left pleura is thickened as in mesothelioma, and the right pleura shows tumor seeding.

Immunohistochemical examinations showed that the tumor was diffusely positive for CK7, CA19-9, and HGM; positive for MUC5AC; and focally positive for PE-10, MUC6, and CK20 (Fig. 4). However, it was negative for TTF-1, napsin A, calretinin, D2-40, villin, and CDX-2. The tumor had a gastric phenotype, and a detailed examination of the gastrointestinal tract revealed an intramural extension of the tumor into the duodenal bulb and gastric pylorus but no evidence of a primary tumor. In addition, there was a high degree of lymphangitis carcinomatosa in both lungs. Pulmonary artery embolization was observed in a small artery in the lower lobe of the right lung, and the embolus was interspersed with tumors. Furthermore, pulmonary tumor thrombotic microangiopathy (PTTM) was highly evident in the small arteries of both lungs. In addition, there were a few findings that suggested drug-induced pneumonia. Therefore, respiratory failure due to lymphangitis carcinomatosa and PTTM was considered to have been the direct cause of death.

Figure 4.

Microscopic findings at autopsy. (A) Tumor cell infiltration is observed in the thickened pleura (*). (B) Carcinomatous lymphangiopathy with tumor cells in the form of poorly differentiated adenocarcinoma and signet ring cell carcinoma is noted [A, Hematoxylin and Eosin (H&E) staining, low-power field; B, H&E staining, high-power field]. Immunohistochemical examinations showed that the tumor was diffusely positive for CK7, CA19-9, and HGM; positive for MUC5AC; focally positive for PE-10, MUC6, and CK20; and negative for TTF-1, napsin A, calretinin, D2-40, villin, and CDX-2.

The gross findings of the autopsy included diffuse thickening of the left visceral pleura, as seen in mesothelioma; however, the epithelial mesothelioma marker was negative, and no findings suggested asbestos exposure. In addition, the tumor extended mainly within the thorax to the bilateral hilar and peritracheal lymph nodes and was positive for PE-10, which is highly specific for pneumocytes, leading to a diagnosis of PMCL. Although there was direct invasion from the pleura, there were no obvious metastatic lesions within the lungs. However, the tumor had metastasized to the bilateral pleura, diaphragm, stomach, duodenum, gallbladder, pancreas, uterus, cervix, bilateral ovaries, peritoneum, mesentery, and several lymph nodes, including the bilateral hilar, peritracheal, perigastric, peripancreatic, and periaortic lymph nodes.

Discussion

PMCL was first reported by Harwood et al. in 1976 (1) and accounts for approximately 0.46% of all lung cancers, with adenocarcinoma being the most common histological type (4,5). PMCL occurs more frequently in men and heavy smokers than in others, and as with malignant pleural mesothelioma, exposure to asbestos has been reported as its etiology (5-7). Owing to extensive pleural involvement, multiple lung cancerous lesions, and a lack of effective treatment, PMCL has a poor prognosis, showing a median survival of 8 (0.5-14) months (6). Differentiating a PMCL from a malignant mesothelioma based on radiological findings alone is difficult because of the tumor's growth pattern; immunohistochemical methods are thus necessary for the differential diagnosis (5,8). In the present case, gross findings on autopsy showed a mesothelioma-like extension; nonetheless, findings for the epithelial mesothelioma markers calretinin and D2-40 were negative. TTF-1 and napsin A, which are commonly used to diagnose lung adenocarcinoma, were negative; however, PE-10, a lung surfactant marker, was focally positive. In addition, the left pleura was thickened, as in mesothelioma; tumor extension was observed in the bilateral hilar and peritracheal lymph nodes; and a high degree of lymphangitic carcinomatosa was observed, leading to a diagnosis of PMCL with the left pleura as the primary site of the lesion.

Autopsy findings showed that approximately 50% of the tumor cells had an SRCC component. The histology of primary lung SRCC is similar to that of SRCC occurring in gastrointestinal tract organs, such as the stomach (2). As SRCC can occur in various organs, a systematic search should be performed to identify the primary tumor. Primary lung SRCC with immunohistochemical evidence of gastrointestinal tract traits accounts for 0.14-1.9% of all lung cancers (2). A retrospective study of 39 cases of primary lung cancer with SRCC traits showed that the mean age at the diagnosis was 54.6 years old, which is often considered an early onset of the disease (2). In addition, high-SRCC with an SRCC component of ≥50% has a higher frequency of an early onset, vascular and lymphatic invasion, and lymph node metastasis than low-SRCC, which has a component of <50%, or non-SRCC (2,9). Our patient also had high-SRCC, which showed rapid progression at a relatively young age and was associated with a poor prognosis.

Recently, cancer-related genes have been identified in various types of malignancies, including lung cancer, and molecular-targeted drugs have been developed for patients with such genes (10). In the case of PMCL treated with next-generation sequencing, the splicing factor 3B subunit 1 (SF3B1) gene was identified (8). SF3B1 is often found in hematologic malignancies and breast, pancreatic, and prostate cancers and is associated with a poor prognosis and drug resistance in chronic lymphocytic leukemia (11). In addition, a patient with PMCL harboring a HER2 mutation who responded to bevacizumab combination chemotherapy has been reported (12). In contrast, lung adenocarcinomas with SRCC components have an increased frequency of ALK fusion genes (13). Furthermore, KRAS mutations are frequently found in mucus-producing lung adenocarcinomas, and 60% of patients with SRCC were reported to be positive for these mutations (14). In the present case, the patient was a nonsmoker presenting with early-onset lung adenocarcinoma, and some driver gene abnormalities may have been involved in the development of the carcinoma. However, because a comprehensive cancer genome profile was not feasible due to the rapidly deteriorating general condition of the patient, a single plex test was performed for EGFR, ALK, ROS1, and BRAF genes, all of which were negative. In addition, the findings of the autopsy specimen were negative for HER2 immunohistochemical staining.

PMCL and SRCC are rare, with each accounting for approximately 1% of lung cancer cases, and only one case of PMCL showing the morphology of SRCC has been previously reported (3). To our knowledge, this is the first case report of PMCL with morphological characteristics of SRCC in which genetic abnormalities were examined.

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