Abstract
Signet ring cell carcinoma, a subtype of adenocarcinoma, is a rare cause of primary lung cancer. The authors report a case of primary lung signet ring cell carcinoma presenting as a cavitary Pancoast tumor in a 32-year-old male smoker. Beyond the rarity of primary lung signet ring cell carcinoma itself, the youth of the patient, his smoking status, the presence of cavitation, and the location of the tumor in the superior sulcus make it especially atypical.
Lung cancer is the most common cause of cancer worldwide and represents a major cause of morbidity and mortality. In the United States, lung cancer occurs in approximately 225,000 people and causes more than 160,000 deaths each year.
1
The classification of lung cancer into various subtypes has provided physicians with valuable information regarding treatment and prognosis. The World Health Organization (WHO) has traditionally provided the framework for such classification. The WHO classification system is based on the evaluation of traditional tissue biopsy specimens, as well as newer diagnostic techniques, including immunohistochemical staining.
2
According to the 2015 WHO classification system, adenocarcinoma is the most common form of lung cancer, representing approximately 38% of all cases.
2 There are several subtypes of adenocarcinoma. Signet ring cell carcinoma (SRCC) is one form and is marked by a characteristic histologic appearance, whereby the cells resemble signet rings. These signet ring cells acquire their appearance because of the presence of mucin-filled vacuoles that displace the nucleus to the periphery of the cytoplasm.
3,4
Primary SRCC most frequently occurs in the stomach but may also originate elsewhere in the gastrointestinal tract, as well as in the prostate, ovarian stroma, and testis.
5 Pulmonary SRCC is rare. When it does occur, most cases represent metastasis from the gastrointestinal tract.
6 Primary lung SRCC is exceedingly rare. First described by Kish et al
7 in 1989, it has been reported that primary lung SRCC represents only 0.1% to 1.9% of all lung carcinomas.
5,6
Primary lung SRCC is most commonly seen in elderly persons and in smokers. A large retrospective analysis conducted by Ou et al
8 noted the mean age of presentation to be 64 years, with less than 5% of cases occurring in patients younger than 40 years. A large case series by Tsuta et al
5 reported that 67% of patients with SRCC were smokers. Neither study reported statistically significant differences in sex, with Tsuta et al
5 reporting a male-to-female ratio of 1.16:1.00.
Several demographic and prognostic differences exist between primary lung SRCC and non-SRCC lung adenocarcinomas and among smoking and nonsmoking subgroups. Ou et al
8 showed that patients with primary lung SRCC were younger than patients with non-SRCC lung adenocarcinoma (64 vs 67 years, respectively), had more advanced disease, and had decreased overall survival (6 vs 10 months, respectively). Subset analysis comparing never-smokers to ever-smokers revealed that never-smokers comprised a higher portion of patients with primary lung SRCC (31%) compared with patients with non-SRCC (11%) lung adenocarcinoma. Never-smokers with primary lung SRCC were younger and had improved overall survival (median age, 55 years; median overall survival, 8 months) compared with ever-smokers with primary lung SRCC (median age, 59 years; median overall survival, 4.5 months).
Like all cancers, the definitive diagnosis of primary lung SRCC is made by tissue biopsy with histopathologic examination and immunohistochemical staining. Immunohistochemical staining techniques are particularly important in the diagnosis of SRCC for several reasons. First, the histopathologic appearance of SRCC can be mimicked by other phenomena, such as tumor cell balloon type degeneration, clear cell change, and cytoplasmic vacuolization.
9 Consequently, accurately separating true SRCC from these mimics can be challenging. Second, primary pulmonary SRCC must be discerned from metastatic SRCC. The immunohistochemical staining profile for primary lung SRCC typically features positivity for TTF-1, CK7, and napsin A, with negativity for CK20 and CDX-2.
9,10
Primary lung SRCC has recently been associated with rearrangements of the
ALK and
ROS1 genes. A 2014 study by Boland et al
9 found
ALK rearrangements in 14 of 53 SRCC cases (26%) and
ROS1 rearrangements in 3 of 47 SRCC cases (6%). The presence of these rearrangements has therapeutic significance, as tumors with
ROS1 rearrangements and the
EML4-
ALK translocation have been shown to respond to the small-molecule
ALK inhibitor, crizotinib.
8-10
Here we report a case of primary lung SRCC presenting as a cavitary Pancoast tumor in a 32-year-old male smoker. Beyond the rarity of primary lung SRCC itself, we discuss several features of the case that make it noteworthy.
A 32-year-old man with a medical history significant for cigarette smoking (10 pack years) presented to the emergency department with chest pain that started several months earlier. The pain was initially localized to the left anterior region of the chest and later began to involve the left shoulder with radiation to the left arm. No apparent motor or sensory deficits in the left upper extremity were found, and no detectable elements of Horner syndrome were observed.
A subtle left apical opacity was noted on single-view anteroposterior chest radiograph (
Figure 1), and a non–contrast-enhanced chest radiograph (
Figure 2) disclosed a 4.0×4.0×2.7-cm lesion in the left medial pulmonary apex, abutting the superior mediastinum. A focus of air was seen within the periphery of this lesion, along the lateral inferior aspect. The lesion demonstrated a mildly spiculated border, suspicious for malignancy.
The patient was admitted to the hospital for further evaluation. Staging imaging studies included computed tomography (CT) of the head, CT of the abdomen and pelvis, positron-emission tomography of the chest, magnetic resonance (MR) imaging of the brain, and MR imaging of the thoracic outlet. No evidence of other primary lesions, nodal involvement, direct brachial plexus involvement, or metastases was found.
Computed tomography-guided core-needle biopsy was performed, and tumor cells were noted to have the histopathologic appearance of signet ring cells. Immunohistochemical staining yielded a profile consistent with primary lung SRCC, including TTF-1 positivity, CK7 positivity, napsin A positivity, CDX-2 negativity, and CK20 negativity. The result of PD-L1 analysis was also positive for primary lung SRCC. Fluorescence in situ hybridization panel testing did not show evidence of rearrangements of the ALK or ROS1 genes. Stage IIb T3N0 primary lung SRCC was diagnosed.
The patient was treated with chemotherapy (etoposide and cisplatin), surgical resection, radiation, and immunotherapy with pembrolizumab. He developed adrenal and brain metastases approximately 13 months after initial diagnosis and received 2 courses of gamma stereotactic radiosurgery, whole brain radiotherapy, and additional chemotherapy. His disease eventually progressed, and he was provided hospice care after leptomeningeal involvement developed. He died approximately 21 months after the initial diagnosis.
Given the rarity of primary lung SRCC, any reported case presents an opportunity to enhance our understanding of the disease. Several features of this case are atypical. First, our search of the literature revealed that our patient was the youngest documented patient with primary lung SRCC in a male ever-smoker. Second, primary SRCC is strongly associated with a solid tumor type.
3 A review of the literature did not reveal any known cases of cavitary primary SRCC. Third, less than 5% of all lung cancers are Pancoast tumors. Of that 5%, about two-thirds are adenocarcinomas, with the remainder being large cell and squamous cell carcinomas.
11 A search of the literature revealed no other reported cases of primary SRCC presenting as a Pancoast tumor. Last, this patient's 21-month survival was uncharacteristically long.
8 These atypical demographic, anatomic, and prognostic features suggest potentially greater variability in the assumed typical behavior of primary lung SRCC. Conversely, the immunohistochemical staining profile of this case was quite typical, reinforcing the reliability of these markers in diagnosing primary lung SRCC.
Although this case involves a disease that most physicians will never encounter, it illustrates several points that are applicable to the everyday practice of medicine. A careful history performed in the emergency department alerted the physician to the possibility of a superior sulcus mass and facilitated the recognition of subtle findings on the chest radiograph. In this age of increased technology use, the value of basic clinical skills can sometimes be underappreciated. This case serves as a reminder of the diagnostic power of a thorough history. Simultaneously, it also provides an example of the utility of technologically advanced diagnostic techniques. The need to separate true SRCC from histopathologic mimics and primary lung SRCC from metastatic SRCC necessitates the use of immunohistochemical staining. An accurate diagnosis of primary lung SRCC in this patient could not have occurred without it.
This case report illustrates that primary lung SRCC, a rare disease itself, can present in an atypical fashion and in an atypical patient demographic. Specifically, it demonstrates that primary lung SRCC can occur in young ever-smokers and, furthermore, that it can cavitate and present as a Pancoast tumor. Additional case reports, case series, and large studies are necessary to refine our understanding of the characteristics of primary lung SRCC, the prognostic significance of these characteristics, and the selection of specific therapies based on the presence or absence of gene rearrangements.