|Year : 2023 | Volume
| Issue : 1 | Page : 25-29
Signet-ring cell adenocarcinoma of the lungs: An unusual and rare case
Ravindran Chetambath, Nadini Sylesh, K Praveen Kumar, Gayathri Nair Karedath, Anju Chacko
Department of Pulmonology & Pathology, Baby Memorial Hospital, Kozhikode, Kerala, India
|Date of Submission||16-Sep-2022|
|Date of Acceptance||25-Oct-2022|
|Date of Web Publication||27-Dec-2022|
Dr. Ravindran Chetambath
Navaneeth, Civil Station, Kozhikode - 673 020, Kerala
Source of Support: None, Conflict of Interest: None
Signet-ring cell adenocarcinomas (SRCCs) are rare tumors that most commonly originate from the stomach, colon, or breast. Lung as a site of the primary signet-ring variant of adenocarcinoma is extremely uncommon. Primary SRCC of the lung is a highly aggressive variant of adenocarcinoma with characteristic clinicopathological features. Here, we present a case of a young female with a rapidly progressive tumor in the left lung with metastasis to the pleura, pericardium, and lymph nodes having a histopathological proof of primary adenocarcinoma with signet-ring features.
Keywords: Adenocarcinoma, anaplastic lymphoma kinase mutation, signet-ring cell, thyroid transcription factor-1
|How to cite this article:|
Chetambath R, Sylesh N, Kumar K P, Karedath GN, Chacko A. Signet-ring cell adenocarcinoma of the lungs: An unusual and rare case. J Adv Lung Health 2023;3:25-9
|How to cite this URL:|
Chetambath R, Sylesh N, Kumar K P, Karedath GN, Chacko A. Signet-ring cell adenocarcinoma of the lungs: An unusual and rare case. J Adv Lung Health [serial online] 2023 [cited 2023 Jun 10];3:25-9. Available from: https://www.jalh.org//text.asp?2023/3/1/25/365492
| Introduction|| |
Pulmonary adenocarcinoma with signet-ring features (PASRF) is a rare variant of pulmonary adenocarcinoma. Signet-ring cell adenocarcinoma (SRCC) can be primary or metastatic. Usually, it presents as metastasis from the stomach, colon, or breast. Lung as a site of the primary signet-ring variant of adenocarcinoma is extremely uncommon, with very few reports available in the literature.,, It is most common in nonsmokers and younger ages with no sex predilection. It follows a more aggressive clinical course. Histopathologically, it is characterized by tumor cells that are filled with intracytoplasmic mucin and an eccentrically displaced nucleus, giving an appearance of a signet ring. Adenocarcinomas showing more than 50% signet-ring cell morphology are considered SRCC. SRCC component is also considered a potential prognostic factor in primary lung tumors with a higher proportion of signet-ring cells associated with worse outcomes. Signet-ring cell feature in lung adenocarcinoma is no longer considered a distinct subtype, but as a cytologic change that may occur in association with multiple histological patterns. About 3%–7% of SRCC pulmonary adenocarcinomas are found to be positive for anaplastic lymphoma kinase (ALK) gene rearrangement, which is associated with a better response to targeted chemotherapy.
| Case Report|| |
This is the history of a 39-year-old female, teacher by profession, presented with exertional dyspnea and cough for the past 5 months. She has dull aching chest pain on the left side for 3 months and hoarseness for 2 months. Her exertional dyspnea progressed from MMRC grade I to grade 3 over the past 5 months with a sudden worsening to grade 4 within the past 4 days and she was experiencing low-grade fever. Cough was predominantly dry in nature. Chest pain was on the left side, which was dull aching with no postural or diurnal variation and no radiation. She gave a history of COVID-19 infection (category A) 6 months back and hence being treated as a case of post-COVID lung for the past 5 months. There was no history of hemoptysis, or stidor. There was a history of losing 3 Kg weight in the past 5 months. Appetite was normal. There was no history of any significant illness in the past. Her father had a diagnosis of cancer in the oral cavity, the details of which were not available.
On examination, she was conscious and oriented. A hard, fixed, non-tender lymph node of size 2 cm × 1 cm was palpable in the left supraclavicular region. The patient was dyspnoec at rest with a respiratory rate of 24 breaths/min. Her blood pressure was 136/90 mm Hg. Oxygen saturation was 91% on room air.
The upper respiratory tract was normal. The trachea was shifted to the right. There was a fullness of the left hemithorax. Chest movements were reduced on the left. Chest expansion was 1.5 cm and it was 0.5 cm on the left. Vocal fremitus was decreased over the left side except over the left upper interscapular area, where it was increased. On percussion stony dull note was felt in the left mammary, infraaxillary, infrascapular, and lower interscapular areas. The dull note was percussed in infraclavicular, axillary, suprascapular, and upper interscapular areas on the left side. The resonant note was percussed on the right side. Liver dullness was percussed in the right 5th intercostal space in the midclavicular line. Tidal percussion was positive. Breath sound was absent over the left side except in the left upper interscapular area, where it was bronchial in quality. Vocal resonance was decreased over the left side except, the left upper interscapular area, where VR was increased.
A clinical diagnosis of a left lung mass with pleural effusion, left recurrent nerve palsy, and left supraclavicular lymph adenopathy was made.
Total white blood count count was slightly raised with polymorphonuclear cell predominance. All other blood investigations were within the normal limits. Sputum culture and sensitivity, sputum acid-fast bacilli and sputum fungal culture were within the normal limits. No malignant cells were detected in sputum cytology.
X-ray chest taken at the onset of symptoms (April 2022) showed superior mediastinal widening and elevated left dome of diaphragm [Figure 1]. X-ray chest during the present admission [Figure 2] showed a slight shift of trachea and mediastinum to right, homogeneous opacity occupying the left lung zone and an elevated left dome of the diaphragm.
|Figure 1: X-ray chest taken in April 2022 after one month of onset of symptoms. X-ray showed superior mediastinal widening and elevated left dome of diaphragm|
Click here to view
|Figure 2: X-ray chest PA view taken in July 2022 which showed slight shift of trachea and mediastinum to right, homogenous opacity occupying left lung zone and an elevated left dome of diaphragm. PA: Posteroanterior|
Click here to view
Contrast-enhanced computed tomography of the thorax was done, which demonstrated homogeneously enhancing mass lesion in the left upper lobe with the collapse of the left lung and left pleural effusion [Figure 3]. Minimal pericardial effusion and mediastinal adenopathy were also seen. Mass encases the left main pulmonary artery, aorta, esophagus, phrenic nerve, and recurrent laryngeal nerve. Left main bronchus is completely occluded [Figure 4]a and [Figure 4]b.
|Figure 3: Contrast enhanced CT thorax (Mediastinal windows) (a and b) showed large homogeneously enhancing mass lesion in the left upper lobe with collapse of left lung and left pleural effusion. (CT: Computed tomography)|
Click here to view
|Figure 4: Contrast enhanced CT thorax (a: Mediastinal window, b: Lung Window) showed large homogenously enhancing mass lesion in the left upper lobe with collapse of left lung, left pleural effusion, pericardial effusion and mediastinal adenopathy. Mass encases left main pulmonary artery, aorta, esophagus, phrenic nerve and recurrent laryngeal nerve. Left main bronchus is completely occluded. CT: Computed tomography|
Click here to view
Moderate pericardial effusion was detected with no evidence of cardiac tamponade. No regional wall motion abnormality was detected, and left ventricular function was normal.
Bronchoscopy revealed left vocal cord palsy, normal trachea, and blunt carina with multiple nodular lesions. The right bronchial tree was normal. The left main bronchus was completely occluded within 0.5 cm of the carina [Figure 5]. Biopsy was taken from the nodular lesions near the carina. Bronchial washings were sent for mycobacterium tuberculosis polymerase chain reaction and cytology. Both were negative. Result came as pulmonary adenocarcinoma- signet-ring cell variant. Histopathological examination of bronchial biopsy shows signet-ring cells arranged in lobules [Figure 6]a, [Figure 6]b, [Figure 6]c, [Figure 6]d.
|Figure 5: Videobronchoscopy image showed widened carina, inflamed mucosa, multiple nodular lesions and an obstructed left main bronchus|
Click here to view
|Figure 6: Histopathological examination (a and b: Low power field and, c and d: High power field) of lung biopsy shows signet ring cells arranged in lobules. Cells showed abundant cytoplasm pushing the nucleus to one side attaining a signet ring shape|
Click here to view
Ultrasonography (USG) neck
Multiple enlarged lymph nodes were seen in the left level IV region and left supraclavicular region. Another similar hypoechoic lymph node was seen in the right level IV station.
Fine-needle aspiration cytology left supraclavicular lymph node showed metastasis from poorly differentiated carcinoma.
Lymph node biopsy
Excision biopsy of the left supraclavicular lymph node was done, and the report came as metastasis from SRCC of the lung [Figure 7]a.
|Figure 7: (a) Lymph node biopsy showing features of signet-ring cell adenocarcinoma metastasis from the lung. Immunohistochemistry revealing tumor cells positive for CK 7 (b), negative for CK 20 (c) and positive for TTF1 (d). CK: Cytokeratin, TTF1: Thyroid transcription factor-1|
Click here to view
Immunohistochemistry staining revealed tumor cells positive for cytokeratin (CK) 7 [Figure 7]b, negative for CK 20 [Figure 7]c and positive for thyroid transcription factor-1 (TTF1) [Figure 7]d.
Adenocarcinoma lung – signet-ring cell type with supraclavicular lymph node metastasis, pleural and pericardial effusion, and involvement of left recurrent laryngeal nerve and left phrenic nerve.
| Discussion|| |
SRCC is a variant of mucin-producing adenocarcinoma, which most commonly arises from the stomach, colon, urinary bladder, prostate, and breast. Primary SRCC in the lung is very rare, with very few reports available in the literature.,,, It is a highly aggressive tumor when found in the lung, but few case reports show good response in patients who were found positive for ALK mutation.,, This is most frequently seen in nonsmoking and younger patients with no sex predilection. Histopathologically, it is characterized by tumor cells that are filled with intracytoplasmic mucin and an eccentrically displaced nucleus, giving an appearance of a signet ring. Adenocarcinomas showing more than 50% signet-ring cells are considered SRCC. SRCC component is also considered a potential prognostic factor in primary lung tumors, with a higher proportion of signet-ring cell carcinomas meet with worse outcomes.
These cases represent an unusual histological growth pattern of primary lung adenocarcinoma that may be often mistaken for a metastasis from an occult primary. The recognition of this pattern of primary lung tumors is important for proper treatment. TTF-1 is a domain-containing transcription factor that is almost exclusively expressed in the thyroid as well as pulmonary epithelial cells. TTF-1 expression in a high percentage of pulmonary SRCCs is very specific, and hence, TTF-1 would be extremely valuable in distinguishing primary pulmonary SRCCs from metastatic lesions. Mucin-histochemistry showed a close similarity between lung SRCC and goblet cell-type or bronchial gland cell-type adenocarcinoma of the lung. Eighty percent of SRCCs showed positive immunoreactions for lactoferrin, a marker of bronchial gland cell differentiation, the results being consistent with the conclusions in previous studies that lung SRCC is closely related to bronchial gland cell-type adenocarcinoma. The incidence of K-ras mutation detected by the restriction fragment length polymorphism method was relatively high in lung SRCC (three of five) and goblet cell-type adenocarcinoma of the lung (four of four). Mucin-histochemistry indicated that lung SRCC has mucin production similar to that of the colon and colorectal-type SRCCs of the stomach but not to that of gastroduodenal-type SRCC of the stomach.
PASRF represents between 0.14% and 1.9% of all pulmonary adenocarcinomas. ALK gene mutations are present in 2%–7% of lung adenocarcinoma and are known to have a strong association with signet-ring subtype.
Comprehensive biological characteristics of pulmonary adenocarcinomas with signet-ring cell features (SRC⁺) are not well known. Boland et al. systematically evaluated clinical and molecular features of SRC-positive cases with particular attention to smoking status. Surgically treated lung adenocarcinomas (n = 763) with follow-up ≥5 years in three cohorts were reviewed: all patients in 2006 to 2007 (n = 222; 168 ever-smokers), a never-smoker cohort (n = 266), and a cohort of ever-smokers (n = 275). SRC-positive tumors had ≥10% of SRCs agreed by two pathologists. SRC-positive cases were tested for rearrangement of ALK and ROS1, as well as 187 known mutations in 10 oncogenes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET, and PIK3CA. Overall, 53 of 763 cases (7%) were SRC positive. In the 2006 to 2007 cohort, 9% were SRC positive. In the never-smoker cohort, 9% were SRC positive. In the smoker cohort, 3% were SRC positive. Univariate analysis showed that SRC positive, never-smokers had shorter overall and disease-free survival (P = 0.006 and 0.0004, respectively). For the other two cohorts, crude 5-year survival was decreased by 6% to 27% in SRC-positive cases without reaching statistical significance. In SRC-positive tumors, KRAS mutation was most common (29%), followed by ALK (26%), EGFR (18%), ROS1 (6%), BRAF (6%), and PIK3CA (3%). Clinical management of this cancer is challenging, with chemoradioresistance and poor outcomes in advanced stages. Most of these patients present at an advanced stage with an aggressive course. If limited to the thoracic cavity, surgery and chemotherapy are preferred. If extended outside the thorax, chemotherapy and radiotherapy are advised. About 3%–7% of SRCC pulmonary adenocarcinomas are found to be positive for ALK gene rearrangement, which is associated with a better response to crizotinib therapy.
| Conclusion|| |
SRCC is a variety of mucin-producing adenocarcinoma, which most commonly arises from the stomach, colon, urinary bladder, prostate, and breast. Lung as a site of the primary signet-ring variant of adenocarcinoma is extremely uncommon, with very few reports available in the literature. It is a highly aggressive tumor when found in the lung, but few case reports show good response in patients who were found positive for ALK mutation.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hayashi H, Kitamura H, Nakatani Y, Inayama Y, Ito T, Kitamura H. Primary signet-ring cell carcinoma of the lung: Histochemical and immunohistochemical characterization. Hum Pathol 1999;30:378-83.
Merchant SH, Amin MB, Tamboli P, Ro J, Ordóñez NG, Ayala AG, et al.
Primary signet-ring cell carcinoma of lung: Immunohistochemical study and comparison with non-pulmonary signet-ring cell carcinomas. Am J Surg Pathol 2001;25:1515-9.
Castro CY, Moran CA, Flieder DG, Suster S. Primary signet ring cell adenocarcinomas of the lung: A clinicopathological study of 15 cases. Histopathology 2001;39:397-401.
Tsuta K, Ishii G, Yoh K, Nitadori J, Hasebe T, Nishiwaki Y, et al.
Primary lung carcinoma with signet-ring cell carcinoma components: Clinicopathological analysis of 39 cases. Am J Surg Pathol 2004;28:868-74.
Nishino M, Klepeis VE, Yeap BY, Bergethon K, Morales-Oyarvide V, Dias-Santagata D, et al.
Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol 2012;25:1462-72.
Ha SY, Ahn J, Roh MS, Han J, Lee JJ, Lee B, et al.
Cytologic features of ALK-positive pulmonary adenocarcinoma. Korean J Pathol 2013;47:252-7.
Lee HY, Ahn HK, Jeong JY, Kwon MJ, Han JH, Sun JM, et al.
Favorable clinical outcomes of pemetrexed treatment in anaplastic lymphoma kinase positive non-small-cell lung cancer. Lung Cancer 2013;79:40-5.
Vallonthaiel AG, Jain D, Madan K, Arava S. Pulmonary adenocarcinoma with signet ring features: Detailed cytomorphologic analysis. Diagn Cytopathol 2016;44:607-11.
Boland JM, Wampfler JA, Jang JS, Wang X, Erickson-Johnson MR, Oliveira AM, et al.
Pulmonary adenocarcinoma with signet ring cell features: A comprehensive study from 3 distinct patient cohorts. Am J Surg Pathol 2014;38:1681-8.
Li Y, Zhu Z, Ma F, Xue L, Tian Y. Gastric signet ring cell carcinoma: Current management and future challenges. Cancer Manag Res 2020;12:7973-81.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]