Histopathology 2016, 68, 356–366. DOI: 10.1111/his.12763
Mucinous micropapillary pattern in lung adenocarcinomas: a unique histology with genetic correlates Tsugumasa Kamata,1,2,3 Akihiko Yoshida,1 Kouya Shiraishi,4 Koh Furuta,5 Tomoo Kosuge,3,6 Shun-ichi Watanabe,2 Hisao Asamura7 & Koji Tsuta1,8 1
Division of Pathology and Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan, 2Division of Thoracic Surgery, National Cancer Centre Hospital, Tokyo, Japan, 3Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan, 4Division of Genome Biology, National Cancer Centre Research Institute, Tokyo, Japan, 5Division of Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan, 6Division of Hepatobiliary and Pancreatic Surgery, National Cancer Centre Hospital, Tokyo, Japan, 7Department of Surgery, Division of General Thoracic Surgery, School of Medicine, Keio University, Tokyo, Japan, and 8Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan
Date of submission 20 March 2015 Accepted for publication 19 June 2015 Published online Article Accepted 25 June 2015
Kamata T, Yoshida A, Shiraishi K, Furuta K, Kosuge T, Watanabe S-i, Asamura H & Tsuta K (2016) Histopathology 68, 356–366. DOI: 10.1111/his.12763
Mucinous micropapillary pattern in lung adenocarcinomas: a unique histology with genetic correlates Aims: In lung adenocarcinoma (ADC), micropapillary carcinomas (MPCs) are associated with poor prognosis because these tumours exhibit higher metastatic potential. Despite this, there are no studies investigating the differences between mucinous and non-mucinous MPC. Methods and results: We evaluated the proportion of micropapillary components in lung ADCs, and compared the differences with respect to the presence or absence of associated mucin. Tumour specimens from 694 patients with consecutively resected primary lung ADC were reviewed, and 37 cases of invasive mucinous ADCs were excluded. A significant (≥5%) micropapillary component was noted in 320 (48.7%) of 657 evaluable cases. When the cases with
micropapillary component were divided into 67 (20.9%) mucinous and 253 (79.1%) non-mucinous subtypes, tumours with mucinous micropapillary component exhibited significantly more aggressive pathological features, a higher proportion of HER2 mutations (P = 0.002) and ALK rearrangements (P < 0.001), and a lower proportion of EGFR mutations (P = 0.038) compared to those with a non-mucinous micropapillary component. In survival analyses, mucinous MPC tended to be more aggressive compared with non-mucinous MPC, but its prognostic value was not statistically significant (P = 0.076). Conclusions: Mucinous micropapillary pattern is an under-recognized unique growth associated significantly with HER2 mutation and ALK rearrangement.
Keywords: human epidermal growth factor receptor 2 mutation, lung adenocarcinoma, micropapillary, mucinous
Introduction Primary lung adenocarcinomas (ADCs) have five major architectural growth patterns: lepidic, papilAddress for correspondence: K Tsuta, Department of Pathology and Laboratory Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. e-mail: [email protected]. ac.jp © 2015 John Wiley & Sons Ltd.
lary, acinar, micropapillary and solid. Approximately 80% of the cases show ≥2 of these growth patterns.1 In the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification, invasive ADCs are classified according to their predominant subtype.2 This new classification reflects disease prognosis, and defines associ-
Mucinous micropapillary pattern in lung ADCs
ated driver gene alterations.3 However, the presence of a small percentage of micropapillary or solid growth pattern is a strong predictor of poor prognosis and an increased risk of recurrence.4,5 Micropapillary carcinoma (MPC) was first described in the breast as a rare variant of invasive breast carcinoma,6 and subsequent studies have shown that breast MPC is a highly aggressive histological subtype.7–9 MPCs are also found in the salivary glands, lungs, ovaries, colon, pancreas and urinary bladder.10 In the lung, MPC is characterized by papillary structures with tufts lacking a central fibrovascular core and extensively shed within alveolar spaces. In lung ADC, micropapillary components are associated with poor prognosis, because these tumours exhibit higher metastatic potential.11–13 Recently, micropapillary mucinous breast carcinoma has been reported as an aggressive counterpart to conventional pure mucinous tumours.14 With the advent of molecular-targeted therapy for lung cancer, the presence or absence of mucin production in lung ADCs has become increasingly important. This was exemplified by evidence that the presence of a signetring cell component15 or a mucinous cribriform pattern16 was well correlated with anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusions. In addition, invasive mucinous ADCs (IMAs) have been associated with Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations as well as spread characteristically like lobar pneumonia, with distinctive clinical features different from non-mucinous ADCs.2 Conversely, non-mucinous lepidic, papillary and micropapillary subtypes were associated significantly with epidermal growth factor receptor (EGFR) mutations.2,17 To elucidate the clinicopathological differences of mucin production in lung MPC, we evaluated the proportion of micropapillary components in consecutively resected ADCs, and furthermore we compared the clinicopathological, immunohistochemical (IHC) and genetic differences of mucinous and non-mucinous MPC.
Materials and methods STUDY POPULATION
The patients gave informed consent, and the study was performed according to the Declaration of Helsinki. This study was approved by the Institutional Review Board of National Cancer Centre Hospital (2010-0077; Tokyo, Japan). Tumour specimens, © 2015 John Wiley & Sons Ltd, Histopathology, 68, 356–366.
357
surgically resected from patients diagnosed with primary lung ADC between January 1998 and December 2001, were reviewed retrospectively. Clinical information was collected regarding patient age, sex, smoking history, duration of any tumour recurrence and survival. HISTOLOGICAL ANALYSES
The records of the histological specimens and all available haematoxylin and eosin (H&E)-stained tissue sections, in addition to any available sections with specific stains or immunohistochemical analyses, were reviewed. Tumours
Mucinous micropapillary pattern in lung adenocarcinomas: a unique histology with genetic correlates Tsugumasa Kamata,1,2,3 Akihiko Yoshida,1 Kouya Shiraishi,4 Koh Furuta,5 Tomoo Kosuge,3,6 Shun-ichi Watanabe,2 Hisao Asamura7 & Koji Tsuta1,8 1
Division of Pathology and Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan, 2Division of Thoracic Surgery, National Cancer Centre Hospital, Tokyo, Japan, 3Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan, 4Division of Genome Biology, National Cancer Centre Research Institute, Tokyo, Japan, 5Division of Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan, 6Division of Hepatobiliary and Pancreatic Surgery, National Cancer Centre Hospital, Tokyo, Japan, 7Department of Surgery, Division of General Thoracic Surgery, School of Medicine, Keio University, Tokyo, Japan, and 8Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan
Date of submission 20 March 2015 Accepted for publication 19 June 2015 Published online Article Accepted 25 June 2015
Kamata T, Yoshida A, Shiraishi K, Furuta K, Kosuge T, Watanabe S-i, Asamura H & Tsuta K (2016) Histopathology 68, 356–366. DOI: 10.1111/his.12763
Mucinous micropapillary pattern in lung adenocarcinomas: a unique histology with genetic correlates Aims: In lung adenocarcinoma (ADC), micropapillary carcinomas (MPCs) are associated with poor prognosis because these tumours exhibit higher metastatic potential. Despite this, there are no studies investigating the differences between mucinous and non-mucinous MPC. Methods and results: We evaluated the proportion of micropapillary components in lung ADCs, and compared the differences with respect to the presence or absence of associated mucin. Tumour specimens from 694 patients with consecutively resected primary lung ADC were reviewed, and 37 cases of invasive mucinous ADCs were excluded. A significant (≥5%) micropapillary component was noted in 320 (48.7%) of 657 evaluable cases. When the cases with
micropapillary component were divided into 67 (20.9%) mucinous and 253 (79.1%) non-mucinous subtypes, tumours with mucinous micropapillary component exhibited significantly more aggressive pathological features, a higher proportion of HER2 mutations (P = 0.002) and ALK rearrangements (P < 0.001), and a lower proportion of EGFR mutations (P = 0.038) compared to those with a non-mucinous micropapillary component. In survival analyses, mucinous MPC tended to be more aggressive compared with non-mucinous MPC, but its prognostic value was not statistically significant (P = 0.076). Conclusions: Mucinous micropapillary pattern is an under-recognized unique growth associated significantly with HER2 mutation and ALK rearrangement.
Keywords: human epidermal growth factor receptor 2 mutation, lung adenocarcinoma, micropapillary, mucinous
Introduction Primary lung adenocarcinomas (ADCs) have five major architectural growth patterns: lepidic, papilAddress for correspondence: K Tsuta, Department of Pathology and Laboratory Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. e-mail: [email protected]. ac.jp © 2015 John Wiley & Sons Ltd.
lary, acinar, micropapillary and solid. Approximately 80% of the cases show ≥2 of these growth patterns.1 In the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification, invasive ADCs are classified according to their predominant subtype.2 This new classification reflects disease prognosis, and defines associ-
Mucinous micropapillary pattern in lung ADCs
ated driver gene alterations.3 However, the presence of a small percentage of micropapillary or solid growth pattern is a strong predictor of poor prognosis and an increased risk of recurrence.4,5 Micropapillary carcinoma (MPC) was first described in the breast as a rare variant of invasive breast carcinoma,6 and subsequent studies have shown that breast MPC is a highly aggressive histological subtype.7–9 MPCs are also found in the salivary glands, lungs, ovaries, colon, pancreas and urinary bladder.10 In the lung, MPC is characterized by papillary structures with tufts lacking a central fibrovascular core and extensively shed within alveolar spaces. In lung ADC, micropapillary components are associated with poor prognosis, because these tumours exhibit higher metastatic potential.11–13 Recently, micropapillary mucinous breast carcinoma has been reported as an aggressive counterpart to conventional pure mucinous tumours.14 With the advent of molecular-targeted therapy for lung cancer, the presence or absence of mucin production in lung ADCs has become increasingly important. This was exemplified by evidence that the presence of a signetring cell component15 or a mucinous cribriform pattern16 was well correlated with anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusions. In addition, invasive mucinous ADCs (IMAs) have been associated with Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations as well as spread characteristically like lobar pneumonia, with distinctive clinical features different from non-mucinous ADCs.2 Conversely, non-mucinous lepidic, papillary and micropapillary subtypes were associated significantly with epidermal growth factor receptor (EGFR) mutations.2,17 To elucidate the clinicopathological differences of mucin production in lung MPC, we evaluated the proportion of micropapillary components in consecutively resected ADCs, and furthermore we compared the clinicopathological, immunohistochemical (IHC) and genetic differences of mucinous and non-mucinous MPC.
Materials and methods STUDY POPULATION
The patients gave informed consent, and the study was performed according to the Declaration of Helsinki. This study was approved by the Institutional Review Board of National Cancer Centre Hospital (2010-0077; Tokyo, Japan). Tumour specimens, © 2015 John Wiley & Sons Ltd, Histopathology, 68, 356–366.
357
surgically resected from patients diagnosed with primary lung ADC between January 1998 and December 2001, were reviewed retrospectively. Clinical information was collected regarding patient age, sex, smoking history, duration of any tumour recurrence and survival. HISTOLOGICAL ANALYSES
The records of the histological specimens and all available haematoxylin and eosin (H&E)-stained tissue sections, in addition to any available sections with specific stains or immunohistochemical analyses, were reviewed. Tumours
