폐결절: 언제, 어떻게 추적할 것인가?

서울대학교 의과대학 분당서울대학교병원 호흡기내과 이춘택

호흡기내과로 의뢰되는 환자의 이유?

1. 기침, (만성기침 포함) 2. 방사선 이상 소견 (chest PA, CT)

1) 폐결절: 60% GGN (간유리음영)

2) 폐침윤 3) 무기폐

전형적인 폐암환자의 변화

1995

남자 흡연자 고령, 70세 이상 증상 기침, 가래 혈담, 호흡곤란 Chest PA, CT Mass Central location Squamous cell ca Advanced stage

2015

여자 비흡연자 중년, 50-60 대 증상 없음 Chest PA, CT Solitary pulmonary nodule including GGN Peripheral location Adenocarcinoma Early stage

Nomenclature

•

Solitary Pulmonary Nodule ( 고립성 폐결절 )

– a sharply-defined circular opacity: 2 to 30 mm in diameter (by Fleischner society) •

Micronodule

– discrete, small, round, focal opacity, less than 5 mm (3 mm) 1. Pure solid nodule (former SPN) 2. Non-solid nodule, pure ground glass opacity nodule (pGGO,

pGGN,

순수간유리음영결절 ) 3. Partly solid nodule, mixed ground glass opacity nodule (mGGO,

mGGN,

복합간유리음영결절 )

pGGN (순수간유리음영) mGGN (복합간유리음영) mGGN (복합간유리음영)

Chest PA에 보이는 폐결절

• 위양성: 폐결절이 아닌 경우에도 chest PA 에서 폐결절로 오인 – – – – – – 폐혈관음영 늑골 이상음영 (bony island, healed fracture, focal arthritic scar) Nipple shadow Subcutaneous nodule Breast nodule Mucus filled bronchus • 위음성 – Retrocardiac, retrophrenic shadow의 nodule – – Too small nodule Most GGN

Type

Neoplastic: malignant Neoplastic: benign Inflammatory Infectious Vascular Congenital

Causes of SPN

Entity Primary lung cancer

Solitary metastasis Carcinoid Primary lung lymphoma Hamartoma Chondroma Rheumatoid Wegener's granulomatosis Inflammatory bowel syndrome Sarcoidosis (nodular)

Tuberculosis, NTM

Fungal infection

Round pneumonia

Abscess

Toxocara

Arteriovenous malformation Pulmonary infarction Lung contusion Pulmonary sequestration Pulmonary atresia

Initial Evaluation of SPN

• 환자의 연령 – 35-39: 3% (악성도) – – – 40-49: 15% 50-59: 43% >60: 50% • 위험요소 : – smoking, family history, emphysema, prior cancer etc • Size: – < 5mm: <1 % – – – 5-9 mm: 2-6 % 8-20 mm: 18% >20 mm: >50% • Attenuation: GGN versus Pure solid nodule

Issues of GGN

1. Transient or persistent GGN 2. Natural history and Characteristics of persistent GGN 3. How to and how long follow up GGN 4. Diagnostic Method of GGN 5. Multifocal nGGO 6. Genetic abnormality of GGN 7. When and how to treat GGN 8. Unsolved problem

GGN: transient or persistent

Persistent GGN: showing either no change or an increase in size or opacity over a follow-up period of 3 months or longer

GGN: 186 pGGN: 69 mGGN: 117 disappeared or regressed confirmed follow-up disappeared or regressed confirmed follow-up 26* 10 33 57** 29 31 Benign: 3 Malignancy: 7 Benign: 3 Malignancy: 26 AAH: 1 BACC: 5 Adenoca: 1 BACC: 9 Adenoca: 16 Large cell ca: 1 *: probability of disappearance or regression of pGGO: 26/69(37.6%) **: probability of disappearance or regression of mGGO: 57/117(48.7%) (

분당서울대병원

)

Characteristics of Transient Nodule (especially mGGN) in Korea

• • • 30-40%의 mGGN이 3개월 이내 소실 염증 (폐렴) 및 Pulmonary Infiltrate with eosinophilia (PIE) 특히 한국에서는 toxocara (개회충)에 의한 PIE가 흔함 – – – – – 소생간 복용력 혈액검사: 호산구 (5%, 500/mm 3 Single 또는 multiple mGGN Margin: ill defined 3개월 이내 소실 또는 이동함 이상)

Transient nGGO or Persistent nGGO Favor Transience

– younger age – male – Respiratory symptom – current smoking – eosinophilia : very high specificity but low sensitivity; – multiple – ill defined border

Favor Persistence

– spiculated border, – air-bronchogram, – bubble lucency, – pleural or fissural retraction – well defined border

Natural course of persistent GGN

Initial 2 year 9 year

Natural history of persistent GGN

First author

Size

Inclusion Criteria

GGO proportio n Follow-Up period

Patients

Hiramatsu (2008) Matsuguma (2013) Chang (2013) ( 삼성의료원 ) Lee (2013) ( 분당서울대 병원 ) Kobayashi (2013) <2 cm <3 cm any >20% 100% (pGGN) any >50% >3 mo > 2 yr > 2 yr > 6mo 125 171 89 114 61

Lesion

125 174 122 175 108

Follow Up (years) With growth n, (%)

2.9

2.4

4.9

3.8

4.2

26 (21%) 41 (24%) 12 (10%) 45 (26%) 29 (27%)

Perisistent Ground Glass Opacity Nodule pGGN



mGGN



pure SPN



mass (AAH



AIS



MIA



Inv ADCC)

Correlation of GGN CT finding and pathology

Adenocarcinoma in situ (former BAC): pGGN

Correlation of GGN CT finding and pathology

MIA: mGGN (less than 5 mm solid component)

Correlation of GGN CT finding and pathology

Characteristics of malignant GGN

• Size : >15 mm: high malignant potential • Margin – well defined – spiculated • Solid portion – mGGN: high malignant potential – Appearance of solid portion – Increase of solid portion • Persistence • Growing nature – Ordinary SPN: benign if no growth over 2 year – GGN: can grow after 3 years • Air bronchogram • Bubble lucency • Pleural or fissure retraction • Aerogenous spread

(A) (B) (C) Features of GGN suggesting malignancy (A) GGN with air-bronchogram and pleural retraction, (B) GGN with air-bronchogram, spiculated border with minimal fissural retraction (C) GGN with bubble lucency

How to follow up GGN?

Recommendations for management of subsolid pulmonary nodules detected at CT: A statement from the

Fleischner Society

(Radiology 2013) Solitary GGN pGGN ≤ 5 mm pGGN > 5 mm Part-solid component (mGGN) Follow-Up thin section CT at 3 months No follow-up required Follow-Up thin section CT in 3 mo To confirm persistence Persistent and solid portion <5mm: Persistent and solid portion ≥ 5 mm Annual surveillance CT for a minimum 3 years Annual surveillance CT for a minimum 3 years Biopsy or Surgical Resection * Frequency and duration of follow up CT: yet definitely defined

How to follow up GGN?

Recommendations for management of subsolid pulmonary nodules detected at CT: A statement from the

Fleischner Society

(Radiology 2013) Multiple GGN Pure GGNs ≤ 5 mm Pure GGNs >5 mm without dominant lesion(s) Dominant nodules(s) with part-solid or solid component Obtain follow-up CT at 2 and 4 years Initial follow-up CT at 3 month to confirm persistence Then annual surveillance CT for a minimum 3 years Initial follow-up CT at 3 month to confirm persistence.

If persistent, biopsy or surgical resections for lesion with >5 mm solid component.

Consider lung sparing surgery

How to follow up pure Solid Pulmonary Nodule?

Fleischner Society

(Radiology 2005)

Nodule Size (average of length and width)

<4 mm 4 – 6 mm 6 – 8 mm

Low risk patient High risk patient

No follow up Follow up CT at 12 mo: If unchanged, no further f/u Follow Up CT at 6-12 mo: then 18-24 mo if no change Follow up CT at 12 mo: If unchanged, no further f/u Follow up CT at 6-12 mo: then 18-24 mo if no change Follow up CT ay 3-6 mo, then 9-12 and 24 mo if no change >8 mm Follow up CT at 3, 9 and 24 mo: dynamic enhanced CT, PET and/or biopsy Same as low risk Risk factor: smoking, family hx, occpational exposure, prior cancer hx Pure SPN: follow up to

2 year

if no change

How Long

Should Small Lung Lesions of

Ground-Glass Opacity

be Followed? (Kobayashi Y et al.

J Thorac Oncol.

2013;8: 309-314) • All 29 tumors among 108 tumors began to grow within 3 years 1) 2) 3) < 1 year: 13 GGN 1- 2 year: 12 GGN 2-3 year: 4 GGN • 1) 2)

Conclusions:

The tendency to grow was clear within the first 3 years in all cases. Therefore, we conclude that these lesions should be followed for

at least 3 years.

Pathologic Diagnostic Method of GGN

Yes

• High diagnostic rate (PCNB and radial EBUS) • PET: high value for mGGO > 5 mm solid

No

• PCNB: difficult, time consuming, high radiation exposure to performer, complication • PET: no value for pGGO and mucinous BAC: • High correlation of HRCT finding and pathology • Wide use of VATS (diagnosis and treatment simultaneously)

Pathologic Diagnostic Method of GGN

: Radial EBUS + Transbronchial lung biopsy pGGN mGGN Normal Blizzard Sign ( Overall diagnostic accuracy was 67.5% (143 of 212 cases).

J Thorac Dis 2015;7(4):596-602 )

Pathologic Diagnostic Method of GGN

•

Surgical resection

of nodular ground-glass opacities

without percutaneous needle aspiration or biopsy

(Cho J et al

. BMC Cancer

2014, 14:838: 분당서울대병원 ) 356 nGGOs of 324 patients resected between January 2009 and October 2013 330 nGGOs (92.7%) of 300 patients without preop. tissue diagnosis 26 nGGOs (7.3%) with preop. tissue diagnosis 16 nGGOs (4.8%) were benign including AAH 314 nGGOs (95.2%) were AIS: 38 MIA: 63 Invasive: 213

Rate of malignancy = 95.2%

Genetic Abnormality of GGN

pGGO mGGO Solid nodule

How to treat single GGN?

Lobectomy

• Standard treatment • Noguchi type C (solid portion >5 mm) or over

Limited resection

• Increasing use in Noguchi type A and B (mGGN with solid portion 5 mm 이하 ) • Good treatment result • Possible multifocal origin: save lung parenchyme • Good localization (coil, dye) Another options: Op contraindicated 1. Radiofrequency ablation 2. Interstitial PDT 3. RT (particle RT: positron, carbon)

Lobectomy vs Limited resection (sublobar resection)

(Transl Lung Cancer Res 2014) Current recommendation for limited resection

1) Poor PFT with GGN 2) Reasonable PFT: pGGN, mGGN : < 2 cm, solid portion < 5 mm or C/T ratio<0.25

Percutaneous Radiofrequency Ablation of GGN

Iguchi et al. Cardiovasc Intervent Radiol 2014

Initial RFA After 53 month

• Overall survival and disease specific survival rates were 93.3 and 100 % at 1 year and 93.3 and 100 % at 5 years, respectively.

• Complication: Pneumothorax: 15/20 session (One required C-tube insertion), minor pulmonary hemorrhage in two

Multifocal GGN

• 10-30% of GGN: multifocal • Multiclonality >> Intrapulmonary Metastasis Another discrete pGGO in LUL (7mm) PCNB for mGGO in LLL : ADCC How to manage this patient?

Another ill defined pGGO in RUL (5mm)

How to treat multifocal GGN?

• Multifocal GGN: multifocal origin > metastasis • Fleischner society recommendation:

– resect dominant lesion (lung saving surgery if possible) and clinical follow up

Unsolved problem

• Etiology of GGN?

– Passive smoking – Virus: jaagsiekte sheep retrovirus and ovine lentivirus.

– Household toxic fume: female • Epidemiologic and clinco-pathologic features – No relation to smoking – Female preponderance – Relatively young – Multifocal origin – Indolent course – High EGFR mutation