Slide Presentation (SL-26): Pulmonary Pathology Jae Y. Ro, M.D., - - PowerPoint PPT Presentation

Slide Presentation (SL-26): Pulmonary Pathology

Jae Y. Ro, M.D., PhD Weill Medical School of Cornell University, Houston Methodist Hospital and UT MD Anderson Cancer Center, Houston, TX

October 17, 2018

Cornell University

Case: SMP18-xx405

 81 year-old female with no past medical

history

 No smoking history  1.1 cm RML mass was found on CT scan

in Feb. 2016 when she came to “Emergency Room” for abdominal problems

 No symptoms related to mass, followed

with CT scans and the mass had increased in size to 1.5 cm in April, 2017, and 1.7 cm in April, 2018

Case: SMP18-xx405

 MRI brain was negative and no

metastases found on PET scan

 CT-guided FNA in 4, 2018 positive for

adenocarcinoma

 Under the clinical diagnosis of stage

IA2 (T1b, N0, M0), robot-assisted videoscopic right middle lobectomy and mediastinal lymph node dissection

• Feb. 2016

April 2017

April 2018

1 cm

1.7 cm greatest dimension

SMP18-xx405

Diagnosis: Lung, RML, wedge resection:

• Adenocarcinoma with micropapillary

(40%), lepidic with papillary (40%) and acinar pattern (20%), 1.7 cm, high grade

• Spread through alveolar space (STAS)
• Pleura, free of tumor involvement
• No LVI identified
• Margins free of tumor
• N1 and N2 LNs, free of tumor (0/13)

Final TNM: pT1b pN0 cM0, stage IA2

SMP18- XX405

Molecular Diagnostic Results (SMP18-xx405)



CCDC6-RET gene rearrangement

 ALK gene rearrangement Not Detected  ROS1 gene rearrangement Not Detected  NTRK1 gene rearrangement Not Detected  MET14 exon skipping Not Detected  EGFR mutation Not Detected  KRAS mutation Not Detected  BRAF mutation Not Detected  ERBB2/Her2 mutation Not Detected

Molecular Diagnostic Results (SMP18-xx405)

PD-L1 negative in tumor and

immune cells

CCDC6-RET gene rearrangement

• acquired resistance to EGFR

directed treatment is the development of the T790M mutation in exon 20 of EGFR

• another mechanism of acquired

EGFR resistance

Micropapillary component in lung adenocarcinoma (MPC): a distinctive histologic features with possible prognostic significance

 Am J Surg Pathol 2002 Mar;26 (3): 358-64

• Amin MB, Tamboli P, Merchant SH,

Ordonez NG, Ro J, Ayala AG and Ro JY

• Department of Pathology, The University
• f Texas M.D. Anderson Cancer Center,

Houston, Texas 77030, USA

Micropapillary carcinoma (MPC)

 Reported 35 cases, MDACC experience  Of 35 cases, 15 cases available for blocks

• CK7+ (14/15), CK20+ (2/15), TTF1 (12/15)

 33 of 35 metastasis: LN (n=26), lung (n=17),

brain and bone (n=9, each), and other sites

 F/U on 29 (mean F/U months, 25): 16 of 29

patients (55%) AWD, 5 (17%) DOD, and 8 (28%) AWOD

 MPC, possible primary in lung in addition

to breast, urinary bladder, and ovary

Am J Surg Pathol 2002 Mar;26 (3): 358-64

2004 WHO Classification of Adenocarcinoma

 Adenoca, mixed subtype: majority (80-85%)  Acinar adenocarcinoma  Papillary adenocarcinoma  Bronchioloalveolar carcinoma

–Non-mucinous, –Mucinous, –Mixed

 Solid adenoca with mucin production  Fetal adenocarcinoma  Mucinous “colloid” carcinoma  Mucinous cystadenocarcinoma  Signet ring adenocarcinoma  Clear cell adenocarcinoma

MPC of lung

In 2002 Drs. Ro and Ayala with

fellows

Unique pathologic, clinical and

molecular features

Aggressive clinical course EGFR TKI therapy: Targeted

therapy: cornerstone for new lung tumor classification (IALCS/ATS/ERS)

Proposed IASLC/ATS/ERS Adenocarcinoma classification (2011)

 Preinvasive lesions

• Atypical adenomatous hyperplasia
• Adenoca in situ (BAC): non-mucinous

 Minimally invasive adenoca (lepidic predominant tumor

with ≤5 mm invasion)

 Invasive adenocarcinoma

• Lepidic predominant (non-mucinous BAC)
• Acinar predominant
• Papillary predominant
• Micropapillary predominant
• Solid predominant
• Variants: Mucinous adenoca (mucinous BAC),

Colloid, Fetal (low, high grade), and Enteric

2015 WHO Classification of Adenocarcinoma

 Lepidic adenocarcinoma  Acinar adenocarcinoma  Papillary adenocarcinoma  Micropapillary adenocarcinoms  Solid adenocarcinoma  Invasive mucinous adenocarcinoma

• Mixed invasive mucinous and non-mucinous

 Colloid adenocarcinoma  Fetal adenocarcinoma  Enteric adenocarcinoma  Minimally invasive adenocarcinoma

• Non-mucinous
• Mucinous

 Preinvasive lesions: AAH and adenoca in situ

MP

Papillary and MP

Micropapillary carcinoma in WHO 2015

 Papillary tufts forming florets that lacks

fibrovascular cores

 These may appear detached from and/or

connected to alveolar walls

 Tumor cells are usually small and cuboidal

with variable nuclear atypia

 Ring-like glandular structures may floats

within alveolar spaces

 Vascular and stromal invasion common  Psammoma bodies may be seen

Lepidic

Lepidic with microinvasion

Acinar

Solid with mucin

True Papillary Carcinoma of the Lung: A Distinct Clinicopathologic Entity

Silver and Askin. Am J Surg Pathol 1997;21:43-51

Am J Surg Pathol 1997;21:43-51

Miyoshi et al: Am J Surg Pathol 27:101–9, 2003

• 1. Multiple

tight clusters in spaces

• 2. Thin slender

nests, < 4 cell thick

• 3. Nuclei,

inverted polarity

MPC in lung adenocarcinoma, 2002

 Micropapillary carcinoma component has

been reported in other organs to have worse prognostic significance:

Breast Urinary bladder Ovary

 2004 WHO classification of lung tumors, four

major types and five variants of adenocarcinoma (histologic growth patterns)

No reference to micropapillary histology

Amin, Tamboli, Merchant, Ordonez, Ro, Ayala and Ro. Am J Surg Pathol. 2002; 26(3): 358–364

 Size of primary tumors: 0.8 to 6.0 cm  Tumors

Well circumscribed Gray-white/tan-yellow cut surface Focal areas of hemorrhage and necrosis Mixture of various histologic subtypes

(acinar, papillary, solid, BA)

Amount of micropapillary component varied

21%, focal (<5%); 58%, moderate (5-30%);

21%, extensive (>30%)

MPC in lung adenocarcinoma, 2002

Amin, Tamboli, Merchant, Ordonez, Ro, Ayala and Ro. Am J Surg Pathol. 2002; 26(3): 358–364

 74% had metastasis at initial presentation

(additional ones at follow up)

 81% lymph node metastasis (additional ones

to extra-mediastinal LN)

 53% intrapulmonary metastasis  Other sites of metastasis

Brain, bone, liver, jejunum Adrenal gland, skin

MPC in lung adenocarcinoma, 2002 & 2004

Follow up 4-144 months

Amin, Tamboli, Merchant, Ordonez, Ro, Ayala and Ro. Am J Surg Pathol. 2002; 26(3): 358–364

• Nassar. Adv Anat Pathol. 2004;11(6):297-303

MPC: A distinct pathological marker of poor prognosis, 2005

 Study

122 cases of small lung adenocarcinoma, 55% MPP positive vs. 45% negative

MMP (+) MMP (-) Lymph node metastasis 74% 26% Pleural invasion 55% 34% 5 year survival 54% 81%

Makimoto, et al. Histopathology. 2005; 46(6):677-84

MPC: A distinct pathological marker of poor prognosis, 2005

Makimoto, et al. Histopathology. 2005; 46(6):677-84

MPC: A distinct pathological marker of poor prognosis, 2005

Summary:

• Significant association

with MP and

• LN metastasis
• Pleural invasion
• Stage
• MP distinct pathological

marker

• Presence crucial, size

and amount NOT

Makimoto, et al. Histopathology. 2005; 46(6):677-84

Clinicopathologic factors

 Significantly associated

with MP  Smoking  LN metastasis  Pleural invasion  Lymphatic invasion  Venous invasion  Dominant BAC subtype  Dominant papillary subtype

 No association with age,

gender or tumor size

• Prognostic significance

Histopathological features and prognostic significance of MPC in lung adenoCA, 2008

Kamiya, et al. Mod Pathol. 2008;21(8):992-1001

Kamiya, et al. Mod Pathol. 2008;21(8):992-1001

Histopathological features and prognostic significance of MPC in lung adenoca, 2008

Prognostic factors of survival after recurrence in patients with resected lung adenocarcinoma, 2015

Clinicopathologic characteristics of 179 patients with recurrence after complete resection of lung adenocarcinoma

Hung, et al. J Thorac Oncol. 2015

Micropapillary Carcinoma of lung

 The more the MP in stage I lung adenoca, the

worse the prognosis—a retrospective study on digitalized slides: Virchows Arch. 2018 Jun;472(6):949-958.

 Presence of MP and solid patterns are

associated with nodal upstaging and unfavorable prognosis among patients with cT1N0M0 lung adenocarcinoma: a large-scale analysis: J Cancer Res Clin Oncol. 2018 Apr;144(4):743-749.

 Prognostic significance of the IASLC/ATS/ERS

(WHO 2015) classification of stage I lung adenocarcinoma: A retrospective study based

• n analysis of 110 Chinese patients. Thorac
• Cancer. 2017 Nov;8(6):565-571.

A Grading System of Lung Adenoca Based on Histologic Pattern is Predictive of Disease Recurrence in Stage I Tumors Am J Surg Pathol 2010;34:1155–1162

Lepidic (BAC) Acinar, papillary Solid, micropapillary

Adenocarcinoma scoring system (Sica et al)

Total score 2 most pred components

 Score 2 (1, 1)  Score 3 (1, 2); (2, 1)  Score 4 (2,2);(1,3);(3,1)  Score 5 (2,3); (3, 2)  Score 6 (3, 3)

WHO lung ca types

 Lepidic  Lepidic, acinar, papillary  acinar, papillary patterns,

• r lepidic with

solid/micropapillary or Pure acinar or papillary

 acinar/papillary and

micropapillary or solid

 Pure solid or pure

micropapillary

Am J Surg Pathol 2010;34:1155–1162

100% for micropapillary, 86% for solid, 42% for acinar, 23% for papillary types Primary vs. metastasis Am J Surg Pathol 2010;34:1155–1162

Kadota et al’s grading

Modern Pathology (2012) 25, 1117–1127

 Combined architectural/mitotic grading

system

• low grade: low architectural grade with

any mitotic count or intermediate architectural grade with low mitotic count (0-1/10HPFs)

• intermediate grade: intermediate

architectural grade with intermediate (2- 4) or high mitotic counts (> 5/10HPFs)

• high grade: high architectural grade with any

mitotic count

Kadota et al, Modern Pathology (2012) 25, 1117–1127

micropapillary ALK trans

EGFR Association

 Never smokers  Female  10-20% Westerns, 35-45% East Asians  Lepidic pattern adenocarcinoma  Papillary adenocarcinoma  Micropapillary adenocarcinoma  Not present in mucinous carcinoma

KRAS Mutations in NSCLC

Smokers 30% adenocarcinoma Mucinous adenocarcinoma Rare in micropapillary ca

Genetic alterations in MP vs non-MP

EGFR KRAS EML4- ALK MP non-MP 32.1 % 30.4% 3.6% 12.3% 10.7% 2.2%

Mol Clin Oncol 2016;4:195-200

57

Micropapillary adenocarcinoma of the lung:

.

Morphologic criteria and diagnostic reproducibility amongst pulmonary pathologists

Paloma del C. Monr loma del C. Monroig-Bosq

• ig-Bosque, pu

e, pulmonar lmonary pathologists, Jae Y y pathologists, Jae Y. R Ro

107 USCAP Annual Meeting Vancouver, British Columbia, Canada, March 19, 2018 107 USCAP Annual Meeting Vancouver, British Columbia, Canada, March 19, 2018

MPC Lung

 As indicated before, MPC of lung is well

known as an aggressive variant of lung adenocarcinoma frequently manifesting with advanced stage and poor prognosis.

 Recent studies indicate that any MPC

component, regardless of overall percentage is critical to identify as it has negative prognostic implications.

 To date, no studies have investigated the

morphological criteria used by pathologists to classify MPC of lung.

 Randomly collected 30 MPC cases: 15

Pulmonary Pathologists from10 institutions among the US and Canada

MPC Lung, Results

 Our study results provide (for the first

time) objective criteria to diagnose MPC lung.

 For

cases with predominant MPC pattern, most commonly identified criteria were:

• Multiple nests in same alveolar space
• Small tumor nest size (< 4 cell thick)
• Peripherally oriented nuclei

MPC

• More than four cells per

cluster

• Multiple clusters in single

lacuna space (or air space) with very slender (3-4 cell thickness) cell thickness

• Inverted nuclear polarity

(no fibrovascular core)

MPC Lung, Results

Identification of morphologic

criteria were not different among pathologists with different years of experience (<15 vs. ≥15 years)

Novel method for rapid identification of micropapillary or solid components in early-stage lung adenocarcinoma: J Thorac Cardiovasc Surg. 2018 Aug 2. pii: S0022-5223(18)32045-2. Chromogen density to detect MPC and solid patterns of adenoca

STAS – Spread through air spaces

Solis, et al. Cancer. 2012;118:2889-99

Lung Cancer, 2018;123:121-126

STAS

STAS

 Associated with LV invasion, LN

metastasis, higher stage, high-grade histologic subtype

 STAS was frequently found in tumors with

wild-type EGFR or ALK -rearrangement.

 Associated with presence of micropapillary,

solid, cribriform predominant type, and absence of lepidic component

 Associated with shorter recurrence-free

survival and recurrences to extrathoracic sites as well as intrathoracic sites

Summary

 Proper identification of MPC component

• Multiple tight clusters in spaces with no

fibrovascular cores

• Thin slender nests, < 4 cell thick
• Inverted nuclear polarization

 Any amount MPC component important  Grading system based on growth

patterns

 STAS important prognostic factor:

mention in pathology report

Thank you for your attention!