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Classification of congenital lung cysts and malformations

Minnesota Society of Pathologists Fall MeetingOctober 29 2016October 29, 2016

Megan K. Dishop MDMedical Director, Pediatric Anatomic PathologyChildren’s Hospitals and Clinics of MinnesotaMinneapolis-St. Paul, Minnesota, USA

History of congenital lung cysts

• Documented as early as 1859

• Chin & Tang 1949 – Congenital adenomatoid malformation

• Van Dijk 1972 – Congenital cystic adenomatoid malformation (cystic, intermediate, solid)

• Stocker 1977 – CCAM types 1 2 3

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Stocker 1977 CCAM types 1, 2, 3

• Stocker 1994 – CCAM types 0, 1, 2, 3, 4

Stocker Classification, current

• “Congenital Pulmonary Airway Malformation” (CPAM)

• Type 0 CPAM, acinar dysgenesis (1-2%)

• Type 1 CPAM, large cyst type (65%)

• Type 2 CPAM, medium cyst type (10-15%)

• Type 3 CPAM solid/adenomatoid type (5 8%))

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• Type 3 CPAM, solid/adenomatoid type (5-8%))

• Type 4 CPAM, peripheral cyst type (10-15%)

Conceptual relationship to anatomy

From: JT Stocker. Chapter 12. The Respiratory Tract. In: JT Stocker, LP Dehner, AN Husain, eds. Stocker and Dehner’s Pediatric Pathology, 3rd ed. Lippincott, Williams & Wilkins: Philadelphia, 2011. p 464.

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CPAM type 0

• Acinar dysplasia/dysgenesis

• Described in 1986.

• Severe, diffuse, bilateral. Unresectable and incompatible with life. Survive a few hours.

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• Term or preterm, immediate respiratory distress.

• Reported in siblings, likely genetic.

From: JT Stocker. Chapter 12. The Respiratory Tract. In: JT Stocker, LP Dehner, AN Husain, eds. Stocker and Dehner’s Pediatric Pathology, 3rd ed. Lippincott, Williams & Wilkins: Philadelphia, 2011. p 464.

CPAM type 1

• “Large cyst” type

• Usually first week to month, but also adolescents

• Single or multiple large cysts (3-10cm), surrounded by smaller cysts.

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y y

• Lined by ciliated columnar epithelium; muscle, cartilage

• 45% with mucigenic cells, precursor to BAC

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CPAM type 2

• “Medium/small cyst” type

• “Exclusively in 1st year of life”; “poorer outcome due to associated anomalies”

• Smaller cysts (0.5-2 cm); “Back-to-

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y ( 5 );back” bronchiolar structures; thin muscular layer− Rhabdomyomatous dysplasia

− No cartilage or mucigenic cells

• Seen in 50% of ELS.

CPAM type 3

• “Small cyst”, “solid”, “adenomatoid”

• First days-months of life; high mortality; polyhydramnios, fetal hydrops

• Large unilateral mass; lobe or lung.

• Small cysts (<0 2 cm); resembles immature

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Small cysts (<0.2 cm); resembles immature lung; stellate irregular bronchiolar structures.

• No mucigenic epithelium, cartilage, or skeletal muscle.

CPAM type 4

• “Peripheral cyst” type− “hamartomatous proliferation of the

distal acinus”

• Newborn to 4 years.− Single lobe (80%); rarely bilateral

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− Respiratory distress +/- PTX

• Large air-filled cysts− Lined by alveolar epithelial cells or low

columnar epithelium.

− Loose mesenchymal tissue with prominent vasculature.

Problems with CPAM classification

• Stocker classification is not comprehensive. Lesions not included: bronchial atresia, ELS, ILS,

bronchogenic cyst Some lesions do not fit “classic patterns”, ex. fetal

• “CPAM” encompasses broad morphologic spectrum Based on gross and microscopic anatomy not pathogenesis

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Based on gross and microscopic anatomy, not pathogenesis

• No standard criteria, definitions or terminology bridging disciplines

Pathology, radiology, pediatric and fetal surgery, maternal-fetal medicine, pediatric pulmonary medicine, neonatology

A very confusing medical literature:o CCAM vs. CPAM, CPAM with sequestration (hybrid lesion?)

• Misidentification of cystic PPB as CPAM

Langston Classification

• Stocker type 0 = Acinar dysgenesis

• Stocker type 1 = CPAM, large cyst type

• Stocker type 2 = Intrauterine bronchial obstruction (bronchial atresia) sequence

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( ) q

− Microcystic developmental abnormality seen in BA, ILS (BA with systemic arterial / venous connection), and ELS

• Stocker type 3 = Pulmonary hyperplasia (adenomatoid or solid type)

• Stocker type 4 = Pleuropulmonary blastoma, type 1

Claire Langston. New concepts in the pathology of congenital lung malformations. Sem Pediatr Surg 12: 17-37, 2003.

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CPAM, large cyst typeCPAM, large cyst type4 day old infant girl with cystic lung lesion. Right lower lobectomy.4 day old infant girl with cystic lung lesion. Right lower lobectomy.

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Bronchial Atresia - the hidden pathology

• Bronchial atresia sequence− Pattern of maldevelopment widely associated with airway

obstruction (bronchial atresia, ILS, ELS)

− Rarely without identifiable airway obstruction

• Common finding in many types of developmental lung lesions− 22/25 lung resections of IUUS identified lesions at Children’s

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22/25 lung resections of IUUS identified lesions at Children s Hospital Boston assessed for bronchial atresia 14 CPAM, 9/13 assessed with BA 3 CLO, 2/3 with BA 1 ELS with BA 1 ILS (not assessed) 6 CPAM/seq 5/5 assessed with BA

Kunisaki et al. Bronchial atresia: the hidden pathology within a spectrum of prenatally diagnosed lung masses. J Ped Surg 2006; 41:61-65

Segmental bronchial atresiaSegmental bronchial atresia

RLL segmental BA with microcystic maldevelopment8 day old

ExtralobarExtralobar sequestrationsequestration

Left-sided ELS with microcystic maldevelopmentand lymphangiectasisassociated with RLL ILS; prenatal dx, resected at 3 months

BronchopulmonaryBronchopulmonary foregut foregut malformationmalformation

Infradiaphragmatic mass seen by prenatal US, accessory lung with esophageal bronchus

Bronchial Atresia

• Isolated− Segmental or subsegmental− Formerly rarely seen in infancy

Later presentations: incidental x-ray finding, recurrent pneumonia, or dyspnea

− Now common pathology of many IUUS lesions

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Now common pathology of many IUUS lesions Usually asymptomatic at birth

− Gross pathology Lobar enlargement, sometimes pseudofissures Bulge at hilum sometimes marks atretic bronchus Subhilar mucocele and mucus in regional airways Microcystic parenchymal maldevelopment, hyperinflation

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BRONCHIAL ATRESIABRONCHIAL ATRESIA

9 month old male infant with lung lesion 9 month old male infant with lung lesion identified on prenatal ultrasound. No identified on prenatal ultrasound. No

respiratory problems at birth; RLL respiratory problems at birth; RLL removed electively at 9 months. removed electively at 9 months.

Lobe weight 74.2 gm. Lobe weight 74.2 gm.

Expected R lung wt 53 gm.Expected R lung wt 53 gm.

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Bronchial Bronchial atresiaatresia

13 year old boy with shortness of breath

while playing trumpet.

21 | © 2015Asymptomatic 10 month old girl with cystic lesion on imaging

You won’t find it if you don’t look.

• Bronchial atresia is a gross diagnosis made by carefully examining the lobe or lung specimen.−Microscopic examination alone can only suggest the

diagnosis.

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g

• Section lungs and lobectomies in a parasagittal plane, moving lateral to medial.−Segmental distribution of cysts.

−Mucus stasis with central mucocele.

−Point of atresia identified by retrograde probe of most dilated bronchial profile/cyst.

Bronchial Atresia and Sequestration

• BA with Systemic Vascular Connection− Also called: Intralobar sequestration (ILS)− Except for systemic vascular connection, identical gross and histology

with isolated− More frequent in left lower lobe− Systemic artery usually single and from distal thoracic or proximal

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Systemic artery usually single and from distal thoracic or proximal abdominal aorta, but multiple vessels and a wide variety of origins reported

− Systemic venous connection, less common• Intralobar sequestration is congenital (not acquired).

− Numerous examples detected prenatally.− Examples of ILS and ELS in same patient.

Feeding vesselIntralobar sequestration

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Intralobar sequestration

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Intralobar sequestration

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Extralobar Sequestration

• Aberrant pulmonary mesenchyme develops apart from the normal lung; “accessory lobe”

• Location− usually thoracic (L>R)− anterior or posterior mediastinum, infradiaphragmatic,

retroperitoneal typically near adrenal

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retroperitoneal typically near adrenal

• Relation to adjacent tissues− Systemic artery typically from descending thoracic aorta− Rarely communicates with esophagus or stomach

• Associated abnormalities - congenital diaphragmatic hernia

• Often asymptomatic− Sometimes hydrothorax, fetal hydrops, death

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4 day old infant girl with congenital diaphragmatic hernia repair.

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Complex Bronchopulmonary Foregut Malformation

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Bronchogenic CystBronchogenic Cyst

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Congenital lobar overinflationBronchomalacia, webs, stenoses, airway compression by vascular structures

35 | © 2015CPAM 3Massively enlarged lung, preterm stillborn – multilobar bronchial narrowing

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Pulmonary hyperplasia

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Pulmonary hyperplasia (19-20 wga)

Due to laryngeal atresia

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4 month old male infant with prenatal diagnosis of 5 cm cystic lesion in LUL

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Second excision5 months of age 1cm cystic lesion RLL

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Pleuropulmonary Blastoma

• TYPE 1 Cystic (low-grade)

• TYPE 2 Cystic and solid

• TYPE 3 Solid (high-grade)

T ( l ti ) PPB i il i t k f St k t

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• Type 1 (purely cystic) PPB is easily mistaken for Stocker type 4 CPAM (peripheral large cyst type).− Is type 4 CPAM an underdiagnosed, undersampled, or regressed

type I PPB? Yes!

S99-3042Recurrent PPB type 3

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S99-2036 PPB type 1

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PPB: Associated Neoplasms

• Germline DICER1 abnormalities in PPB families

• Dysplastic/neoplastic diseases in 25% of PPB patients’ relatives, often siblings

• Multicentric PPB, PPB in siblings/cousins

• Cystic nephroma Wilms tumor

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Cystic nephroma, Wilms tumor

• Ovarian/testicular Sertoli-Leydig cell tumors

• Germ cell tumors

• Lymphoma/leukemia

• Thyroid malignancy

• Pituitary blastoma

• Various sarcomas….

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Pathogenesis of congenital lung cysts

• Acinar dysgenesis (CPAM 0): Diffuse developmental/genetic disorder

• CPAM 1: Unknownb i ti l lf ti

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−benign cystic neoplasm vs. malformation

• BA/ILS/ELS (CPAM 2): Bronchial obstruction in utero

• CPAM 3: Unknown−hyperplasia vs. neoplasm vs. hamartoma

• PPB type 1 (CPAM 4): Neoplasm

SiteSt. Louis

Mich London Houston Wash DC

Saudi Belgium Japan Total

Time period

1970-1988

1974-1993

1980-1989

1983-1993

1970-1995

1985-1995

1979-1996

1962-1996

CLO 6 7 - 6 10 37 5 3 74

CAM 9 17 5 7 5 7 14 4 68

BC 13 6 3 2 6 8 13 13 64

PS 6 15 2 6 20 5 16 6 76

ILS (9) (2) (5) (16)

ELS (6) - (1) (7)

Other BA - 1 2 1 BA-20 24

Ages 1d-13y 1d-11y 8d-17y 1d-11y 1d-16y 1d-5y 1d-62y

M:F 23:12 24:19 7:5 12:10 - 39:18 30:18 17:9 1.6:1

# 35 45 12 22 61 57 48 26 306

# R

RU

L

RM

L

RL

L L

LU

L

LL

L

Other Age range M:F

CLO 16 6 1 5 10 10 2d-14m 8:7

CPAM 1 13 6 3 2 1 7 2 5 1d-15y 10:3

“CPAM 2” 3 1 1 2 2 5d-26d 2:1

Congenital lung malformations, surgical specimens, cumulative data from 11 year review (1990-2000, Houston) and 10 year review (2000-2009, Denver)

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CPAM 3 1 1 1 1d 1:0

BC 15 4 3 1 5 4 6 1d-14y 8:7

BA 30 14 4 2 8 16 5 11 1d-14y 17:13

ILS 11 3 3 8 8 1m-16y 6:5

ELS 22 5 15 2 3d-2y 16:6

Total 111 40 13 9 13 63 23 24 8 1d-16y70:41 (1.7:1)

Time for re-classification?

• Our goal should be to re-define and classify according to pathogenesis− CPAM 1 and CPAM 3 remain poorly understood

• Stocker classification describes a set of morphologic patterns, which should lead to search for underlying etiology

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− Clinical – imaging – gross – microscopic correlation

− CPAM 2 pattern – bronchial atresia sequence

− CPAM 4 pattern – regressed/undersampled cystic PPB

22 wga fetus with 4.8 cm RUL lung mass.

Fetal surgery at 22 2/7 wga.

Lobe wt 37.7 gm

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25 3/7 wga fetus, 6-7 cm RLL cystic and solid mass by ultrasound.

Lobectomy by fetal surgery at 25 6/7 wga.

Lobe wt 21.4 gm

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Conclusion: Future goals

• Resolve pathogenesis of large cyst CPAM (type 1)…

• Resolve pathogenesis of solid CPAM (type 3)…

• Provide definitions of cystic lung malformations which are inclusive of fetal phenotypes…

• Unify terminology used by pathologists and other medical

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Unify terminology used by pathologists and other medical disciplines…