IAP-SL26: Lung Mass Walid E. Khalbuss, MD PhD Professor of - - PowerPoint PPT Presentation

Walid E. Khalbuss, MD PhD

Professor of Pathology and Director of Cytology; Deputy Chair of Pathology; NGHA- Riyadh; KSA

IAP-SL26: Lung Mass

62/F; non-smoker, with lower back pain for 7 months. She found to have Rt lung mass with adjacent multiple variable sizes nodules in both lungs. CT-Guided core-needle lung biopsy was done

• Glandular neoplasm with a garland-like arrangement
• Columnar cells/goblet cells
• Pseudostratified nuclei
• Eosinophilic cytoplasm
• An apical brush borders

Columnar cells/goblet cells Pseudostratified nuclei Eosinophilic cytoplasm An apical brush borders

CK7

CK20 CDx2

Napsin A

• CK7+; TTF1+; Napsin A
• CDx2+, Mucin+
• CK20-
• EGFR: Positive (Exon 19 Deletion)
• ALK (D5F3): Negative
• ROSE1 (FISH): Negative
• PDL1 (22C3): Negative (0%)

TTF1

CK7 CDx2

• Invasive adenocarcinoma:

– Subtypes:

• G1: lepidic
• G2: Acinar, papillary
• G3: micropapillary, solid

– Variants:

• invasive mucinous; colloid;

fetal; and enteric

– Features, not variant or subtypes:

• Signet-ring feature
• Clear cell feature

Adenocarcinoma Classification-WHO 2015

J Thorac Oncol. 2011 February ; 6(2): 244–285.

• To draw attention to this rare primary

histologic type that can share some morphologic and immunostain features with colorectal adenocarcinoma.

• It is not known whether there are any

distinctive clinical or molecular features

Rationale for adding enteric adenocarcinoma

• First described by Tsao and Fraser in 1991

(recently added into WHO, 2015).

• Rare variant; peripheral location.
• The IASLC definition: >50% of cellular

structures resembling colorectal carcinoma plus at least one positive markers: CDX-2, CK20; MUC1, MUC2, MUC5.

• ? colorectal metastasis requires the full

attention.

• Majority mixed with acinar, lepidic,

papillary, micropapillary, solid, and mucinous.

Pulmonary enteric adenocarcinoma

Intestinal and non-intestinal nasal cavity adenocarcinoma: Impact of wood dust exposure. Eur Ann Otorhinolaryngol Head Neck Dis. 2018: S1879-7296(18)30130-3 Primary intestinal-type adenocarcinoma of the buccal mucosa: A case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 May 30. pii: S2212-4403(18)30954-4 Intestinal-type adenocarcinoma of the larynx: Report of a rare aggressive phenotype and discussion

• f histogenesis. Head Neck. 2014 May;36(5):E44-7.

Primary intestinal-type adenocarcinoma of the oral tongue: Case report and review of histologic origin and

• ncologic management. Head Neck. 2018 Jul;40(7):E68-E72

Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma. Am J Surg Pathol. 2015 Apr;39(4):541-8 Primary enteric-type tubulovillous adenocarcinoma arising in the renal pelvis. Pathol Int. 2018 Jun;68(6):388-390. Primary enteric-type adenocarcinomas of the urinary bladder are histogenetically analogous to colorectal carcinomas: Immunohistochemical evaluation of 109 cases. Journal of Advanced Research, Volume 1, Issue 2, 2010, 151–156

• Described in Para nasal sinuses;

tongue, larynx, extrahepatic biliary tree, uterine cervix,

• vary, renal, thymus, bladder

and lung

• Rare

Pulmonary Adenocarcinoma With Enteric Differentiation: Immunohistochemistry and Molecular Morphology Appl Immuno Mol Morphol; 26(6), Jully; 2018

• 46 samples (26 surgical & 20 biopsies)
• 45 adenocarcinomas & 1 has focal adenosquama ca.
• 17% has a pure intestinal morphology
• 83% displayed <50% of:
• Solid 39%; mucinous (22%); acinar (13%); lepidic

(2%); papillary (4%), and micropapillary (2%).

• CDx2: 46 cases showed CDx2+ in the area with intestinal

morphology (score 1 in 12 cases; (26%), score 2 in 13 (28%), score 3 in 15 (33%), and score 4 in 6 (13%) cases.

• CK20 was expressed in 15/46 cases (33%), weak or focal +
• MUC2 was present in the same CK20+ cases.
• Villin: in the brush border in 35/46; 76% of cases
• Coexpression of TTF-1 & Napsin A/CDx2 seen in 21

cases: 1/6 (17%) with CDX2 score 4,

5/15 (33%) with score 3, 7/13 (54%) with score 2, and 8/12; (67%) with score 1

Pulmonary Adenocarcinoma With Enteric Differentiation: Immunohistochemistry and Molecular Morphology Appl Immuno Mol Morphol; 26(6), Jully; 2018

Pulmonary Adenocarcinoma With Enteric Differentiation: Immunohistochemistry and Molecular Morphology Appl Immuno Mol Morphol; 26(6), Jully; 2018

• ALK rearrangement in 6/46 (13%) of cases
• EGFR Mutation: in the exon 19 in 1/46 (2%),
• KRAS Mutation: codon 12 mutated in 28/46 (60.9%)
• BRAF mutation: None (0/46)

Clinicopathologic Significance of Intestinal-type Molecules' Expression and Different EGFR Gene Status in Pulmonary

• Adenocarcinoma. Appl Immunohistochem Mol Morphol.

2018 Feb 27:10.1097

• 60 patients with resected pulmonary adenocarcinoma were divided into the

enteric differentiation group (I group, n=30) and the usual group (U group, n=30).

• Patients in the I group were mainly female individuals and in clinical

stages III to IV, prone to lymph node metastasis (P<0.05). The

patients in the I group with CDX2/ CK20 phenotype (tumor size>5 cm) had a shorter survival time (P<0.05).

• Conclusions: patients with enteric differentiation have

unique clinical characteristics and different prognosis, which may play important roles in diagnosis and choosing therapeutic strategies for pulmonary adenocarcinoma patients in clinical practice.

Clinicopathological, radiographic, and oncogenic features of primary pulmonary enteric adenocarcinoma in comparison with invasive adenocarcinoma in resection specimens. Zhao et al. Medicine (2017) 96:39 28 patients

• TTF1+ in 10/28 (36%)
• CK7+ in 18/28 (67%)
• Napsin A+ in 5/28 (14%)
• CK20+ in 9/28 (32%)
• CDx2+ in 16/28 (57%)
• MUC2 in 4/28 (14%)

ALK all neg BRAF all neg

Zhao et al. Medicine (2017) 96:39

CDX2: highly sensitive and specific for intestinal differentiation

• Positivity is also seen in adenocarcinomas of pancreatic-biliary,

gastric, small bowel, lung, ovarian (mucinous and endometrioid, up to 25%); uterine cervix (30%) and bladder origin (urachal);

93 primary lung non-enteric adenocarcinomas.:

• CK7+ in ALL (variable CK20 staining in 4 tumors)
• TTF-1+ and Napsin A+ in 81/93 (87%),
• CDx2+ in 11/93 (12%) ; 5/strong, 3/mod, 3/ weak
• CK20+ in 1/93
• Mutation studies for EGFR/K-ras/ALK were performed in 4 CDX-2-positive tumors

and detected a K-ras mutation in one of them. Conclusion: CDX-2 positivity should not be used as the only criteria to exclude lung origin.

Pulmonary adenocarcinoma with enteric differentiation: Dissecting oncogenic genes alterations with DNA sequencing and FISH analysis. Exp Mol Pathol.102(2):276-279; 2017.

A series of 8 PAEDs 1/8 (12.5%) case had a simultaneous PIK3CA mutation (E545K) and an EML4-ALK translocation. KRAS gene showed a mutation

in the codon 12 in 4/8 of PAED (50%), NRAS, BRAF and

EGFR genes were wild type in all tumor samples. We concluded that PIK3CA mutations and ALK rearrangement occur also in PAEDs, while NRAS mutations might be a very rare event similarly to pulmonary adenocarcinomas of conventional type. KRAS is the prevailing gene mutated in this class of adenocarcinoma.

CDH17 and SATB2 in pulmonary metastatic colorectal adenocarcinoma.

Combination of cadherin-17 and SATB homeobox 2 serves as potential

• ptimal makers for

the differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal adenocarcinoma. Oncotarget. 2017;8(38):63442- 63452.

SATB2 SATB2 CDH17 CDH17

62/F; non-smoker, Lung mass CT-Guided core-needle lung biopsy was done

Clinical Follow up

• Chemotherapy initially, then,
• Target therapy
• Initial improvement; 8 months;
• Brain met and progression;
• Died 10 months after dx.

Other variants

• Invasive adenocarcinoma:

– Subtypes:

• G1: lepidic
• G2: Acinar, papillary
• G3: micropapillary, solid

– Variants:

• invasive mucinous; colloid;

fetal; and enteric – Features, not variant or subtypes:

• Signet-ring feature
• Clear cell feature

Low grade: Good outcome. High-grade: worse outcome: mixtures with

• ther histologic subtypes. Uniquely: mutations in the beta-catenin gene,

and the epithelial cells express aberrant staining by immunostain

Rationale for fetal adenocarcinoma variant

Colloid Carcinoma: Mucinous cystadenocarcinoma” are very rare,

and they probably represent a spectrum of colloid adenocarcinoma.

Rationale for invasive mucinous adenoCa. variant

Studies: very strong correlation with KRAS mutation (nonmucinous AdenoCa: more likely EGFR mutation. The formerly mucinous BAC, now recognized to have invasive components in the majority of cases Rationale for removing clear cell and signet ring carcinoma as adenocarcinoma subtypes: No clinical significance beyond a strong

association with the solid subtype. A solid pattern with more than

10% signet ring cell features in up to 56% ALK+. J Thorac Oncol. 2011 February ; 6(2): 244–285.

• Pulmonary enteric adenocarcinoma is rare.
• Requires morphology + one immunostain (CDx2; CK20, & Muc1)
• Almost all CK7+ (few are CK7-; requires colonoscopy)
• It can be TTF1+ & Napsin A+ (our case)
• CDx2+ positivity alone is inadequate for diagnosing

primary enteric lung ACA

• Majority are KRAS+ and EGFR/ALK/BRAF negative

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