J Pathol Transl Med.  2017 Jan;51(1):56-68. 10.4132/jptm.2016.09.17.

Size of Non-lepidic Invasive Pattern Predicts Recurrence in Pulmonary Mucinous Adenocarcinoma: Morphologic Analysis of 188 Resected Cases with Reappraisal of Invasion Criteria

• Hwang S
• Han J
• Choi M
• Ahn MJ
• Choi YS

• KMID: 2367681
• DOI: http://doi.org/10.4132/jptm.2016.09.17

Abstract

BACKGROUND
We reviewed a series of 188 resected pulmonary mucinous adenocarcinomas (MAs) to clarify the prognostic significance of lepidic and non-lepidic patterns.
METHODS
Non-lepidic patterns were divided into bland, non-distorted acini with uncertain invasiveness (pattern 1), unequivocal invasion into stroma (pattern 2), or invasion into alveolar spaces (pattern 3).
RESULTS
The mean proportion of invasive patterns (patterns 2 and 3) was lowest in small (≤ 3 cm) tumors, and gradually increased in intermediate (> 3 cm and ≤ 7 cm) and large (> 7 cm) tumors (8.4%, 34.3%, and 50.1%, respectively). Adjusted T (aT) stage, as determined by the size of invasive patterns, was positively correlated with adverse histologic and clinical features including older age, male sex, and ever smokers. aTis tumors, which were exclusively composed of lepidic pattern (n = 9), or a mixture of lepidic and pattern 1 (n = 40) without any invasive patterns, showed 100% disease- free survival (DFS). The aT1mi tumors, with minimal (≤ 5 mm) invasive patterns (n = 63), showed a 95.2% 5-year DFS, with recurrences (n = 2) limited to tumors greater than 3 cm in total size (n = 23). Both T and aT stage were significantly associated with DFS; however, survival within the separate T-stage subgroups was stratified according to the aT stage, most notably in the intermediatestage subgroups. In multivariate analysis, the size of invasive patterns (p = .020), pleural invasion (p < .001), and vascular invasion (p = .048) were independent predictors of recurrence, whereas total size failed to achieve statistical significance (p = .121).
CONCLUSIONS
This study provides a rationale for histologic risk stratification in pulmonary MA based on the extent of invasive growth patterns with refined criteria for invasion.

Keyword

Lung; Mucinous adenocarcinoma; Adenocarcinoma in situ; Lepidic; Disease-free survival

MeSH Terms

Adenocarcinoma in Situ
Adenocarcinoma, Mucinous*
Disease-Free Survival
Humans
Lung
Male
Mucins*
Multivariate Analysis
Recurrence*
Mucins

Figure

• 

  Fig. 1. Examples of lepidic pattern and non-distorted acini (pattern 1). (A–F) Low-powered (A, C, E) and high-powered (B, D, F) view. (A, B) Typical lepidic pattern showing strips of tumor cells clinging to alveolar walls. (C, D) In areas where the stroma is increased, acinar structures (pattern 1) are formed without alteration of cytomorphologic features. (E, F) Densely spaced, bland acinar structures (pattern 1). The stroma is elastotic, not desmoplastic. (G, H) Immunohistochemical staining for thyroid transcription factor 1 reveals that round-to-oval spaces embedded in the central scar are alveolar spaces partially lined by tumor cells. Complete replacement of these spaces by tumor cells may form an acinar structure.

• 

  Fig. 2. Examples of invasive patterns: pattern 2, invasion into stroma (A–D) and pattern 3, invasion into alveolar spaces (E, F). (A) Jagged, fused glands with loss of nuclear polarity support invasiveness. (B) Anastomosing glands with increased nuclear atypia (pattern 2) seen on the right is distinguished from the bland, non-distorted acinar structure (pattern 1) noted on the left. The photomicrographs 2A and 2B were taken from the same case as in 1E and 1F. (C) Intracytoplasmic mucin is replaced by eosinophilic cytoplasm, resulting in squamoid appearance. (D) The area of glandular fusion shows loss of nuclear polarity and paler cytoplasm compared to the area of lepidic pattern on the right. (E) Proliferation towards alveolar spaces results in a serrated appearance. (F) A micropapillary pattern with ring-like structures is seen.

• 

  Fig. 3. Disease-free survival according to T stage (A) and adjusted T stage (B). aTis, no invasion; aT1mi, minimal (≤5 mm) invasion; aT1a1, ≥ 5 mm, ≤1 cm invasion; aT1a2, ≥1 cm, ≤2 cm invasion; aT1b, ≥2 cm, ≤3 cm invasion; aT2a, ≥3 cm, ≤5 cm invasion or visceral pleural invasion (PL1–2); aT2b, ≥5 cm, ≤7 cm invasion; aT3, ≥7 cm invasion or satellite tumor nodule in the same lobe or parietal pleural invasion (PL3); aT4, satellite tumor nodule in a different ipsilateral lobe.

• 

  Fig. 4. Disease-free survival in separate T stage subgroups according to the adjusted T stage (A, C, E) and grouped adjusted T stage (B, D, F). (A, B) T1b subgroups (n=42). (C, D) T2a subgroups (n=49). (E, F) T2b subgroups (n=18). aTis, no invasion; aT1mi, minimal (≤5 mm) invasion; aT1a1, >5 mm, ≤1 cm invasion; aT1a2, >1 cm, ≤2 cm invasion; aT1b, >2 cm, ≤3 cm invasion; aT2a, >3 cm, ≤5 cm invasion with or without visceral pleural invasion (PL1-2); aT2a-PL*, ≤3 cm invasion but with visceral pleural invasion (PL1-2); aT2b, >5 cm, ≤7 cm invasion.

• 

  Fig. 5. Disease-free survival in separate adjusted T stage subgroups according to the T stage (A, C) and grouped T stage (B, D). (A, B) aT1a subgroups (n=34). (C, D) aT2a subgroups (n=21). aT1a, >5 mm, ≤2 cm invasion; aT2a, >3 cm, ≤5 cm invasion or visceral pleural invasion (PL1–2).

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