The Significance of Pleural Elastica Invasion by lung Carcinomas

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1 The Significance of Pleural Elastica Invasion by lung Carcinomas BRRY GLLGHER, MD, ND STEFN J. URBNSKI, MD Invasion of visceral pleura by primary lung carcinomas is an important parameter in staging. The complex histology of visceral pleura requires special elastic stains for proper evaluation, yet only approximately 10% of peripheral lung carcinomas seen in consultation (S.J.U.) are thus assessed. The objective of this study was to examine the prognostic importance of microscopic visceral pleura invasion by lung carcinomas. Retrospective analysis of 23 cases of peripheral T2, NO, MO carcinomas with mi- From the Department of Pathology, University of Calgary, Calgary, lberta, Canada; and the Tom Baker Cancer Centre, Calgary, lberta, Canada. ccepted for publication September Kqr wow!.s: lung carcinoma. visceral pleura, invasion. ddress correspondence and reprint requests to Stefan J. Urbanski. MD, Department of Histopathology, Foothills Hospital, St NW, Calgary, lberta, Canada by W.B. Saunders Company /90/ $5.00/O croscopic pleural invasion on elastic stains and a matched control group documented a statistically significant (P = ) difference in survival between squamous cell carcinoma subgroups. This study therefore suggests the need for histologic assessment of peripheral lung carcinomas for invasion of internal pleural elastic lamina. HUM PTHOL 21: by W.B. Saun- ders Company. Several studies have reaffirmed the importance of staging in lung cancer in determining prognosis and treatment.lw5 Of particular importance is the selection of patients who may benefit from radiotherapy in addition to surgery. Visceral pleura invasion by lung carcinomas clearly represents an important parameter in staging and is included in the two major staging classifications. Thus, according to both the International Union gainst Cancer6 and the merican Joint Com- FIGURE 1. n adenocarcinoma is seen to invade through pleural internal elastic lamina (arrow). The invasion is not associated with significant inflammation or fibrosis. (Movat s stain, magnification x 390.)

2 PLEURL INVSION BY LUNG CRCINOMS (Gallagher & Urbanski) mittee s:taging, tumor of any size which invades the visceral pleura is classified as T2. system of nomenclature and histologic criteria for visceral pleura invasion a.re also available8 but because of the structure of pleura these are rather complex and are subdivided into P,, P,,, P,, P,, and P,. There is no study that documents the prognostic and therapeutic slgnificance of various histologic subtypes of visceral pleura invasion. This may partly explain why in the consulted lung malignancies (S.J.U.), among approximately 40 cases of lobectomies for peripheral lung carcinomas seen annually, the status of visceral pleura is assessed in only approximately 10%~ of cases. This study attempted to assess the prognostic importance of pleural internal elastic lamina breaching in primarv lung carcinoma. MTERILS ND METHODS Retrospective analysis ( ) of the files of the Calgary, and the Cross Cancel Institute, Edmonton, identified 1,799 cases of pulmonary carcinoma with information available regarding staging. In this group there were 440 stage I carcinomas. Three hundred sixty-four cases were classified as either Tl, NO, Tom Baker Cancer Centre, MO or T2. NO, MO. ll these cases were then tzxamined. The medical charts were reviewed fbr clinical data and to check the clinically assigned stage. The size and location of the tumor were taken from the gross pathology report in the chart. Histologic assessment was then performed, firstly, to confirm histologic grade and type and secondly, to determine if tumor approached but did not penetrate the pleural surface. In such cases the pleural elastic lamina was assessed using three elastic stains: Verhoeff Van Gieson. Movat s. and Victoria Blue. Five distinct layers have been described in pleuraq: ( 1) Mesothelial layer. This consists of a single layer of variably shaped mesothelium; (2) Submesothelial layer (75 pm). This relatively thin layer consists of connective tissues immediately beneath the mesothelial la!er. (3 I External elastic lamina (100 Fm). This contains elastic fibers. (4) Interstitial layer (250 km). This outer half contains abundant lymphatic vessels and giant capillaries ten times larger than alveolar capillaries. The inner half contains abundant fibrous tissue. (5) Internal elastic lamina (250 km). Closest to the pulmonary parenchyma, it consists of relatively thin elastic fibers and may partly belong to the subpleural tissues. Pleural elastic lamina breaching was defined as invasion by tumor cells of internal pleural elastic lamina and such cases were assigned to the pleural elastic lamina group. FIGURE 2. Squamous cell carcinoma (arrows) has invaded through pleural elastic lamina. There is prominent elastic lamina reduplication and fragmentation, resulting in formation of common elastic lamina. (Movat s stain, magnification x 195.)

3 Volume 21, No. 5 (May HUMN PTHOLOGY FIGURE 3. Occasionally the pleura may undergo fibrosis with retraction of common elastic lamina. Such cases are particularly deceptive and pleural invasion may not be suspected unless the slides are stained for elastic fibers. (Verhoeff-Van Gieson stain, magnification x IOO]. The insert illustrates low magnification of a deep wedge-shaped pleural retraction with fibrosis filling in the created defect. mor size, tumor type, date of diagnosis, and tumor differentiation. The presence of invasion of endothelium-lined spaces was assessed in both groups. With the exception of large-cell carcinoma (treated by lobectomy and radiation) all the other cases were treated by lobectomy only. None of the cases with pleural invasion or the control groups had lymph node metastases. We have analyzed a total of 46 cases, 23 with and 23 without internal pleural elastic invasion (Table 1). Of the cases with pleural elastic invasion, 12 were squamous carcinomas (Table 2). The remaining cases were represented by 10 adenocarcinomas and one large-cell carcinoma. The groups were compared for length of survival. Mean survival rate for each histologic type was also calculated. Statistical analysis of the data was performed with the Kaplan-Meier method, followed by Wilcoxon s test. McNemar s test was done in a separate analysis to confirm the statistical significance of the previously obtained data. In some instances the tumor invaded pleural elastic lamina without eliciting any visible secondary changes (eg, fibrosis, inflammatory response, or elastic lamina reduplication, Fig 1). In other cases breaching of internal elastic lamina was associated with prominent elastic reduplication and inflammatory infiltrate (Fig 2). The value of elastic stains was best documented in those cases where pleural invasion was accompanied by thick fibroblastic proliferation (Fig 3). Only in the first of these three morphologic variants could distinct internal elastic lamina be seen. For this study, therefore, we have decided to diagnose pleural invasion when the tumor cells were seen to invade internal elastic lamina (Fig 1) or common elastic lamina (Fig 2). Those cases where entire pleura was permeated by tumor (P2), with carcinoma cells seen on the pleural surface, were not included in this analysis. matched control group was assembled from those cases of peripheral lung carcinoma without elastica breaching. Factors cross-matched included age, sex, treatment, tutble 1. Total Summary Dead TBLE 2. of ll Cases Percent live Censored Breached Nonbreached Totals Summary of Cases With Squamous Cell Carcinoma Total Dead live Percent Censored Nonbreached Breached Totals

4 PLEURL INVSION BY LUNG CRCINOMS (Gallagher & Urbanski) TBLE 3. Breached Squamous Cell Carcinoma Invasion of Tumor Size Follow-up livei Lndothelium Patient No. ge Sex km) Differentiation TX in months Dead Lined Spaces - I 75 M 4 Moderate 1. 8 D + 2 TO M 6 Moderate F -1 Poor L -1 r) M :i Moderate L 1 I) 5 73 M 5 Moderate I. 10 I) M 3 Poor M 3 Moderare 1. x4.4 - x 61 M 2 Moderate I M 4 Poor 1. x3,i 10 riti IV 1.5 Poor \ M 2.x Moderate L ri1 F 2.5 Poor L 29 -.i\hhre\iations: Ts. treatment: L. lobecromy TBLE 4. Nonbreached Squamous Cell Carcinoma Tumor Size Follow-up Patient No. ge Sex (cm) Differentiation TX in months I 7.3 M 3.5 Poor M 5 Well :I -13 F 3.2 Poor L x M :i Well L I5 5 7i M 3.5 Poor L 84 6 fi 1 M 3.5 Poor- L M 3.5 Poor L 78 x 9 7 ) 63 M I.3 3. I Poor Poor L L IO 7 M 2 Poor L 13 II 74 M 2 Moderate L 16 I2 65 F 2 Poor I. 46,4hhre\,iatiolls: 7-x. treatment: L, lobectom\. --- Invasion of.4livel Endothelium Dead Lined Spaces D rz TBLE 5. Breached-denocarcinoma, Large-Cell Carcinoma In\ asion of Tumor Size Follow-up live! Endothelium Pntient No. ge sex km) Differentiation TX in months Dead Lined Spaces 1 7x M 5 Moderate L ti F 4 Poor I :3 F 5.5 Moderate I F 2.3 Moderate L F 3 Moderate i F 2 Moderate L F 2 Moderate L M.5 Poor L !, M 3 Poor L 45 D + IO 5 1 M 2.2 Moderate L 7 D II 63 M 2.5 Large cell LRx ti D + bbreviations: TX. treatment; L. lobectomy; Rx, radiotherapy. 515

5 HUMN PTHOLOGY Volume 21, No. 5 (May 1990) Patient No. ge Sex TBLE 6. Nonbreached-denocarcinoma, One Large-Cell Carcinoma Tumor Size (cm) Differentiation TX Follow-up in months live/ Dead Invasion of Endothelium Lined Spaces 1 74 M 3 Poor LRx 2 D 2 52 F 2.2 Poor L F 5 Moderate L F 1.2 Moderate L 56 : F Poor Moderate L D M 2 Moderate L M 2 Poor L M 2.1 Poor L 10 D M 3.5 Moderate L M 2.3 Large-cell LRx 78 bbreviations: TX. treatment; L, lobectomy; Rx, radiotherapy Of the 364 cases studied, 173 were peripheral. mong these 173 cases, transpleural carcinoma invasion was described in six original pathology reports and these cases have not been reexamined. Subsequently, we have reexamined with elastic and hematoxylin and eosin (H&E) stains the remaining 167 cases. There were 81 cases of peripheral carcinomas with the original histopathology report describing tumor separated from pleural by normal lung parenchyma or inflammation; no pleural invasion has been seen within this group. The pathology reports of the remaining 86 cases described tumor to closely approximate but not penetrate pleura or did not mention the status of pleura at all. mong these 86 cases, two showed transpleural migration and 23 showed pleural elastica invasion without transpleural migration. We have therefore identified among 173 cases of peripheral carcinoma eight cases with transpleural invasion (4.6%), 23 cases with breaching of pleural elastic laminallaminae (13.3%), and 142 cases without pleural invasion (82.1%). In the group with elastic lamina invasion the distinction between internal and external elastic lamina could not be made in I9 out of 23 cases examined. This was due to fusion and duplication of elastic laminae (common elastic lamina formation, Figs 2 and 3) in 18 cases, and in one case because of marked fragmentation and dispersion of laminae by pools of mutin and inflammation. Formation of common elastic lamina was seen not only among cases with pleural invasion but also in approximately 15% of cases with tumor separate from pleura. The great majority of such cases were associated with endogenous pneumonia. The formation of a common elastic lamina was not associated with any specific histologic tumor type. There were 12 cases of squamous cell carcinoma in both breached and nonbreached pleural elastic lamina groups (Tables 3 and 4), and 10 adenocarcinomas with one large-cell carcinoma in both groups 1.0-w o=breched is COV b= NON-BRECHED Om 0. C p oodooo0 cxmwocoooooo o - 0Rn.o.W is 0. Cm. o= BRECHED 5 0. =NON-BRECHED Ooo UY 0 8 KOCCOO J I 0.01,,,,, (,,,,, MOS FIGURE 4. Kaplan-Meier survival analysis of all cases I31 MOS FIGURE 5. Kaplan-Meier survival analysis of cases with squamous cell carcinoma. 516

6 PLEURL INVSION BY LUNG CRCINOMS (Gallagher & Urbanski) (Tables 5 and 6). In both squamous cell carcinoma groups there were 10 males and two females. In the breached adenocarcinoma-large cell group there were six females and five males whereas in the nonbreached group there were five females and six males. t the time of analysis, 15 in the breached group and 19 in the control group were still alive. Eight of 11 patients were still alive in both adenocarc-inoma and large cell carcinoma groups. In the squamous cell carcinoma groups seven of 12 in the breached group and 11 of 12 in the nonbreached group wlere still alive. Kaplan-Meier survival analysis data are shown in Figs 3 and 5. generalized Wilcoxon test showed no significant differ.ence between the overall breached and nonlbreached groups. However, there was a significant diff-erence (P = ) between the squamous cell carcinoma breached and nonbreached groups. This was confirmed on McNemar s test. DISCUSSION ccurate staging is important in determining prognosi:s and treatment for lung carcinoma. Indeed. one study showed that tumor stage was the only significant predictor of survival.2 Furthermore, the assessment of treatment protocols requires that cases be accurately staged. This study found that invasion of the internal pleural elastic lamina significantly reduced the survival rate of patients with peripheral squamous cell carcinoma. It has recently been asserted that peripheral squamous cell carcinoma may carry a better prognosis than central squamous cell carcinoma. Our findings may not be at variance with this; rather, we have delineated a small subgroup of these tumors with a worse prognosis. It is not known why the squamous cell carcinomas with ibreached pleural elastic lamina have a worse prognosis. Intrathoracic spread may be enhanced as occurred with at least one patient in the breached pleural elastic lamina group. lternatively, it may be that the ability of the tumor to breach the pleural elastic lamina is a measure of its invasive potential. In our material the tumors with pleural invasion were on average slightly larger (mean values 3.6/3.2 for squamous, for adenocarcinoma). The significance of this difference is uncertain. Survival rate of the squamous cell carcinoma group wi1.h pleural invasion resembles the stage II tumors more than stage I and therefore radiotherapy may be appropriate for these patients in addition to surgical therapy. Existing histologic criteria for pleural involvement by lung carcinomas recognize five separate variants. There is no uniformity in interpretation of this histologic finding, however, and a significant proportion of lung cancer resections are not assessed by elastic stain. lthough the visceral pleura has obviously been permeated when tumor cells are present on its surface (P2) or the pleural effusions contain tumor cells, a problem of interpretation arises when tumor breaches the pleural elastic larnina but is not present on the pleural surface. The histologic criteria for pleural invasion used initially in our study closely match the P, category in which visceral pleural elastica is invaded. It was subsequently found that in the great majority of cases with pleural invasion the distinction between pleural elastic laminae cannot usually be made, as a common elastic lamina is formed (Figs 2 and 3). It is suggested on the basis of these findings that invasion of either internal elastic lamina or common elastic lamina should be considered indicative of pleural invasion. Occasionally, reactive fibrosis may occur on the pleural surface overlying an area of in\,asion (Fig 3). The tumor in such cases will appear on H&E to be several millimeters away from the pleura, while, in fact, the pleura may be extensively invaded by carcinoma. Pleural invasion in most instances may be visualized only by application of elast.ic stains. The performance of elastic stains is simple and inexpensive but the interpretation of the histologic results may create some difficulty. In summary, the findings of this study confirm the need for histologic assessment of peripheral pulmonary carcinomas for invasion of pleural elastic lamina. If present, such a finding should be considered indicative of pleural invasion and staged appropriately. REFERENCES 1. Elson CE. Roggli VL, Vollmer RT, et al: Prognostic indicators for survival in Stage I carcinoma of the lung: histologic stud, ot 37 surgically resected cases. Mod Pathol l:ii(x-291, Greenbern SD. Fraire E. Kinner BM. 151 al: Tumor cell type versus sta&g in the prognosis of carcinoma of the lung. Path01 nnu 22: , Naruke T, Suemasu K. Ishikawa S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76: Shields TW. Humphrey EW. Matthews M. Eastridge CE. Keehn RJ: Pathologic stag; grouping of patients with resected carcinoma of the lung. I Thorac a Cardiovasc Surer 80: I 0 5. Roggli VL, Vollmer RT. Greenberg SD. et al: Lung cancer heterogeneity: blinded and randomized studv of 100 consecutive cases. I?u.M ti~1.m. 16: Hermaneck P. Sobin LH: TNM Classificaticm 01 Malirmant Tumors (ed 4). New York, NY, Springer-Verlag, p 70y 7. Mountain CF: new international staging system for lung cancer. Chest 89: , 1986 (Suppl) 8. Dail DH, Hammar SP (eds): Pulmonarv Pathology. Nen York. NY. Springer-Verlag. 1988, p Nagaishi C: Functional natomy and H~stologv of the Lung. Baltimore, MD, University Park, Tomashefski JF, Rosenthal E, Connors F: Peripheral vs central squamous cell carcinomas of the lung. comparison of clinical features. histopathology and survival. Mod Path01 1: