The Thorax

© Springer Nature Switzerland AG 2020

N. Sverzellati, M. Silva (eds.)The ThoraxCancer Dissemination Pathwayshttps://doi.org/10.1007/978-3-030-27233-3_1

1. Mechanisms of Tumor Dissemination in Thoracic Neoplasms

Francesca Locatelli¹  , Francesca Ambrosi²   and Giulio Rossi³  

(1)

Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, Hospital degli Infermi, Rimini, Italy

(2)

Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

(3)

Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, Hospital S. Maria delle Croci, Ravenna, Italy

Francesca Locatelli

Email: [email protected]

Francesca Ambrosi

Giulio Rossi (Corresponding author)

Keywords

LungMetastasisInvasionImmunohistochemistryKRASPrimaryTTF-1

1.1 Introduction

Tumors commonly show several patterns of spread due to direct growth into adjacent structures, as well as lymphatic and hematogenous dissemination. However, the lung represents a peculiar site both for primary cancer and metastatic malignancies. In particular, the singularity of lung dissemination is found in aerogenous spread, an old concept recently reintroduced under the definition of spread through airspaces (STAS). STAS is basically related to the unique architecture of the lung where airspaces can be traveled across relatively easily by cells. Although this is a characteristic feature of adenocarcinomas (ADC) (formerly known as bronchioloalveolar carcinoma, BAC), even other histological types may show this dissemination pathway. Of note, aerogenous dissemination justifies some unusual imaging findings mimicking benign diseases, such as miliary pattern or ground-glass opacities (GGO).

Beyond STAS in lung cancer, further primary neoplasms of the thorax show patterns of local growth by direct invasion into adjacent structures and organs, including pleura, mediastinum, chest wall, and spine.

Pleural invasion is the effect of direct extension of tumor growth into the pleura rather than seeding from hematogenous or lymphatic pathway. Demonstration of pleural invasion from lung cancer is highlighted by desmoplastic fibroblastic stroma or disruption of elastic tissue. Growth of tumor cells on the pleural surface may mimic mesothelioma; this phenomenon is also known as pseudo-mesotheliomatous adenocarcinoma (◘ Fig. 1.1). Pleural effusion may be due to pleural seeding; nonetheless, lymphatic or pulmonary venous obstruction as well as inflammatory reaction by the tumor cells can display such evolution.

Fig. 1.1

Generous pleuroscopy biopsy of a pseudo-mesotheliomatous adenocarcinoma of the lung manifesting as a prominent pleura-based neoplasm mimicking mesothelioma growth pattern

Lymphatic dissemination is very common, particularly in lung cancer with adenocarcinoma histology. Lymphatics represent a main structural network within the intangible texture of the lung: the anatomic distribution of lymphatic drainage is diffuse from the pleura to the bronchial structures, namely, from the very periphery to the hila, including a tight network throughout. Lymphatic dissemination in lung cancer becomes a determinant of therapeutic approach (e.g., surgery or medical therapy), and it represents a major prognostic factor, as deployed in lung cancer staging system. Tumor spread through lymphatic channels is also characteristic of other neoplasms beyond lung cancer, notably lymphoproliferative diseases and metastatic tumors (◘ Fig. 1.2).

Fig. 1.2

A low magnification of lung parenchyma with lymphangitic carcinomatosis involving the interlobular septa (arrows), pleural surface (dots), and bronchovascular bundles (circle)

Finally, vascular invasion is extremely common in carcinomas, involving large or small vessels, veins, or arteries. Vascular invasion translates into hematogenous dissemination leading to systemic tumor cell dissemination to extrathoracic sites. Massive lymphatic/hematogenous invasion is the cause of neoplastic thrombotic microangiopathy often simulating interstitial lung diseases on pathology as well as on imaging. Notably, this pattern is becoming more and more challenging in the evolving scenario of medical oncology because adverse events to new agents are increasingly common (sometimes asymptomatic) and their imaging pattern might substantially overlap signs of tumor progression. Different mechanisms of metastasis in primary and secondary neoplasms are here presented.

1.2 Shared Dissemination Pathways of Primary and Secondary Malignancies of the Thorax

Growth and spread of primary and secondary thoracic neoplasms mainly depend on the peculiar anatomy of the thoracic region (in particular the pulmonary structure), the type of tumor, and the colonized tissue.

The most common category of tumors in the lung parenchyma is metastatic malignancies [1]. This fact can be explained by two pivotal anatomic characteristics of the lung: the whole venous and lymphatic drainage of the body is collected into the right heart toward the lungs. Namely, systemic bloodstream and lymphatics of most organs are in parallel with one another, but lung is in series. Therefore, any organ is drained into the lung, which ultimately can filter out metabolic derivate as well as becomes a first stop site of neoplastic cells that are filtered through its exceptionally dense capillary bed. Noteworthy, such rich capillary bed provides abundant oxygen to early metastasis, which will thereafter be supplied by bronchial arteries [2].

Lung metastasis and primary lung tumors share the same dissemination pathways. Hematogenous dissemination, either arterial or venous, is the most common pathway, followed by lymphatics, endobronchial, pleural, and aerogenic diffusion, and direct extension. A combination of the above pathways is quite common in lung cancer at the time of diagnosis [1, 2].

Primary lung carcinomas mainly disseminate by lymphatic channels or airway dissemination, while pulmonary metastases from carcinoma, sarcoma, and lymphoma metastasize to the lung via the bloodstream [3]. As expected, adenocarcinoma from any organ is the most common subgroup of lung metastasis because of its epidemic incidence, notably from the breast, digestive tract, kidney, head/neck region, pancreato-biliary region, uterine leiomyosarcoma, and lung itself [2–6].

Similar spreading routes can determine similar histopathologic patterns of spread in both primary lung cancer and secondary thoracic malignancy. Patterns of spread are classified into infiltrative/destructive, interstitial, lepidic, and alveolar filling [1–4]. Such pathways rely on the structure of the secondary lobule: a polygonal unit, sized 1–2 cm in diameter, consisting of acinar structures with peripheral boundary by the pleura and/or connective tissue of interlobular septa, the latter including lymphatics and venules [7, 8]. The center of the lobule is represented by the bronchovascular bundle made up of bronchioles and arterioles; it is usually larger than the peripheral veno-lymphatic complex. Indeed, it is also depicted on computed tomography, whereas the lobule periphery is seen only in case of abnormal thickening. The most volume of the secondary lobule is represented by alveoli surrounded by intralobular septa that contain the smallest branches of arterioles and venules and the capillary network [7–9]. Lung metastasis can simulate primary tumors both grossly and microscopically, and sometimes the differential diagnosis can be challenging and critical, even at pathology. Radiologists and clinicians must be aware that an independent primary lung tumor should always be considered in a patient with metastatic disease and vice versa. The detailed description of both radiologic and histopathologic findings in cancer patients allows accurate image interpretation throughout its wide spectrum of display and robust reasoning toward diagnosis. Immunohistochemistry and extractive molecular biology can become relevant for assisting the pathologist to refine the differential and drive the final diagnosis.

1.3 Tumor Dissemination in Primary Malignant Lung Tumors and Metastases

Primary lung tumor typically exhibits a histologic infiltrative/destructive pattern. It occurs more frequently as solitary nodule in the upper lobes and shows infiltrative dissemination to the surrounding lung parenchyma. In the destructive pattern, general characteristics such as site, location, and multicentricity, together with the clinical history, can suggest the distinction between primary lung tumor and metastasis, but unusual presentation can occur. Expansive borders are seen as the second most common dissemination pathway across the intangible pulmonary texture. There are exceptions to the aforementioned dissemination pathways; notably some adenocarcinomas (e.g., lepidic adenocarcinoma) happen to show dissemination by cellular leaning over alveolar epithelium (pulmonary structure is preserved).

Most primary lung tumors are represented by non-small-cell lung cancer (NSCLC) into either adenocarcinoma (ADC) or squamous cell carcinoma (SCC) histology and neuroendocrine tumors (NET) including carcinoid tumors and high-grade neuroendocrine tumor such as large-cell (LCNEC) and small-cell-lung carcinoma (SCLC). Primary invasive ADC of the lung and roughly one third of primary SCC present as a peripheral solitary nodule or mass, more frequently involving the upper lobes [2, 3]. A large peripheral mass is more commonly an ADC, while a hilar mass is more commonly a SCC or a SCLC [1], and they usually associate with lymph node involvement, either unilateral or bilateral. SCLC is an aggressive, smoking-related, high-grade NET that characteristically presents as a large hilar mass with bulky mediastinal lymph nodes. Unlike NSCLC, SCLC tends to involve adjacent structures by direct invasion, and it translates into frequent onset of superior vena cava syndrome. Occasionally, SCLC can occur as a predominant endobronchial mass and in about 5% of cases can be detected by CT screening as a peripheral nodule, even node-negative [2, 3]; however, the outcome of SCLC remains poor even with screening [10]. LCNEC occurs more frequently peripherally, and it is seldom associated with bulky intrathoracic lymph nodes. Signs, symptoms, and imaging findings of other rarer histological types mostly overlap with NSCLC.

Unlike primary lung cancer, metastases are more frequently multiple and bilateral and show a random nodular distribution. Metastases used to be overall smaller than primary lung cancer; notably, they show heterogeneous size depending on the temporal evolution of spread or on the type of soil, according to Paget’s theory [6]. Furthermore, hematogenous metastases to the lung usually appear as well-delimitated findings with smooth margins; they mostly are round, oval, or lobulated in shape. Like most primary lung ADC, metastases tend to be peripherally located, but unlike ADC they prefer the lower or middle lung fields according to perfusion gradient [1, 2]. Metastases have usually a rapid growth, substantially faster than primary adenocarcinoma. The most common spreading patterns in primary lung cancer and metastatic tumors to the lungs are reported in ◘ Table 1.1.

Table 1.1

Tumor cell dissemination in lung primary and metastasis

Abbreviations: TRU terminal respiratory unit, LAM lymphangioleiomyomatosis, DIPNECH diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

However, exceptions to this rule can occur, such as solitary lung metastasis or multiple primary lung tumors. Solitary lung metastases are reported in 3–9% of the cases [2]; they can present as large cannon ball, even larger than 5 cm, formerly frequent event from colorectal carcinoma [2]. Solitary metastases to the lung are also seen in melanoma, sarcoma, testicular carcinoma, and extrathoracic ADC [2]. Metastases to the lung are also seen in young age, with sarcoma and germ cell neoplasms being the most frequent cause of hematogenous dissemination [3, 4]. Lung metastases are expected to follow a clinical history of extrapulmonary neoplasms; however, it happens in 20–54% of cases. Otherwise, in 15–25% of cases, the lung is the only site of the so-called anachronous metastasis, be they solitary or multiple [2].

Nonetheless, clinicians must be aware that solitary lung nodules in patients with extrathoracic neoplasms can also be a primary tumor. According to Filderman, this situation is more likely to occur in cancers of the lung (e.g., second primary), breast, stomach, prostate, and head and neck. Conversely, primary lung cancer is less frequent in case of melanomas and sarcoma. Lung solitary nodules in patients with carcinomas of kidneys, colon, or testes have the same probability to be either primary or secondary [11].

Unfortunately, there is no perfect panel of immunostains to distinguish a primary from a metastatic tumor; hence, careful clinico-radiological correlation is mandatory. This is especially true for the differential diagnosis between a primary SCC and a metastatic SCC of head and neck, esophagus, or cervix origin. The comparative use of p16 and p53 immunostaining status can sometimes be helpful to the purpose of histological differential [2, 3]: the association of SCC from head and neck with HPV/p16 is more straightforward than its pulmonary counterpart. Finally, SCC should be distinguished from metastatic urothelial carcinoma, which is positive for GATA3 [2, 3, 12–16] (◘ Fig. 1.3). A practical list of the most important immunostains involved in the diagnosis of primary versus secondary malignancy is summarized in ◘ Table 1.2.

Fig. 1.3

Transbronchial biopsy a showing a tiny aggregate of tumor cells into a lymphatic channel b. Positive anamnesis of mammary neoplasm and expression of estrogen receptors c supported the diagnosis of pulmonary dissemination/metastasis from breast cancer

Table 1.2

Practical summary of the most important immunohistochemical stains in the identification of cell differentiation of various primary/metastatic neoplasms

Abbreviations: IHC immunohistochemistry, TTF-1 thyroid transcription factor-1, CK cytokeratin, CDX caudal-type homeobox, ER estrogen, PGR progesterone, GCDFP gross cystic disease fluid protein, NF neurofilament, PAX8 paired box gene 8, alpha-FP alpha fetoprotein, SALL4 Sal-like protein 4, PLAP placental alkaline phosphatase, HCG: human chorionic gonadotropin, PSA prostate-specific antigen, PSAP prostate-specific acid phosphatase, AR androgen receptor, FLI1 Friend leukemia integration, HBME1 Hector Battifora mesothelial-1, LMW low molecular weight, HMW high molecular weight, EMA epithelial membrane antigen, RCC renal cell carcinoma, PEComas perivascular epithelioid cell tumors, NSE neuron-specific enolase

Multiple primary lung cancers are not uncommon, especially invasive mucinous ADC and lepidic ADC, formerly known as bronchioloalveolar carcinomas (BAC). Such histology tends to be multicentric, bilateral, and usually peripheral. The differential between multiple synchronous primary ADC and alveolar/aerogenous spread is quite challenging both at pathology and imaging. Synchronous intrapulmonary metastases from primary lung cancer can also manifest as multiple nodules or masses and should be differentiated from a primary tumor because of substantially different clinical management and prognosis. The comprehensive histologic subtyping, characterization of cytology (clear cells or signet ring features), and stromal features (desmoplasia or inflammation) are most useful in case of multiple ADC.

1.3.1 Radiopathologic Correlation of Ancillary Signs of Thoracic Malignancy

Both primary and metastatic malignancies of the lung can occur with ancillary radiologic findings such as cavitation, calcification, hemorrhage, and cyst, which, together with other clinical characteristics, can suggest the proper diagnosis. The pathological counterpart of such radiological signs explains the heterogeneity of pulmonary malignancies, either primary or secondary, and the variable confidence in the differential. The radio-pathologic parallel is thereafter given.

1.3.1.1 Alveolar Pattern

Peculiar patterns of spread in the lung are the lepidic growth, the alveolar filling, and a recently recognized aerogenous (airspace) spread known as STAS. All these kinds of spread can be radiologically classified in the field of alveolar pattern [1, 2, 7]. Two signs can reflect the alveolar pattern on computed tomography: ground glass opacities (GGO) and parenchymal consolidation, the latter also typical of pneumonia. In histology, they are seen as filling of airspaces that ranges from partial (GGO) to complete (consolidation) [1, 2, 7] (◘ Fig. 1.4).

Fig. 1.4

Lung adenocarcinoma with micropapillary pattern a and dissemination of tumor cells through airspaces (b, circle)

In particular, the alveolar pattern is most commonly encountered in primary lung cancer with lepidic and mucinous ADC histology, respectively, associated with ground glass opacity and pneumonia-like consolidation [1, 2]. Papillary and micropapillary invasive ADC can also present with this pattern. As an aerogenous spread, this pattern of dissemination is oftentimes associated with multifocal and multilobar tumors, without a dominant nodule, and is characterized by the presence of satellite discontinuous neoplastic foci along the airspaces and airways around the tumor or, at distant, even in the contralateral lung [17, 18]. A very unusual variant of is represented by discohesive tumor cells filling and engulfing the alveolar spaces mimicking desquamative interstitial pneumonia (DIP), then called malignant DIP [19] (◘ Fig. 1.5).

Fig. 1.5

An unusual pattern of tumor cell dissemination in lung adenocarcinoma with intra-alveolar growth of discohesive tumor cells with signet ring cell features mimicking macrophages in desquamative interstitial pneumonia

Lepidic Growth

Lepidic growth is considered a grade I histological pattern of invasive lung ADC [20], mucinous or not. The lepidic spreading is characterized by the growth of the neoplastic cells along the intact alveolar walls like Lepidoptera on a fence. It respects the microscopic structure of alveoli, without displacing or destroying the adjacent lung (◘ Fig. 1.6). Pure lepidic or predominantly lepidic pattern is a mandatory criterion for the diagnosis of in situ ADC (AIS) and minimally invasive ADC, respectively. This definition applies to solitary and discrete tumor up to 3 cm in diameter. The radiological counterpart of AIS is nonsolid nodule (sole GGO component), while minimally invasive ADC is associated with part-solid nodules with solid component up to 5 mm.

Fig. 1.6

Lung adenocarcinoma with lepidic growth characterized by preservation of the pulmonary alveolar architecture

Rarely, metastatic ADC to the lungs may show a lepidic pattern, but they do not typically express TTF-1 and type II pneumocytes and/or club (Clara) cell morphology [21]. Examples of metastatic melanoma were described with an alveolar/interstitial growth, mimicking primary ADC and thus relatively insidious at differential [1, 2]. Metastases from pancreato-biliary or colorectal ADC also may grow in a lepidic fashion [21] (◘ Fig. 1.7).

Fig. 1.7

Pulmonary metastasis from pancreatic cancer a and primary mucinous invasive adenocarcinoma b showing an identical growth pattern with mucin-rich tumor cells lining the alveoli forming papillary projection

Mucinous invasive ADC can be radiologically characterized by consolidation that must be differentiated from both lipidic and obstructive pneumonia. Furthermore, mucinous invasive ADC is also characterized by the so-called bubble-like lucencies or pseudo-cavitations that are frequently described on computed tomography. The pathological counterpart of bubble-like lucencies is dilation of bronchioles from a valve mechanism of bronchiolar obstruction or desmoplastic traction or expression of spared pulmonary lobules. The bubble-like lucency can also present as pseudo-cavitation, which however must be distinguished from real cavitation [1, 2]. Lepidic growth of primary mucinous ADC comes into the differential with primary lung colloid ADC (characterized by abundant extracellular mucin that destroys and replaces the parenchyma) and with metastases from pancreatic, biliary, colorectal, gastric, and breast carcinoma. Immunohistochemistry can help in such differential [3, 4, 22].

Intra-alveolar Pattern of Growth

Intra-alveolar pattern of growth is typical of epithelioid hemangioendothelioma, described previously as intravascular bronchioloalveolar tumor, usually a multifocal vascular neoplasm typical of young female that can have a nodular pattern in the lung; it is histologically characterized by nodular aggregates of epithelioid cells with intracytoplasmic lumina embedded in a myxochondroid or hyaline stroma, simulating ADC, sarcoma, metastatic cardiac myxoma, or sclerosing pneumocytoma.

Spread Through Airspaces

Recently, the term spread through airspaces (STAS) has been reintroduced by Kadota et al. [23] to define the presence of micropapillary clusters, solid nests, or single cells in alveolar spaces beyond the edge of the main tumor and within the surrounding lung parenchyma. STAS probably contributes to the significantly increased risk of recurrences for patients with small stage I ADC who undergo limited resections and to the worse survival observed by others. Kadota et al. [23] found STAS to be significantly associated with any recurrence in small (≤2 cm) stage I lung ADC treated by limited resection, compared with lobectomy. After the validation of STAS in two studies [24, 25], the 2015 WHO classification introduced it as a fourth type of invasion of ADC beyond lepidic pattern (such as acinar, papillary, micropapillary, solid, colloid, or enteric), tumor cells within myofibroblast stroma, and vascular or pleural invasion. STAS is indeed considered an exclusion criterion for the diagnosis of minimally invasive ADC, together with tumor necrosis and vascular or pleural invasion [3, 4]. Unfortunately, there is no presurgical noninvasive parameter for direct measurement of STAS, the risk which can only be rated by solid proportion on computed tomography. Its prognostic value is however debated by who considers STAS not an in vivo effect but an artifact induced by the cutting that, in fact, was proved to increase the extension of the tumor cells at the lung periphery. Tumor islands, originally described by Onozato in 2013 [26] as isolated, large collection of cells, with no clear micropapillary configuration, distant at least a few alveoli by the main tumor, are considered the forerunner of the solid-type STAS and a subset of spread proved to exist by three-dimensional reconstruction study. They have been correlated to smoking, solid or micropapillary high-grade pattern, K-RAS mutations, and a higher nuclear grade and have been associated with low recurrence-free survival. Despite that the distance of STAS has been defined in different ways according to different studies, up to now, all studies have demonstrated its prognostic value independently from the extent and its relevance both in ADC and SCC [27], and in the latter it is considered a new unfavorable prognostic parameter together with cell nest size, nuclear diameter, and tumor budding. Importantly, STAS resulted to be a significant prognostic factor independent from lymph vascular invasion and predominant pattern but dependent from stage. Of note, micropapillary STAS has been associated with lymph vascular invasion, recurrence-free survival, and mortality, so much that tumor cells within airspaces in a micropapillary feature should be assigned to a micropapillary pattern, which is known to be associated with poor prognosis even in small amounts.

The exact reason for the association of STAS with prognosis is unknown, but we can speculate that STAS could be the epiphenomenon of the tumor diffusion between interalveolar pores of Kohn and bronchiole-alveolar communications of Lambert that normally guarantee the collateral ventilation, and this is why tumor cells could remain undetected in alveolar spaces beyond the surgical margin. Another possible explanation is that tumor cells may reenter in the interstitium around the terminal bronchioles.

For the aforementioned reasons, the inclusion of STAS in pathology report could have potential implication on treatment decisions, therapy, and surveillance, including meticulous radiological follow-up of recurrence, even if more studies on margin distance are warranted. Of note, more recently, the prognostic role of STAS phenomenon has been reported even in primary NET of the lung [28].

1.3.1.2 Halo Sign

Peripheral halo of ground-glass (aka halo sign) can be seen by computed tomography in both primary and secondary malignancies of the lung. Hemorrhage is the pathological counterpart of halo sign, which can be associated both with neoplastic and benign conditions (e.g., angioinvasive aspergillosis). Metastastases with halo sign are mostly reported in choriocarcinoma and angiosarcoma. Nonetheless, it can also be observed in nonhemorrhagic metastases with a peri-nodular lepidic growth [9].

1.3.1.3 Cavitation

Cavitation is radiologically characterized by a lucent cavity surrounded by solid wall of varying thickness [1, 7, 9]. Cavitation occurs more frequently in primary lung carcinomas and in particular in lung SCC, where it reflects tumor necrosis in the core of the lesion where angiogenetic stimuli and metabolic demand substantially mismatch. However, cavitation is not exclusive to primary lung SCC; indeed, it is also seen in metastases and in nonneoplastic conditions such as infections, Langerhans cell histiocytosis, necrobiotic rheumatoid nodules, granulomatosis with polyangiitis, and septic embolism. Therefore, oncologic perspective should not fail to recognize further conditions associated with nodule/mass cavitation, especially in case of known malignancy and potentially overlapping nonneoplastic disorder. The erosion of necrotic cavitation into the pleura can be responsible for pneumothorax