Tratamentul şi prognosticul metastazelor cutanate ale cancerului bronhopulmonar

Introduction

Bronchopulmonary cancer is one of the most common and aggressive neoplasms, representing a major cause of mortality worldwide⁽¹⁾.

The particularity of this pathology lies in its ability to metastasize early hematogenously at a distance, with the appearance of metastases, including at the skin level⁽²⁾. Although the incidence of skin metastases is low, they have particular clinical and prognostic significance⁽³⁾. Skin metastases can be found in all histological subtypes of lung cancer, but they occur predominantly in lung adenocarcinoma and squamous cell carcinoma, being less common in microcellular forms, although the latter are notable for their marked aggressiveness and increased capacity for systemic dissemination^(1,2). 

The skin manifestations of metastases are varied and often nonspecific, the most common form of presentation being firm, round or oval nodules, single or multiple, located in the dermis or hypodermis. The skin covering these lesions may appear normal, erythematous or purplish, and in some cases these formations may ulcerate, bleed or become painful⁽³⁾.

Due to their clinical presentation, skin metastases can be confused with benign or malignant dermatological conditions that are less aggressive, which delays diagnosis and, in particular, the treatment, with an impact on the patient’s prognosis⁽¹⁾. 

The most common locations of skin metastases originating from lung cancer include the anterior thorax, abdomen, back, head and neck. The scalp has been found to be an area of interest for these types of metastatic lesions, with a particular predilection due to the rich vascularization and higher temperature of the scalp⁽³⁾.

The diagnosis of skin metastases requires a biopsy and histopathological examination, which must be supplemented by immunohistochemical staining in order to make a differential diagnosis with skin metastases secondary to primary skin cancer and also to guide the identification of the primary tumor^(1,4).  

Beyond their diagnostic value, these skin lesions are of major prognostic importance, as their appearance marks a metastatic stage of cancer, correlated with a poor prognosis and limited survival. Rarely, when the skin metastasis is unique and does not coexist with other visceral disseminations of the oncological disease, the prognosis is favorable, with prolonged survival^(1,4,5).

The therapeutic approach is adapted to the patient’s clinical context. The treatment includes the surgical excision of solitary lesions, local radiotherapy for analgesic or hemostatic purposes, and systemic therapies, depending on the histological and molecular profile of the primary tumor^(4,6). Beyond local control of the disease, the management of these patients must be multidisciplinary, involving a multidisciplinary team of oncologists, dermatologists, radiotherapists and palliative care specialists, in order to ensure not only a prolonged survival, but also the best possible quality of life^(3,6).

Case presentation

We present the case of a 72-year-old male patient with no history of cancer who presented with a rapidly evolving skin lesion on his chin with a tendency to ulcerate. The medical history revealed that, approximately two months prior to presentation, the patient had experienced a persistent dry cough, dyspnea on light exertion, fatigue and weight loss. The clinical respiratory examination at presentation revealed a diminished vesicular murmur in the right lower lobe and subcrepitant rales, and the laboratory tests identified moderate anemia associated with an inflammatory biochemical syndrome.    

The chronology of first-line imaging investigations included two chest X-rays and an imaging investigation (chest CT with contrast medium) which did not reveal any active pulmonary lesions; the heart was assessed as being within normal limits, the diaphragm and costophrenic angles were free; degenerative vertebral changes (spondylosis/thoracic discopathy) were noted. Due to the lack of data pointing to a pulmonary pathology, a new imaging examination (chest MRI with contrast medium) was performed, which revealed a pulmonary mass in the right upper lobe measuring approximately 48/50 mm, heterogeneous, with bronchial invasion (upper lobar bronchus and partially right main bronchus), accompanied by right hilar adenopathy (approximately 23×19 mm) and right paratracheal and subcarinal mediastinal adenopathies (up to approximately 21×17 mm). A right T9 costovertebral formation measuring 7.3×4.2 cm with foraminal and intracanal invasion and secondary osteolysis of the right IV rib was detected. Abdominal-pelvic MRI revealed the presence of liver metastases in the form of two large masses (left anterosuperior lobe 8.7 cm; right lobe 16.7 cm) and metastases in the left suprarenal gland, measuring 25×16 mm.

As a first therapeutic measure, radical excision of the skin lesion in the chin area was performed, with macroscopic histopathological results showing a skin fragment that included an exophytic, sessile, ulcerated tumor formation (approximately 1.5×1.2×1.2 cm) and on microscopic examination, ulcerated skin with intradermal neoplastic infiltrates of poorly differentiated squamous carcinoma was described, interpreted as skin metastasis in the context of clinical and imaging suspicion of bronchopulmonary neoplasm. 

To assess bone involvement, bone scintigraphy (whole-body with 99mTc-HDP) was performed, which revealed multiple secondary findings with intense/heterogeneous hyperfixation in the sternum, thoracic vertebrae T2, T4 and T7, T10, ribs (I and VI left; V and IX right), as well as in the left iliac crest and right femur (femoral head and middle diaphyseal third). 

Native and contrast-enhanced CT examination of the skull and cervical region revealed no cerebral parenchymal metastases; however, the presence of craniocervical bone metastases was confirmed: left occipital bone (approximately 27×14.5×6 mm, with extracranial extension), right C1 vertebra (approximately 25×23.5×22 mm) with bone lysis and obliteration of the right vertebral artery, and a small osteolytic lesion at the level of the C4 cervical vertebra (approximately 7×6 mm). 

Overall, the clinical, imaging and histopathological data converge towards a diagnosis of right upper lobe bronchopulmonary neoplasm (squamous carcinoma, poorly differentiated), detected by imaging at the metastatic stage with skin, bone (ribs, sternum, pelvis, cervical-thoracic spine), liver and left adrenal gland. Given the symptomatic metastatic disease manifested by severe pain in the affected bone segments, emergency radiotherapy was initiated for pain relief, according to standard protocols, using a Clinac linear accelerator. At the sternum, thoracic spine and pelvis, a hypofractionated irradiation regimen of 20 Gy in five fractions (4 Gy/fraction, daily) was administered, with the aim of rapid pain relief and functional stabilization.

The treatment was completed in full, with good tolerance and no severe acute reactions requiring interruption or adjustment of the treatment plan. The chosen hypofractionated regimen is established as the treatment of choice in palliative radiotherapy due to the favorable ratio between the speed of pain relief, patient comfort and low toxicity profile. An analgesic response was anticipated and achieved in the weeks following the completion of irradiation, which made it possible to reduce opioid doses (Fentanyl® patch and sublingual Lunaldin®). The patient was subsequently reevaluated clinically in the oncology department, where he was referred for further treatment (chemotherapy and/or immunotherapy).

Discussion

The incidence of skin metastases in bronchopulmonary cancer is far from uniform, with the international medical literature describing a wide range of values. In a large Portuguese retrospective study conducted over 25 years, these lesions were found in less than 1% of patients with lung cancer, a figure that speaks to the rarity of the phenomenon⁽⁵⁾. However, other analyses paint a more nuanced picture: between 1% and 12% of patients diagnosed with lung cancer may develop skin metastases during the course of the disease⁽⁷⁾, and approximately 2.8% of patients with non-small cell lung cancer (NSCLC) present to their doctor with skin lesions as the first sign of the disease⁽⁸⁾.

Most studies place the incidence of skin metastases between 3% and 4%, but there are selected populations where the proportion has risen dramatically to 24%⁽⁹⁾. In other studies, the reported data varies from 0% to 4%, which once again highlights the diversity of clinical situations and the difficulty of establishing a universal value for the incidence of skin metastases as the first manifestation of lung cancer. Thus, the overall picture suggests that, although rare, skin metastases can occur in multiple contexts and can sometimes even be the first sign of lung cancer^(9,10). In a large study that analyzed the progression of 7316 patients with various types of cancer, it was found that approximately 0.8% of them had skin metastases as the initial manifestation, before any other clinical or imaging signs that would raise suspicion of cancer⁽¹¹⁾. Data from the literature show that the skin may be the first site of metastatic spread of cancer in up to a quarter of cancer patients, a situation that gives these lesions particular importance in the context of early detection of cancer⁽⁵⁾. 

A proportion of 25% illustrates how unpredictable the spread of malignant cells can be and how important it is for doctors to consider the pulmonary origin when faced with suspicious skin lesions during clinical examination⁽¹¹⁾. In other words, in the case of lung cancer, the patient’s first visit to the doctor is not only prompted by the presence of respiratory symptoms such as cough, hemoptysis or dyspnea, but also by the appearance of a skin lesion located in any area of the skin, apparently isolated and unique, or by the appearance of several skin lesions, but suspicious in clinical appearance and which may be the first sign of systemic disease with primary pulmonary localization. However, the analysis of the medical literature published in the last decade reveals that, although skin metastases may be correlated with squamous cell lung cancer, the most common histological type involved in the development of skin metastases is adenocarcinoma⁽⁵⁾. The observation of this phenomenon in various clinical studies highlights the fact that the biology of adenocarcinoma has a particular tropism and its often-insidious progression favors the spread to the skin. Although the incidence rates reported in the literature vary considerably, 32.63% of all skin meta­stases are attributed to lung adenocarcinoma⁽⁹⁾. These values reflect not only an increased overall prevalence of skin metastases originating from pulmonary adenocarcinoma, but also its distinct biological ability to metastasize to the skin.

Skin metastases originating from squamous cell carcinoma of the lung are generally rare and definitely less common than in the case of adenocarcinoma or other histological types of lung carcinoma. Thus, the classic study by Terashima and Kanazawa, conducted on a group of 34 patients and a series of autopsies, showed that squamous lung carcinoma has a reduced tendency to metastasize to the skin compared to other histopathological subtypes of lung cancer⁽¹²⁾. These findings have been confirmed in other clinical studies, such as that by Khaja et al., where lung adenocarcinoma was found to be most commonly involved in the development of skin metastases, and squamous cell carcinoma (SCC) had a modest frequency⁽¹³⁾. On the other hand, the results reported in the specialist journals noted significant geographical variations in the occurrence of skin metastases originating from lung adenocarcinoma or squamous cell carcinoma⁽¹⁴⁾.

In a study conducted in South Asia, squamous cell carcinoma of the lung was involved in half of the skin metastases of pulmonary origin. Other research conducted in the USA has found lower proportions of skin metastases originating from squamous cell carcinoma of the lung. However, regardless of incidence, it is important to note that the prognosis for patients with skin metastases originating from squamous cell carcinoma or lung adenocarcinoma is unfavorable. The study by Simsek et al. reported a median survival between 2.9 and 4.9 months after the onset of skin metastases, with no innovative oncological therapies (molecular targeted therapy, immunotherapy) able to significantly alter this prognosis^(15,16).

Skin metastases are a biological marker of extremely high metastatic capacity, indicating that the primary tumor has acquired the ability to cross multiple tissue barriers and adapt to the hostile skin microenvironment. The process of skin metastasis requires a complex cascade of molecular events that include detachment from the primary tumor, vascular invasion, survival in the systemic circulation, extravasation, and colonization of skin tissue. The skin microenvironment itself contributes to the poor prognosis by inducing a state of constant cellular stress that accelerates tumor progression. Relative hypoxia in the deep layers of the dermis activates the transcription factor HIF-1a, which promotes tumor angiogenesis, resistance to apoptosis and genetic instability. The skin extracellular matrix, rich in collagen and elastin, provides mechanical signals that activate pro-survival signaling pathways (PI3K/AKT, NF-kB) and promote the stem-cell phenotype of cancer cells. This constitutional activation of cell survival pathways, combined with chronic inflammation in the surrounding tissue, creates an environment that not only supports tumor growth but also accelerates dissemination to other organs through the continuous release of prometastatic factors into the systemic circulation^(15-17).

The therapeutic benefit of chemotherapy or resistance to chemotherapy in skin metastases is based on tissue pharmacology limitations and specific metabolic adaptations. The skin layers form a pharmacokinetic barrier through the impermeable stratum corneum and the dermal vasculature with low capillary density in the deep areas, resulting in subtherapeutic concentrations when cytostatics are administered. The decreasing oxygen gradient towards the deep layers of the dermis induces anaerobic cellular metabolism, which reduces the effectiveness of many chemotherapeutic agents whose efficacy is maximized when the area in which they act is efficiently oxygenated. In addition, chronic oxidative stress in the skin microenvironment activates cellular detoxification enzyme systems, including glutathione-S-transferases and enzymes of the cytochrome P450 family, which rapidly metabolize chemotherapeutic agents before they can exert their cytotoxic effect^(18-21).  

The failure of immunotherapy in skin metastases results from the unique immunological properties of skin tissue, which creates a teratogenic microenvironment. The skin functions as a specialized immune organ with constitutional mechanisms for suppressing inflammatory responses to prevent autoimmune reactions to environmental antigens. Skin dendritic cells exhibit a constitutive tolerogenic phenotype, with increased expression of coinhibitory molecules and production of immunosuppressive cytokines (IL-10, TGF-b). The dense extracellular matrix in the deep dermis creates physical barriers to effector T cell migration, while abnormal tumor vasculature with altered endothelial junctions prevents efficient lymphocyte extravasation. Tissue hypoxia activates metabolic pathways that promote macrophage differentiation towards the immunosuppressive M2 phenotype and induce the expression of inhibitory immune checkpoints (PD-L1, CTLA-4) on both tumor cells and cells in the tumor microenvironment^(21-23).

The diagnosis and correct staging of lung cancer cannot be achieved without careful integration of histopathological data with clinical and imaging data. This correlation is the foundation of modern oncology, ensuring therapeutic success and improving patient prognosis⁽²¹⁾. Of all the available methods, positron emission tomography (PET-CT) has established itself as the technique of choice for the accurate staging of lung cancer. This method provides a detailed morphological image and functional information on tumor metabolism, facilitating the detection of secondary metastatic lesions even at millimetric sizes, as well as the detection of atypical locations⁽²¹⁾. Thus, PET-CT is not only a diagnostic tool, but also a means of global staging, indispensable in therapeutic decision-making. 

Skin metastases in non-small cell lung cancer are a biological marker of increased tumor aggressiveness. Their presence has a particular prognostic significance, almost always indicating an unfavorable outcome and significantly reduced survival. The difference between patients who develop skin lesions and those with other forms of dissemination is clear: studies have shown that the median overall survival is 3.9 months for patients with skin metastases, while for those without this type of metastatic spread, it is around 10 months, a statistically significant difference (p<0.001)⁽²⁴⁾. In most published series, the median survival of patients with skin metastases originating from lung cancer varies between 3 and 6 months, with most patients surviving for 5-6 months^(4,8). The short interval between the onset of skin metastases and death reflects not only increased tumor biological aggressiveness, but also the limited ability of available therapies to modify the natural course of the disease after the onset of skin metastases The poor prognosis due to skin metastases in bronchopulmonary cancer is the result of a complex combination of factors: aggressive primary disease, systemic skin dissemination, vascular and physical barriers specific to skin tissue, as well as molecular mechanisms of resistance to chemotherapeutic drugs and immunotherapy. The unfavorable prognosis highlights the importance of early diagnosis, but especially the need to develop innovative therapeutic strategies to improve outcomes in this category of patients⁽²²⁾. Thus, studies reported in specialist journals have shown that skin metastases are an independent unfavorable prognostic factor, with a hazard ratio (HR) of 1.88, which means that their mere presence doubles the risk of death⁽²⁴⁾.

The results of other studies confirm this impact even more drastically, indicating that skin metastasis is the factor with the highest negative load among the multiple variables analyzed, with an HR of 4.49⁽²⁵⁾.

Conclusions

Skin metastases in bronchopulmonary cancer remain a rare clinical manifestation, but one with unfavorable prognostic significance. Although they can occur in all histological subtypes, adenocarcinoma and squamous cell carcinoma have an increased predilection for developing skin metastases. Skin metastases are biological markers of tumor aggressiveness, associated with a severe prognosis and compromised quality of life.

The therapeutic approach can only be integrated into a multidisciplinary team and individually tailored, in which surgery, local radiotherapy and systemic treatments are complemented by palliative management aimed at controlling symptoms and maintaining the patient’s quality of life.

Skin metastases in lung cancer are not simple peripheral manifestations, but reflect marked tumor aggressiveness. They are a clinical sign that should alert the physician to the existence of disseminated and aggressive disease, which will redefine therapy from the goal of curative control to palliative therapy.   

Corresponding author: Anda-Elena Crișan E-mail: anda_crisan2005@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.