A Rare Presentation of Cutaneous Metastases in Advanced Lung Adenocarcinoma

Cutaneous metastases are generally an uncommon manifestation; however, its presentation is usually a sign of the dissemination of internal malignancy. Besides, other malignancies such as melanomas, haematolymphoid malignancies, germ cell tumours and sarcomas are also associated with metastasis to the skin. Multiple studies reported that the incidence of cutaneous metastasis in lung cancer patients was within a range of 1 to 12 % [1]. The common sites where lung cancers typically invade comprise of hilar nodes, liver, adrenal glands, bones and brain [2, 3] whereas malignant spread to the skin is deemed unusual. However, on the infrequent occasion that transmission through the skin does happen, the metastasis would be anticipated in the chest, abdomen, head and neck [4-6]. Previous studies also reported that lung cancer has a higher incidence of cutaneous metastasizing in men as compared to women [1]. CASE PRESENTATION


INTRODUCTION
Cutaneous metastases are generally an uncommon manifestation; however, its presentation is usually a sign of the dissemination of internal malignancy. Besides, other malignancies such as melanomas, haematolymphoid malignancies, germ cell tumours and sarcomas are also associated with metastasis to the skin. Multiple studies reported that the incidence of cutaneous metastasis in lung cancer patients was within a range of 1 to 12 % [1]. The common sites where lung cancers typically invade comprise of hilar nodes, liver, adrenal glands, bones and brain [2,3] whereas malignant spread to the skin is deemed unusual. However, on the infrequent occasion that transmission through the skin does happen, the metastasis would be anticipated in the chest, abdomen, head and neck [4][5][6]. Previous studies also reported that lung cancer has a higher incidence of cutaneous metastasizing in men as compared to women [1].

CASE PRESENTATION
A 71-year-old Chinese woman first presented with a cutaneous nodule on the left lateral axilla was then progressed to multiple nodules on the upper back and lower abdomen within a year. Aside from that, she also recounted episodes of progressive dyspnoea, haemoptysis, associated constitutional symptoms and significant loss of body weight amounting to 10 kg in the span of that year itself. The patient had a past medical history of hypertension and malignancy. Besides, her family history revealed that both her mother and sister were diagnosed with ovarian cancer.
There were no significant abnormalities in her vital signs on clinical examination except for a lowgrade temperature and the patient being tachypneic, measuring a respiratory rate of 28 breaths per minute. Meanwhile, physical examination of the chest detected bilateral diffuse crackles that were more evident on the right chest with no obvious lymphadenopathy. Skin examination revealed multiple subcutaneous nodules on the right upper back, left axilla and lower abdomen, each approximately 10 to 15 mm in diameter. These subcutaneous nodules were purplish and erythematous in appearance with well-defined borders, being firm, fixed and non-discharging in nature ( Figure 1). The results from other systemic examinations were normal. The results of laboratory tests reflected mild anaemia, leucocytosis, an elevated erythrocyte sedimentation rate (ESR) at 82 mm/hr and abnormal C-reactive protein (CRP) levelling at 12.6 mg/l. The results from other routine investigations were normal.
Chest X-ray depicted bilateral interstitial infiltrates (Figure 2a), whereas CT of the thorax confirmed the presence of a mass on the anterior segment of the left upper lobe of the lung (Figure 2b). Based on the CT scan results, further imaging of the abdominal and pelvic region proceeded accordingly for staging. The imaging results showed that the pleural, nodal and bony areas were positive for metastases, not ruling out the possibility of liver metastasis owing to the discovery of hypodense lesions on the said organ.
Samples were extracted from the subcutaneous nodules on the left axilla and lower abdomen. These samples were subsequently subjected to histopathological evaluation using the haematoxylin and eosin (HE) staining protocol. Microscopic assessment of the specimens pinpointed tumour infiltration within the dermis extending up to the subcutaneous fat layer (Figure 3a; Figure 3b). Morphologically, small, scattered clusters of tumour cells were arranged in a glandular pattern, illustrating mild-to-moderate nuclear pleomorphism and round-tooval vesicular nuclei with prominent nucleoli. Apart from that, a desmoplastic reaction was noted between the stromal component of the cells and the existing scanty fibroadipose tissue. The specimens showcased affinity for thyroid transcription factor 1 (TTF1) and cytokeratin 7 (CK7) markers and thus, being conclusive of underlying lung adenocarcinoma (Figure 3c; Figure  3d).
Following that, bronchoscopy, bronchoalveolar lavage (BAL) and biopsy were performed, and their respective results supported the diagnosis of lung adenocarcinoma. Based on the interpretation of the aforementioned outcomes, the patient was diagnosed with stage IV lung adenocarcinoma with cutaneous metastasis. However, she was unfortunately passed away after two weeks of hospitalization with the cause of death attributing to a massive pulmonary embolism.

DISCUSSION
Cutaneous metastases may spread via venous, arterial or lymphatic systems before the identification of the primary tumour and usually, it is indicative of poor prognosis. Previous studies reported an average survival time between 3 to 5 months [7,8], and such malignant metastases are often associated with disseminated diseases [9,10]. Cutaneous metastases are usually manifested as a painless solitary nodular lesion, which is predominantly located at the head and neck areas and followed by the chest, lower limbs and upper limbs. Nonetheless, cases with multiple skin lesions were also reported, albeit rare. Also, they may manifest as inflammatory lesions, epidermoid cysts, lipomas or basal cell carcinoma of the skin. Even though less common, they can be painful, itchy, exudative and ulcerated [12]. It was reported that tumours from the upper and right lobes were more frequently associated with skin metastases [11]. Besides, adenocarcinoma is the most frequent histology observed in such lesion. Thus, it is recommended to further investigate to exclude other distant metastatic diseases if cutaneous metastases are observed [12].
While cutaneous metastases are commonly known to be rare in women and usually manifested as a solitary nodule, our patient was presented with multiple painful skin lesions all over her trunk. Excisional skin biopsy for histology, IHC and electron microscopy examinations is the gold standard for diagnosis confirmation. Hence, in the present case, the diagnosis was confirmed with the positive results from both the TTF1 and CK-7 IHC staining, which are used to detect immunohistochemical markers for lung adenocarcinoma diagnosis. Moreover, CT thorax and bronchoscopy were also performed to confirm the diagnosis as her symptoms pointing to lung malignancy. However, the prognosis was poor, as expected, and the patient inevitably succumbed to her ailment as a consequence.
The presentation of skin metastases aids the diagnosis in asymptomatic patients or patients with delayed symptoms. However, lung cancers with cutaneous metastases are generally having poor prognosis and are less likely to be cured despite aggressive chemotherapy and/or radiation therapy, which is possibly due to inadequate blood supply to the skin [11]. Therefore, they are usually offered palliative chemotherapy, with or without radiation. Radiation therapy is usually ordered for the patient with skin lesions that are associated with severe pain or bleeding [12].

CONCLUSION
Skin metastases are a rare manifestation of lung cancer in women and even more so if they are identified in multiple anatomical sites. In view of that, any cutaneous lesion accompanied by plausible signs of malignancy should warrant suspicion of skin metastasis or a paraneoplastic growth. To verify such differential diagnoses, histology and IHC techniques should be utilized to aid the diagnosis of the primary malignancy.

Conflict of Interest
Authors declare none.