Multiple skin and subcutaneous metastasis as initial manifestation in neuroendocrine carcinoma lung: A rare case report

Abstract

Pulmonary neuroendocrine tumors are uncommon malignancies, and cutaneous metastasis as the initial presentation is exceedingly rare, often leading to diagnostic delays due to nonspecific clinical features. We reported a case of a 57-year-old male presenting with multiple progressively enlarging, painless cutaneous and subcutaneous nodules on the scalp and left chin without accompanying respiratory and constitutional symptoms. The lesions were initially treated as benign dermatological conditions without improvement. Excisional biopsy of a chin lesion demonstrated dermal infiltration by atypical polygonal cells with neuroendocrine morphology and dermal lymphatic invasion. Immunohistochemistry showed positivity for synaptophysin, cytokeratin 7 (CK7), and Cam5.2, consistent with neuroendocrine carcinoma. Contrast-enhanced computed tomography identified a heterogeneously enhancing mass in the left lower lobe of the lung with widespread metastatic disease. Further evaluation with Gallium-68 DOTATATE positron emission tomography/computed tomography, a somatostatin receptor-targeted imaging study, demonstrated avid lesions in the lung, lymph nodes, subcutaneous tissue, omentum, and skeleton. The patient was treated initially with octreotide hormone therapy. The patient had disease progression; therefore, therapy was changed to carboplatin and etoposide. This case highlights that unexplained skin lesions may present as the initial manifestation of an underlying visceral malignancy, signifying the role of early biopsy and comprehensive imaging to enable timely diagnosis and management of aggressive pulmonary neuroendocrine tumors.

Introduction

Pulmonary neuroendocrine tumors (NETs) comprise a heterogeneous group of epithelial neoplasms arising from neuroendocrine cells and account for approximately 1%-2% of all lung malignancies and 25%-30% of all neuroendocrine tumors [1]. These tumors include typical carcinoids, atypical carcinoids, large-cell neuroendocrine carcinoma, and small-cell lung carcinoma, with varying biological behavior and metastatic potential. Pulmonary NETs commonly metastasize to the liver, lymph nodes, bone, and brain; however, cutaneous metastasis is uncommon and rarely represents the initial clinical manifestation [2]. The cutaneous manifestation of visceral malignancies is a rare presentation, and the incidence of cutaneous metastasis from internal organs is 5.3% [3]. The cutaneous presentation often poses a diagnostic challenge due to its nonspecific appearance and resemblance to benign dermatological conditions, leading to diagnostic delays [4]. The early identification of such atypical cases is essential, as immediate histopathological assessment and radiological imaging can facilitate accurate diagnosis, staging, and appropriate therapy. We present a rare case of pulmonary NETs that initially presented with multiple cutaneous and subcutaneous metastases without respiratory symptoms, underscoring the importance of maintaining a high index of suspicion for underlying malignancy in patients with unexplained skin lesions.

Case presentation

A 57-year-old male presented with multiple progressively enlarging lesions on the scalp and left chin for a duration of 4 months. The lesions were painless and were not associated with fever, weight loss, or any systemic symptoms. The patient had been previously treated with antiallergic medications and topical corticosteroids without clinical improvement. He had a history of spinal tuberculosis successfully treated with anti-tuberculosis therapy (ATT) 12 years ago.

On physical examination, multiple erythematous nodules and purplish soft tissue lesions on the left facial region and scalp were noted. The lesions were nontender, nonulcerated, and firm to soft in consistency. No regional lymphadenopathy was noted.

An excision biopsy was performed from the lesion on the left upper chin. Histopathological examination revealed the dermal infiltration by a tumor comprising atypical polygonal cells with eosinophilic cytoplasm, round nuclei, and characteristic salt-and-pepper chromatin arranged in a nested pattern. Dermal lymphatic invasion was also present (Fig. 1). Immunohistochemistry (IHC) was positive for Cam5.2, CK7, and Synaptophysin, resulting in the diagnosis of neuroendocrine carcinoma with involvement of dermis and dermal lymphatics.

Fig. 1.

Histopathology slide revealed skin with dermis showing a tumor composed of atypical polygonal cells with eosinophilic cytoplasm, round nuclei with salt and pepper chromatin in nested pattern and dermal lymphatic invasion.

Contrast-enhanced computed tomography (CT) of the neck, chest, abdomen, and pelvis was done to identify the primary lesion. A heterogeneously enhancing soft tissue mass lesion in the lower lobe of the left lung was found in close contact with the pericardium and descending aorta. Multiple heterogeneously enhancing subcutaneous nodules were found in the bilateral occipital region, the right paraspinal region in the posterior abdominal wall, and anterior abdominal wall (Fig. 2, Fig. 3).

Fig. 2.

Axial slices of CT revealed multiple soft tissue attenuating nodules in scalp and on face.

Fig. 3.

(A and B) revealed well defined heterogeneously enhancing mass lesion in left lower lobe and (B) revealed subcutaneous nodule in subcutaneous plane of right posterior abdominal wall.

A Gallium-68 (Ga-68) DOTATATE positron emission tomography/computed tomography (PET/CT) scan further demonstrated somatostatin receptor–avid lesions in the left lower lobe of the lung, left axillary lymph nodes, omentum, multiple subcutaneous sites, and focal skeletal involvement of the right femur and tibia (Fig. 4).

Fig. 4.

MIP (A) and fused images (B-E) of Gallium DOTATE scan revealed multiple avid cutaneous nodules (A and B blue arrows; Krenning score 1), left lower lobe mass (A and C, green arrows; Krenning score 1), avid peritoneal deposits (D, blue arrow; Krenning score 1) and avid lesion in left scrotum (E, blue arrow; Krenning score 1).

Octreotide hormone therapy was started for the patient. After completion of 6 cycles, a follow-up Ga-68 DOTATATE PET/CT showed a slight interval increase in the size of the primary lung lesion, development of multiple pulmonary nodules with mixed DOTA avidity, and new peritoneal deposits, while the subcutaneous lesions demonstrated a reduction on the interim scan (Fig. 5). In accordance with molecular imaging response evaluation principles, the emergence of new lesions and the progression of existing disease sites indicate progressive disease, even in the presence of a partial response in certain metastatic lesions. The patient was started on second-line therapy with carboplatin and etoposide.

Fig. 5.

MIP images (A) and fused PET CT DOTATE images (B-D) revealed increase in size of DOTA avid left lung mass (A and C green arrows; Krenning score 1). Interval development of DOTA avid pertioneal deposit in left hemiabdomen (A and D red arrows; Krenning score 1). Redemonstration of stable DOTA avid multiple subcutaneous nodules (A, light blue arrow) and scrotal lesion (A and D dark blue arrows; Krenning score 1).

Following multidisciplinary team discussion, FDG PET/CT was performed to evaluate the possibility of dedifferentiated tumor components and to evaluate potential discordance between somatostatin receptor expression and glucose metabolism. It showed avid subcutaneous lesions with interval development of avid metastatic lesions (Fig. 6).

Fig. 6.

FDG PET revealed avid subcutaneous lesions with interval development of avid metastatic lesions.

Discussion

Pulmonary NETs represent a biologically diverse range that includes well-differentiated carcinoids (both typical and atypical) as well as high-grade neuroendocrine carcinomas (such as small-cell lung carcinoma and large-cell neuroendocrine carcinoma) [2]. About 80% of pulmonary NETs are located centrally in the lung, whereas 20% originate in the peripheral areas. All pulmonary NETs are considered malignant and have the ability to metastasize [5]. Pulmonary NETs are associated with several comorbidities and a high risk of developing secondary primary malignancies. Genetic factors are also involved, especially in relation to multiple endocrine neoplasia type 1 (MEN-1) syndrome. It predominantly presents in males and the 45-55 years age group [6].

Pulmonary NETs have the potential to disseminate to almost all organs, with the most frequently affected sites being hilar lymph nodes, liver, adrenal glands, bones, and brain. The cutaneous metastasis of lung cancers occurs in 1%-12% of cases and cannot be clinically differentiated from metastases originating from other organs. The most prevalent locations for cutaneous metastases are the chest, abdomen, head, and neck [7]. The cutaneous metastasis is usually a delayed presentation signifying advanced metastatic disease, and it could be the initial presentation without any constitutional symptoms, as present in this case. Skin metastases present as round or oval nodules, which may be mobile or fixed and firm. The lesions are mostly skin-colored and sometimes red, dark red, or black. They can manifest as solitary or grouped papules, plaque-like formations, zosteriform lesions, erysipelas-like appearances, or cicatricial alopecia. Typically, the lesions are painless [8]. In this case, the patient had multiple purplish nodular and painless lesions. The nonspecific clinical *presentation often leads to misdiagnosis as a benign dermatological condition.

Histopathological analysis of the persistent or unexplained skin lesions is a potential diagnostic investigation, especially compounded in the absence of constitutional or organ-specific symptoms. Neuroendocrine neoplasms are classified by tumor grade into well-differentiated NETs and poorly differentiated neuroendocrine carcinomas. The well-differentiated NETs typically demonstrate an organoid growth pattern with nests, trabeculae, or rosettes, minimal stroma, and rich vascularity. Tumor cells are usually uniform with abundant cytoplasm, round to oval nuclei, and characteristic “salt-and-pepper” chromatin, with rare mitotic activity [9]. The poorly differentiated neuroendocrine carcinomas show solid growth of more pleomorphic cells with high mitotic rates, frequent necrosis, and marked nuclear atypia. Small-cell NETs exhibit scant cytoplasm and nuclear molding, while large-cell NETs have abundant cytoplasm and prominent nucleoli. NECs may also contain non-neuroendocrine components, including glandular or squamous differentiation [10,11]. The grading of tumors in neuroendocrine neoplasms depends on the mitotic activity and the Ki-67 proliferation index, which are essential therapeutic and prognostic markers. Well-differentiated NETs often have lower Ki-67 indices, while poorly differentiated NETs have high proliferative activity and more aggressive biological characteristics [12].

IHC plays a vital role in the diagnosis of NETs, particularly in the context of small biopsy specimens. A suggested panel of antibodies for immunostaining consists of chromogranin A, synaptophysin, and CD56. Furthermore, the majority of NETs exhibit reactivity to pan-cytokeratin antibodies, which are frequently employed to detect epithelial cells [13]. In this case, positivity for synaptophysin with epithelial markers, such as Cam5.2 and CK7, supported metastatic neuroendocrine carcinoma.

Functional imaging using somatostatin receptor PET has become a major tool for NETs because it can detect receptor-positive lesions. The majority of NETs exhibit somatostatin receptors, which serve as potential targets for radionuclide imaging and treatment. Ga-68 DOTATATE is a radiolabeled somatostatin analog utilized in PET or PET/CT imaging to identify somatostatin receptor-positive NETs. Ga-68 DOTATATE PET/CT has demonstrated a high sensitivity (94%) and specificity (92%) for the localization of NET lesions [14]. In the reported patient, the Ga-68 DOTATATE PET/CT demonstrated multi-site somatostatin receptor–avid disease, including lung, lymph nodes, omentum, multiple subcutaneous deposits, and skeletal lesions, reinforcing the disseminated disease at diagnosis.

Surgical resection is the primary treatment for pulmonary NETs with the primary goal of preserving the maximum healthy lung tissue. Systemic therapy is used for advanced or metastatic pulmonary NETs. The selection of systemic treatment is influenced by various factors, such as tumor grade, the degree of metastasis, and the patient's requirements. The objective of medical management is to manage hormone-related symptoms and prevent disease progression [15]. For tumors demonstrating somatostatin receptor expression, somatostatin analogs are preferred. Octreotide and lanreotide are considered appropriate alternatives, especially in cases involving patients with carcinoid syndrome. A platinum-based chemotherapy protocol, including carboplatin and etoposide, is indicated for tumors that are intermediate to poorly differentiated. Other systemic therapies, such as everolimus, have been shown to provide survival benefits in patients with advanced and nonfunctional lung NETs [16]. The role of radiotherapy remains palliative for patients with symptoms arising from recurrent or metastatic disease. The clinical course in this case reflects the aggressive behavior and therapeutic resistance commonly associated with high-grade pulmonary NETs [17].

Peptide receptor radionuclide therapy (PRRT) with high-dose 177Lu-DOTATATE should also be considered as a viable therapeutic alternative, especially for patients with progressive or metastatic well-differentiated NETs exhibiting sufficient somatostatin receptor expression [18]. The Krenning score, a semi-quantitative method of assessing the degree of tracer uptake on Ga-68 DOTATATE PET/CT, is used to assess the candidacy for PPRT. It evaluates the tracer uptake relative to normal uptake by the liver and spleen. A high Krenning score indicates marked somatostatin receptor avidity, which is predictive of a favorable outcome of PRRT [19]. PRRT has demonstrated considerable benefits in progression-free survival and symptom management in receptor-positive NETs. However, the selection of treatment for pulmonary NETs is significantly determined by histological grade, proliferative activity, and tumor differentiation [20].

The prognosis for pulmonary NETs is affected by factors such as tumor size, grade, disease stage, and advancing age. The earlier diagnosis correlates with a better prognosis. The estimated 5-year survival rates for stages I through IV are 93%, 85%, 75%, and 57%, respectively [21].

Conclusion

This case adds to the limited literature on pulmonary NETs presenting initially with multiple cutaneous and subcutaneous metastases in the absence of respiratory symptoms. The coexistence of widespread painless skin nodules with extensive somatostatin receptor–avid metastatic disease on Ga-68 DOTATATE PET/CT highlights the diagnostic challenge posed by these atypical presentations. The case further demonstrates the importance of correlating histopathological findings and neuroendocrine immunomarkers with functional somatostatin receptor imaging to accurately identify the primary pulmonary lesion and metastatic extent in clinically occult disease.

Authors’ contributions

N.N and A.A. conceived and designed the case report. F.A, and S.M were responsible for data collection and acquisition of data. K.S and AR performed the literature review and wrote the manuscript. N.N and K.S reviewed and critically revised the manuscript. All authors have approved the final manuscript.

Patient consent

Informed signed consent taken from patient.