Cutaneous Facial Nodule: A Presenting Sign of Metastatic Pulmonary Enteric Adenocarcinoma

Cutaneous metastases are a poor prognostic sign and are estimated to occur in 0.6% of non-small cell lung cancer (NSCLC) cases [1]. Pulmonary enteric adenocarcinoma (PEAC) is a type of NSCLC with enteric morphology and tumor markers. Identification and management of PEAC is contingent upon differentiation from other adenocarcinomas with enteric features, such as lung adenocarcinoma with enteric morphology, metastatic colorectal cancer (MCRC), and primary lung adenocarcinoma (PLA). Herein, we describe a rare case of metastatic PEAC presenting as a cutaneous facial nodule [1]. A 64-year-old man with a 40 pack-year smoking history presented with a 2-month history of an enlarging ulcerated nodule on the right chin. Prior treatments included incision and drainage, topical gentamicin, oral sulfamethoxazole/trimethoprim, and doxycycline. He also complained of chronic cough. Exam showed a 3-cm violaceous nodule with central ulceration (Figure 1A,B). Biopsy revealed diffuse infiltration of the dermis by atypical epithelioid cells forming glands with abundant mucin and necrosis, consistent with adenocarcinoma (Figure 2A–D). The cells were positive for CK7, CDX2, and focal CK20. p63, PAX-8, WT-1, and TTF-1 were negative (Figure 3A–F). Chest radiography revealed a 6 cm × 3 cm bilobular mass in the right lower lobe which correlated with further positron emission tomography (PET)-CT findings (Figure 4). Lung core biopsy showed adenocarcinoma with intracytoplasmic mucin and micropapillary growth (Figure 5A,B) positive for CK7, CK20, weakly staining scattered cells for CDX2, and rare Napsin A positivity (Figure 6A–C). The core sample was negative for TTF-1, suggesting a possible extra-pulmonary primary tumor of pancreaticobiliary, gastrointestinal, or renal origin (Figure 6D). The slight discordance of CDX-2 and CK20 immunostaining between the cutaneous and lung biopsies suggested the possibility of two primary tumors. The differential for an alternate primary site included the salivary gland, urinary bladder, pancreatobiliary, or colon adenocarcinoma. PET-CT identified FDG-avid sites in the chin, the right lower lobe, the medial right upper lobe, and the right apex only (Figure 4). A CA 19–9 of 2036 U/mL (RI 0–37 U/mL) prompted magnetic resonance cholangiopancreatography, esophagogastroduodenoscopy, and colonoscopy, which were all unremarkable, lowering suspicion for primary pancreatic or gastrointestinal origin. Based on these findings, the patient was diagnosed with metastatic PEAC originating from the right lower lobe and metastasizing to the medial right upper lobe, right apex, and chin. Molecular studies of the right lower lung mass revealed mutations in STK11 (10.5% VAF) and SMARCA4 (6.4% VAF). PD-L1 analysis exhibited positive staining among tumor cells (5%) and all cells (25%). A palliative chemotherapy regimen including pembrolizumab, carboplatin, and pemetrexed was initially beneficial; however, the patient's disease progressed. He required palliative radiation for each of his involved sites as well as a regimen of docetaxel and ramucirumab. Due to multiple complications related to the progression of his condition and ongoing therapies, he was transitioned to supportive care. PEAC was first described in 1991 and included in the NSCLC classification in 2011 [2]. The World Health Organization first classified it in 2015, and re-termed it as adenocarcinoma, enteric type in its 2021 thoracic tumor re-classification. Diagnostic criteria include over 50% cellular morphology resembling colorectal adenocarcinoma, one or more tumor markers suggestive of enteric differentiation on immunohistochemistry studies, and absent or weak presence of pneumocyte markers (TTF-1 and Napsin A) [1]. To date, two cases of metastatic cutaneous PEAC have been reported [2, 3]. As a cutaneous metastasis was the presenting lesion in this case, the initial differential included metastatic PEAC, MCRC, and metastatic PLA. While PLA is associated with non-smoking women, up to 76.9% of PEAC patients have a strong smoking history [1]. PEAC is most prevalent among older male patients (median age 65), who may report respiratory complaints and/or B symptoms [4]. PEAC often shows elevated CA19-9 (48.4%), CEA (68.2%), and CA125 (50%), distinguishing it from PLA [2, 4]. Notably, CA19-9 and CEA are useful for PEAC diagnosis and disease monitoring [1]. CYFRA21-1 and neuron-specific enolase (NSE) are more specific to NSCLC and SCLC, respectively, and are rarely elevated in PEAC [1]. Our patient's CA19-9 was significantly elevated, consistent with metastatic PEAC. Histopathologic workup is essential to diagnose PEAC accurately. Enteric features of PEAC include high columnar cells with eosinophilic cytoplasm that form irregular glandular or sieving structures [1, 2, 4]. Variable features include luminal necrosis, brush borders, and prominent, vesicular palisading nuclei. While one analysis showed that 17.4% of PEAC cases had pure intestinal morphology, observed non-intestinal features included solid (39.1%), mucinous (21.7%), acinar (13%), lepidic (2.2%), papillary (4.4%), and micropapillary (2.2%) structures [1]. Both of our patient's primary and metastatic biopsies shared mucinous features, while necrotic and micropapillary features were observed in the cutaneous and pulmonary lesions, respectively. PEAC also exhibits heterogeneity, featuring large clusters of cells with reduced cohesiveness, often including intra-tumoral elastic scars, an abundant inflammatory infiltrate, and occasional reports of surrounding interstitial fibrosis [1, 4]. Immunohistochemical criteria for PEAC include the expression of at least one intestinal marker, such as CK20, CDX-2, Villin, or Mucin 2 (MUC2) [1, 2, 4, 5]. Fifty percent of cases will also express TTF-1 or CK7, which can be a useful differentiator from MCRC [2]. When present, these pulmonary markers are retained in enteric-appearing regions of PEAC, whereas enteric differentiation markers in PLA are restricted to enteric-like regions [1]. Our patient's cutaneous lesion had positive immunostaining for enteric markers CDX-2 and CK20 (focally) as well as CK7. The lung core sample showed positive CK7, while CK20 staining was more prominent and CDX-2 expression was weaker, contrasting from the cutaneous site. Concurrent CK7 and CDX-2 positivity have the highest sensitivity (71.3%) and specificity (82%) in distinguishing PEAC from MCRC [4]. Notably, CK7 has more utility in distinguishing PEAC from MCRC and is more frequently retained than CK20, Napsin A, or TTF-1 [1, 4]. Both biopsy sites were CK7 positive with variable CK20 positivity, supporting PEAC in this case. Additional markers observed in PEAC include surfactant A, surfactant B, MUC1, MUC5, and MUC6. Oncogene mutations may provide some additional diagnostic information in PEAC. The most common include CDKN2A, KRAS (44.2%), EGFR (14.9%), ALK (8.3%), and BRAF (2.5%) [4]. PEAC is also associated with HER2 (44.4%) and MMR (38.9%) mutations, which are seen in less than 1% of other NSCLCs [1]. This case harbored less common mutations in STK11 and SMARCA4. These mutations are observed in 10% of lung adenocarcinomas and 8% of NSCLCs, respectively [6, 7]. PD-L1 analysis exhibited positive staining, prompting the use of targeted immunotherapy. PEAC shows higher PD-1 expression compared to typical lung adenocarcinomas, emphasizing the importance of PD-1/PD-L1 analysis in its workup to guide immunotherapy options [8, 9]. We describe a case of cutaneous metastatic PEAC presenting as a facial nodule. The overall concordance of IHC findings between the two neoplastic sites, in addition to the lack of other neoplasms identified via PET-CT and endoscopy, and the elevated CA19-9 all are consistent with metastatic PEAC. Metastatic PEAC represents a rare subset of PLAs which are a diagnostic challenge to dermatopathologists due to the enteric histopathological features and immunohistochemical profile. Arriving at an accurate diagnosis of metastatic PEAC requires clinical, serological, histopathological, immunohistochemical, radiographic, and endoscopic studies to rule out common mimics, including MCRC and PLA. Molecular studies may be useful for diagnosis and therapeutic options. The authors have nothing to report. Sarah Kamsiah Zemlok receives royalties from Kadmon Pharmaceuticals (Sanofi) for the drug Rezurock (belumosudil). All other authors do not have any disclosures. The data that support the findings of this study are available from the corresponding author upon reasonable request.