Acantholytic squamous cell carcinoma of the lung with marked lymphogenous metastases and high titers of myeloperoxidase-antineutrophil cytoplasmic antibodies: a case report

Six years prior to an emergency hospital admission, a 71-year-old Japanese man, with a 43-year history of smoking 2 packs/day, was diagnosed with bilateral pulmonary lesions. Radiographically, the lesions were suggestive of idiopathic interstitial pneumonia (IIP) because of the interstitial reticular markings at their peripheral and basal areas. Due to the patient’s stable condition, the lesions were only observed over time. Three years prior to admission, the 78-kg patient presented with a stomach ache, and declined a medical evaluation of the lung lesions. The patient did not undergo additional routine medical examination.

Seven days before the emergency admission, the patient fainted in a public area, but did not seek medical help. Subsequently, the patient was discovered unconsciousness in his home, and was brought to our emergency department for evaluation. The patient had clouding of consciousness, and his weight had decreased to 58 kg. Marked oral dryness was observed, suggesting dehydration, with fine crackles heard upon auscultation. His reactions to light were normal and no facial nerve palsy was observed; left hemiparesis was suggested due to a positive pronator drift (Barré sign). Lower limb muscular weakness was also found. Upon admission, his laboratory results showed a mildly elevated white blood cell count, with abnormal renal function and coagulation indicated. Non-enhanced computed tomography (CT) imaging revealed a 21-mm pulmonary nodule in the left upper lobe (Fig. 1a), associated with enlarged lymph nodes in the mediastinum, bilateral pulmonary hilum, and para-aortic regions (Fig. 1b). The clinical diagnosis, upon admission, was advanced lung cancer, with small cell lung cancer (SCLC) being suspected. Diffusion-weighted magnetic resonance imaging showed tiny foci of cerebral infarctions, suggestive of Trousseau’s syndrome (Fig. 1c); however, no brain or spinal cord lesions causing the left hemiparesis and lower limb weakness were found. Further laboratory tests confirmed hypercalcemia (corrected calcium level, 11.1 mg/dL [normal, 8.5–10.5 mg/dL]), high serum levels of parathyroid hormone-related protein (PTHrP, 8.3 gmol/L [normal, < 1.1 pmol/L]), and normal Intact PTH levels. The serum levels of various tumor markers were elevated, including SQCC antigen, 39.7 ng/mL [normal, < 1.5 ng/mL]; cytokeratin-19 fragments, 393.6 ng/mL [normal, < 3.5 ng/mL]; and carcinoembryonic antigen (CEA), 10.7 ng/mL [normal, < 5 ng/mL]. To evaluate the cause of IIP, autoimmune disease was investigated using serological markers. Mildly elevated titers of antinuclear antibodies (1:80) and high titers of myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA, 71.4 enzyme-linked immunosorbent assay units (EU)/mL [normal, < 3.5 EU/ml]) were found, but proteinase 3-ANCA levels were within normal limits. Cytological specimens, prepared from bronchoalveolar lavage fluid, confirmed atypical squamoid cells. Therefore, advanced pulmonary SQCC associated with PTHrP-associated hypercalcemia and ANCA-associated vasculitis was clinically diagnosed. As contrast-enhanced CT and positron emission tomography were not performed to closely examine the distant metastasis, the tumor was classified as T1cN3cMx, more than Stage IIIB, according to the TNM classification of malignant tumors, eighth edition [17].

Best supportive care was chosen as the treatment course, after discussion with the patient’s son. Urine tests and creatinine levels improved after hydration, and the clinical features of rapidly progressive glomerulonephritis syndrome were absent. The patient’s serum corrected calcium level showed a gradual increase to a maximum of 20.2 mg/dL, two days prior to his death, which occurred one month after admission.

Approximately 3 h after the patient’s death, an autopsy was performed after securing his son’s permission. Per the son’s request, the central nervous system was not examined. Skin lesions suggestive of malignant tumors were absent. A 23-mm left upper lung lobe tumor was confirmed with sections cut (Fig. 2a), and multiple, vague, nodular lesions that suggested metastasis were present. Honeycombing was seen in the inferior and posterior peripheral regions of the lungs. Contralateral and ipsilateral mediastinal lymph nodes (Fig. 2b) and bilateral hilar lymph nodes were markedly enlarged; swollen lymph nodes were also noted around the aorta. Cardiac effusion was not calculated due to the presence of adhesive pericarditis. No abnormal findings were observed in other organs.

Histologically, the left upper lobe tumor included adenoid or pseudoacinar nests containing discohesive, round, or polygonal atypical cells (Fig. 2c–d); pseudovascular arrangements of the tumor cells were not observed. Individual tumor cells, varying in size and shape, invaded the fibrous stroma (Fig. 2d). A diffuse appearance of the discohesive, monotonous cells, without adenoid or pseudoacinar pattern, was noted (Fig. 2e), and a large portion of them filled the alveoli, suggesting that they spread through air spaces (Fig. 2f). They also demonstrated prominent lymphatic permeation, forming pulmonary lymphangitis carcinomatosis (PLC; Fig. 2g). The discohesive monotonous cells were associated with atypical squamoid cells (Fig. 2d–f) and small numbers of signet-ring atypical cells (Fig. 2f). Extrapleural extension of the tumor cells was not observed. The clear cytoplasm of the signet-ring tumor cells was negative for periodic acid-Schiff (PAS), diastase-PAS, Alcian blue, and adipophilin (clone AP125).

Immunohistochemically, the tumor cells, described above, were diffusely positive for cytokeratin 5 (clone XM26, Fig. 3a and b) and p40 (clone BC28, Fig. 3c), and were negative for cytokeratin 7 (clone OV-TL 12/30), thyroid transcription factor 1 (clone 8G7G3/1), Napsin A (polyclonal), desmin (clone D33), alpha-smooth muscle actin (clone 1A4), anaplastic lymphoma kinase (ALK, clone 5A4), and nuclear protein in testis (NUT, clone C52B1). The monomorphic discohesive tumor cells and squamoid foci were mostly negative for vimentin (clone V9, Fig. 3d), focally positive for CEA (clone II7), and largely positive for E-cadherin (clone NCH-38, Fig. 3e). In total, the left upper lobe tumor showed a mixture of ASQCC and poorly differentiated SQCC, with both components appearing equally prevalent.

Multiple vague, intrapulmonary masses and lymph node metastases (Fig. 2h) in the bilateral hilar, mediastinal, para-aortic regions, and non-regional areas consisted of diffuse acantholytic monomorphic tumor cells with foci of well to poorly differentiated SQCC. Adenoid or pseudoacinar nests were rather minor. Neoplastic pericarditis, with ASQCC cells, induced adhesion of the visceral and parietal pericardial layers. Cytology specimens prepared from the bilateral pulmonary effusion also confirmed the presence of acantholytic tumor cells (Fig. 2i). Blood-borne metastasis was inconspicuous, but some acantholytic tumor cells were seen in the renal corpuscles. The acantholytic component of the tumor apparently worsened the patient’s prognosis.

ANCA-related vasculitis, such as necrotizing vasculitis, was absent in the lungs, kidneys, and other organs. The bilateral lungs showed the usual interstitial pneumonia (UIP) pattern, edema, and small foci of acute pneumonia. The bilateral kidneys showed proximal renal tubule degeneration, compatible with prerenal failure induced by dehydration, probably due to hypercalcemia. Crescent formation in the glomeruli was present in < 0.5% of these structures. The heart and its valves showed neither thrombotic endocarditis nor vegetations. Malignant tumors, except for the lung cancer, were absent.