Pulmonary nuclear protein in testis carcinoma may be difficult to diagnose when characteristic squamous differentiation is minimal and conventional epithelial markers show limited or absent staining. The authors described markedly different microscopic appearances and immunohistochemical profiles in 2 tumors ultimately confirmed as the same malignancy.
Researchers in Japan described the pathological findings and clinical courses of 2 patients with pulmonary nuclear protein in testis (NUT) carcinoma. The first was a man in his 20s with a right hilar and middle lobe mass who underwent cervical lymph node biopsy followed by autopsy. The second was a woman in her 30s with a left lung mass who underwent left pneumonectomy with pericardial resection. The authors evaluated tumor morphology, squamous differentiation, immunohistochemical staining patterns, and clinical outcomes.
The report focused on differences in the extent and distribution of squamous differentiation and the expression of epithelial markers, particularly cytokeratins. Additional assessments included NUT immunostaining, p63 and p40 expression, and Ki-67 labeling indices. The authors also documented treatment responses, metastatic progression, and survival.
In the first case, computed tomography revealed a 3-cm right middle lobe tumor and a 6 × 7-cm right hilar mass. Histological examination demonstrated primitive small round cells intermingled with prominent foci of squamous differentiation. Immunohistochemistry showed positivity for the epithelial markers AE1/AE3 and CAM5.2, along with positivity for p63 and p40. The Ki-67 labeling index was approximately 30%. Although the tumor was initially classified as an unclassified carcinoma, NUT immunostaining performed on a stored lymph node biopsy approximately 10 years later confirmed the diagnosis.
The second patient presented with a 10-cm left lung mass. Initial needle biopsy revealed a small round cell tumor, prompting consideration of lymphoma and undifferentiated sarcoma. Examination of the resected specimen demonstrated diffuse proliferation of primitive round cells with extensive necrosis and only small foci of squamous differentiation. Unlike the first case, AE1/AE3 staining was limited to a few cells, and CAM5.2 staining was negative. However, p63 and p40 were positive, and NUT immunostaining confirmed the diagnosis. The Ki-67 labeling index was approximately 50%.
Both patients experienced aggressive disease progression. The first patient's tumor was resistant to cisplatin and gemcitabine, and he died 5 months after admission. Autopsy revealed metastases involving the lymph nodes, liver, right kidney, right adrenal gland, and bones. In the second case, malignant pleural effusion and metastases involving the pleural cavity, lymph nodes, bones, and right ovary developed approximately 5 months following surgery. Chemotherapy with carboplatin, pemetrexed, and bevacizumab had limited effectiveness. The patient subsequently received palliative radiotherapy and underwent resection of an ovarian metastasis to prevent intestinal obstruction before dying 1 year later.
Abrupt squamous differentiation, although considered characteristic of NUT carcinoma, is not consistently present. The authors cited a previous analysis of 124 patients in which squamous differentiation was identified in only 33% of cases. Another published immunohistochemical analysis found that approximately 20% of NUT carcinomas lacked keratin expression. In thoracic cases from that analysis, p40 and p63 were positive in 63% and 85%, respectively, highlighting the limitations of relying on individual epithelial or squamous markers.
Additional staining patterns may complicate diagnosis. NUT carcinoma can occasionally express thyroid transcription factor-1 or neuroendocrine markers, potentially resembling other thoracic malignancies. The authors emphasized that negative keratin staining does not exclude NUT carcinoma and that diagnosis relies on positive NUT protein immunohistochemistry or molecular testing. The report cited an 87% sensitivity for NUT immunostaining using the C52B1 antibody clone, although this estimate came from previously published research rather than the 2 reported cases.
The report was limited by its inclusion of only 2 patients and its descriptive design. Differences in tissue sampling and retrospective confirmation of the first diagnosis also complicated direct comparisons. Although the cases demonstrated substantial morphological and immunohistochemical variability, the findings cannot establish how frequently these features occur in patients with pulmonary NUT carcinoma.
Pulmonary NUT carcinoma should remaain a diagnostic consideration in poorly differentiated tumors even when squamous differentiation is inconspicuous or keratin staining is negative. "NUT carcinoma should not be excluded based solely on negative keratin staining," wrote lead study author ErikoAtsumi, of the Division of Pathology at NHO Okinawa Hospital in Japan, and colleagues.
Disclosures: The authors reported no funding or conflicts of interest.
Source: Case Reports in Pathology
