New biological research and understanding of Papanicolaou's test

Abstract

The development of the Papanicolaou smear test by Dr. George Nicholas Papanicolaou (1883-1962) is one of the most significant achievements in screening for disease and cancer prevention in history. The Papanicolaou smear has been used for screening of cervical cancer since the 1950s. The test is technically straightforward and practical and based on a simple scientific observation: malignant cells have an aberrant nuclear morphology that can be distinguished from benign cells. Here, we review the scientific understanding that has been achieved and continues to be made on the causes and consequences of abnormal nuclear morphology, the basis of Dr. Papanicolaou's invention. The deformed nuclear shape is caused by the loss of lamina and nuclear envelope structural proteins. The consequences of a nuclear envelope defect include chromosomal numerical instability, altered chromatin organization and gene expression, and increased cell mobility because of a malleable nuclear envelope. HPV (Human Papilloma Virus) infection is recognized as the key etiology in the development of cervical cancer. Persistent HPV infection causes disruption of the nuclear lamina, which presents as a change in nuclear morphology detectable by a Papanicolaou smear. Thus, the causes and consequences of nuclear deformation are now linked to the mechanisms of viral carcinogenesis, and are still undergoing active investigation to reveal the details. Recently a statue was installed in front of the Papanicolaou's Cancer Research Building to honor the inventor. Remarkably, the invention nearly 60 years ago by Dr. Papanicolaou still exerts clinical impacts and inspires scientific inquiries.

Nuclear Morphology and the Biology of Cancer Cells

“…Lamins, the main components of the nuclear lamina that structurally supports the nuclear membrane, are aberrantly expressed in many human tumors. Abnormal expression of lamin isoforms have been reported in multiple studies and vary depending on the subtype of cancer and other biological properties such as tumor grade [16-18]. There is also growing evidence that LINC complexes are important for nuclear size regulation.…”

“…Depending on the individual study, both high and low levels of lamin A/C have been considered poor prognostic markers. Loss or reduced levels of lamin A/C in ovarian cancers were found in some studies [18] while elevated levels were in detected in others [15, 18]. Lamin A/C expression was strikingly reduced or absent in most small cell lung cancers, but preserved in pulmonary squamous cell carcinomas and adenocarcinomas [22].…”

“…Following chronic infection, expression of the viral oncogenes E6 and E7 are critical for this transformation as their corresponding proteins inactivate the tumor suppressors Rb and p53, respectively, activate cyclins, and inhibit apoptosis [36, 37]. Integration of viral DNA into the host also leads to genomic instability [18, 38]. Nuclear morphologic abnormalities are now linked to the mechanisms of viral carcinogenesis.…”

“…Nuclear morphologic abnormalities are now linked to the mechanisms of viral carcinogenesis. Early reports indicate that activation of oncogenes or inactivation of tumor suppressor genes leads to nuclear morphologic changes, but the underlying molecular mechanisms remain unresolved [18]. It is clear that persistent HPV infection causes disruption of the nuclear lamina, which is visible as a change in nuclear morphology on the Pap test (Fig.…”

Prosseguimento de estudo de coorte histórica de pacientes com biópsias de colo uterino alteradas e prognóstico no Distrito Federal de 2012 a 2018

“…O Exame possui as vantagens de ser simples, barato e com uma capacidade de detecção de alterações precoces no colo uterino e, por isso, ideal para ser instituído em larga escala (PAPANICOLAOU; TRAUT, 1941;DAVIM et al, 2005). As células malignas presentes no câncer de colo de útero são identificadas neste Exame por uma variedade de formas nucleares: grandes, irregulares, multilobuladas, e contendo micronúcleos, diferenciando-se das células normais do epitélio cervical, que possuem um núcleo regular arredondado ou ovalado (SMITH et al, 2018).…”