Pathfinders in oncology from the time the causal relation between tobacco use and lung cancer was established to publication of the first Cancer Staging Manual by the American Joint Committee on Cancer.

During the period from 1962 to 1977, several antigens, notably carcinoembryonic antigen and prostate-specific antigen, were discovered and entered clinical use. Ultrasonography, positron emission tomography scanning, and magnetic resonance imaging were introduced, and adjuvant radiation and chemotherapy after limited surgery became routine procedures. Radioimmunoassay and immunohistochemistry techniques were standardized. The announcement in England and the United States that tobacco is a potent lung carcinogen was long delayed, important news. The US Cancer Act of 1971 made it possible to experiment with newly discovered drugs, transfer promising therapeutic agents from the laboratory to the clinic, and finance randomized clinical trials. Oncologists achieved a series of successes with combination chemotherapy in childhood cancers, adult lymphomas, and testis tumors. Clinical trials demonstrated that breast-conserving therapy is as effective as mastectomy. The discovery of retroviruses, reverse transcriptase, and vascular endothelial growth factor was coupled with learning about oncogenes. The 2-hit theory and the reciprocal translocation of chromosomes helped to solve some of the riddles of oncogenesis. The staging classification of cancers by the American Joint Committee on Cancer unified clinical and pathologic handling and prognostication of malignant tumors. The progress made in oncology between 1962 and 1977 came about through the dedicated work of many individuals. However, there were 9 pathfinders (3 medical oncologists, 2 surgeons, 1 medical nuclear physicist, 1 pediatrician geneticist, 1 hematologist geneticist, and 1 virologist) who, despite their diverse backgrounds, personalities, and interest, made extraordinary contributions to oncology.

Pathfinders in oncology from the first clinical use of single-agent chemotherapy to the introduction of mammography.

During the period from 1942 to 1962, treatment attempts with single-agent chemotherapy such as nitrogen mustard and urethan gained limited application. However, the groundbreaking success with aminopterin in the treatment of patients with pediatric acute leukemia and methotrexate in the treatment of gestational choriocarcinoma established single-agent chemotherapy as a pioneering contribution to oncology. The landmark discovery that early-stage Hodgkin disease is curable with radiation made radiotherapy into an essential specialty of oncology. Although radical surgical treatment dominated the field of surgery, the excision of localized cancers with or without adjuvant radiation emerged as new modality in therapy. Cytopathology and surgical pathology became new fields in medicine and pathologists became an integral part of the preoperative, intraoperative, and postoperative care of patients with cancer. The discovery of multiple new drugs demonstrated promising results and widened the field of oncology from the laboratory to the clinic. In the etiology of cancer, precancerous conditions were named and carcinoma of the lung was definitively linked to cigarette smoking. All things considered, the progress made between 1942 and 1962 came about through the dedicated work of many individuals. However, there were 7 distinguished pathfinders (2 pathologists, 1 pediatric pathologist-oncologist, 1 radiation therapist, 1 physician-actuary, 1 gynecologist-oncologist, and 1 chemist) who, despite their different backgrounds, interests, and sex, made groundbreaking contributions to oncology.

Pathfinders in oncology from the beginning of modern surgery of intracranial tumors to the introduction of the Pap smear.

During the period from 1922 to 1942, several carcinogens were identified in coal tar, industrial oils, and petroleum, and radium was added to x-ray as a potential carcinogen. It was proven that some viruses are capable of causing cancer, and the dependency of prostatic and mammary hyperplasia and carcinoma on naturally occurring hormones was established. Colon cancer was linked to hereditary and nonhereditary polyposis. A permanent place for diagnostic radiology was defined and radiation therapy advanced to preoperative and postoperative modalities using x-ray and radium. The trend toward the use of radical surgery for primary and metastatic cancers continued. Although several new radical surgical procedures were developed and advanced as far as the technical skills of surgeons and the anatomic setting permitted, several innovative, less radical procedures were introduced. In chemotherapy, the basic principle of the treatment of advanced cancers with hormones was inaugurated. Pathologists synthesized what was known in tumor pathology, named new microscopic entities, recognized carcinoma in situ, developed histologic grading and pathologic staging of cancers, and introduced aspiration cytology and exfoliative cytology as new fields in oncology. It is interesting that despite profound global economic, social, and political upheaval and wars and preparation for wars, writers and producers of musicals and movies presented more memorable works than ever before. In the fields of science and technology, particularly nuclear physics and chemistry, profound discoveries were made that became a permanent part of human life. The progress made in oncology between 1922 and 1942 came about through the dedicated work of many individuals. However, there were 7 pathfinders (3 surgeons, 2 pathologists, 1 physician-chemist, and 1 physician-cytologist) who, despite their widely diverse backgrounds, personalities, and interest, made outstanding contributions to oncology to the magnitude that they deserve a permanent place in the history of medicine and oncology.

Pathfinders in oncology from the end of the 19th century to the first description of Ewing sarcoma.

During the period 1884 to 1922, the only option in cases of operable cancers was radical surgery, and only a minority of patients were cured. Sporadic attempts were made to treat inoperable cancer patients with bacterial toxins; however, with the discovery of x-ray and radium, the era of radiation treatment as an alternative to surgery began. The discovery of transmissible cancers and experimental growth of cancer cells offered new information and not only led to a better understanding of the cellular composition of cancers but also yielded important information that ultimately paved the way to chemotherapy. These efforts also advanced the understanding of the pathogenesis of tumors and induced new clinical and pathologic classifications and subspecializations. It is important to emphasize that many of the initiatives and discoveries made in Europe in the second half of the 19th century were first put into clinical practice in the United States during the first 2 decades of the 20th century, including the use of x-ray and radium for irradiation and as diagnostic tools. All things considered, the progress made between 1884 and 1922 came about through the hard work of many eminent individuals; however, there were 7 foresighted pathfinders (3 surgeons, 2 pathologists, 1 internist, and 1 physicist) who-despite their widely diverse backgrounds, personalities, and expertise-made remarkable contributions to oncology to an extent that is still felt today.

Pathfinders in oncology from the beginning of the 19th century to the inauguration of the first cancer hospital in the United States.

The fields of medicine and oncology made substantial progress between 1800 and 1885. The first half of this period was dominated by the spectacular progress in physiology, cytology, histology, histopathology, and diagnostic microscopy. In the second half of the period, advancements in surgical techniques, anesthesia, asepsis, and laboratory medicine, including bacteriology, chemistry, and biochemistry, led to the development of medical specialties, including surgical pathology and surgical oncology. Although wars, revolutions, and socioeconomic upheavals interrupted the daily life of the populace, distinguished artists, scientists, and physicians continued, against all odds, to advance their field of interest. Among the many eminent individuals, there were 7 renowned physicians (4 pathologists and 3 surgeons) who revolutionized medical and oncology thinking in ways that are still felt today. They were polyglots with formidable erudition, beloved teachers, and mentors, and are remembered eponymically for their contributions to oncology to this day. As a passing note, the 3 surgeons also were skillful microscopists. Cancer 2018;124:230-41. © 2017 American Cancer Society.

Pathfinders in oncology from the end of the Middle Ages to the beginning of the 19th century.

During the 3 centuries reviewed herein, all that was known regarding cancer was limited to Italy, France, Germany, and England. Practically nothing was written about cancer in the rest of the known world, including the newly discovered geographic areas in the Americas, Africa, and Australia. The 7 pioneer physicians considered in this review lived through some of the most turbulent geopolitical, social, and religious upheavals that Europe had experienced during the Renaissance. Despite their diverse social, political, and religious backgrounds and disparate personalities, they were united in their commitment to the advancement of medicine and oncology and to spreading knowledge through printed texts. Collectively, they established the groundwork for modern anatomy, physiology, chemistry, pathology, surgical oncology, and chemotherapy. It perhaps is noteworthy that 5 of the 7 physicians who contributed the most to the advancement of surgery and surgical oncology served in various wars as army surgeons. Considering everything together, the refusal of physicians of this epoch to use the microscope is a historical enigma. Cancer 2017;123:1888-1897. © 2017 American Cancer Society.

Pathfinders in oncology from ancient times to the end of the Middle Ages.

This commentary highlights the onset and progression of the diagnosis and treatment of cancer from ancient times to the 15th century. During the preparation of this synoptic review of the lives and contributions to oncology of 7 ancient physicians, it became clear that despite separation by centuries, ethnicity, and religion, they had many things in common. For example, with the exception of Chauliac, all were born into wealthy families, had an excellent education in the liberal arts and sciences, and were mentored by outstanding teachers. After they became physicians, they traveled extensively, were polyglots, were sponsored by influential individuals, had inquisitive minds, searched for the true nature of diseases, and were proud to share the results of their observations with others. Except for Galen, all of them were kind and well-mannered individuals. They cared with sincere dedication for the poor and those who had untreatable disease, including cancer. Although their understanding of cancer was limited, they were deeply concerned about the neglect and hopelessness of cancer patients. They were aware of their shortcomings in offering effective treatment beyond the surgical excision of early cancers. For advanced cancers, they had nothing to give beyond palliative care with herbals and minerals. All physicians who care for cancer patients owe these pioneer physicians, whatever their shortcomings, an inexpressible debt for their attempts to cure cancer. Cancer 2016;122:1638-46. © 2016 American Cancer Society.

A note from history: Landmarks in history of cancer, part 7.

In the 2 and half decades reviewed (1970-1995), research established that chromosomal translocation, deletion, and DNA amplification are prerequisites to cancerogenesis and that oncogenes, tumor-suppressor genes, growth factors, and cytokines play crucial roles in the pathomechanism of cancer. Human papillomavirus, human immunodeficiency virus, herpes virus, and hepatitis B virus were identified as cancer-causing viruses. Several laboratory tests were developed for the detection of primary and recurrent cancers, and cancer prevention by screening methods was popularized. Sonography, computerized tomography, magnetic resonance imaging, positron emission tomography, excision of sentinel lymph nodes, and immunohistochemical techniques became routine procedures. Clinicopathologic staging and classification of tumors were standardized. Limited surgery, adjuvant and neoadjuvant chemoradiation, and the therapeutic use of monoclonal antibodies, tumor vaccines, and targeted chemotherapy became routine practice. The decline in cancer incidence and mortality demonstrated that cancer prevention and advancement in oncology are pivotal to success in the crusade against cancer. Above all, it was clearly established that the care of patients with cancer can be accomplished best in a multidisciplinary setting involving surgical oncologists, radiologists, radiation therapists, medical oncologists, surgical pathologists, and laboratory scientists. In conclusion, the 25 years from 1970 and 1995 are the high-water mark in clinical oncology, and this is the period when oncology turned from art to science.

Pathological features and clinical outcomes of breast cancer according to levels of oestrogen receptor expression.

AIMS: Historically, nuclear staining of ≥10% of invasive tumour cells has been used for oestrogen receptor (ER) positivity. In 2010, ASCO/CAP guidelines recommended the cut-off value be changed to nuclear staining of ≥1%. This study will analyse the relationships between levels of ER expression and clinicopathological features and clinical outcomes, with an emphasis on the ER 1-10% subgroup. METHODS AND RESULTS: We analysed clinicopathological features in five subgroups based on ER expression levels in 1700 consecutive invasive breast cancer patients diagnosed and treated at our institution between 2000 and 2011. Of the cases, 24% had ER expression <1%, 2% were ER 1-10%, 5% were 11-50%, 5% were 51-70% and 64% were 71-100%. We observed four subgroups of patient cohorts (ER <1%, 1-10%, 11-70% and 71-100%) that were unique in Nottingham grade, nuclear grade, progesterone receptor expression and disease-free survival. Of the 341 patients with follow-up data, we found no significant differences in pathological features between patients in the ER 11-50% and ER 51-70% subgroups. CONCLUSION: These data support the important role of ER in breast cancer, and the importance of accurate testing and quantitative reporting for ER. Tumours with ER 1-10% are not common, and further studies are needed to understand more clearly this subgroup of breast cancer.

A note from history: Landmarks in history of cancer, Part 6.

In the 3 decades from 1940 to 1970, the United States became the nucleus for research, diagnosis, and treatment of cancer. The discovery of anticancer drugs, and the clinical demonstration that chemotherapy and radiation can cure cancer and have the ability to prevent recurrence of cancer, were incontrovertibly the most remarkable groundbreaking events. Consequently, the trend of less surgery and more multimodality therapy began. The introduction of radioautography, mammography, ultrasonography, computed tomography, Papanicolaou smear, and other novel laboratory tests furthered early detection of cancer and refined accurate diagnosis. The unequivocal linking of lung cancer to cigarette smoking made medical history. The delineation of the potential role of oncogenes adduced new thoughts about oncogenesis and cancer prevention, and pathologists finalized the classification and nosology of tumors. Finally, it is worth noting that although more advances were made in the detection, diagnosis, and treatment of cancers than any other period in history, the overall mortality rate of patients with cancer remained high and unchanged.

A note from history: landmarks in history of cancer, part 5.

In the 3 decades from 1910 to 1940, more progress took place in cancer research and the diagnosis and treatment of cancers than during the prior centuries combined. The discovery of several carcinogens, precancerous conditions, and hereditary cancers adduced new thoughts about the genesis of cancers. Even though diagnostic radiology and radiation therapy became apposite specialties, surgery retained its primacy in the treatment of cancer patients. The delineation of new and distinct neoplastic entities, several precancerous lesions, and noninvasive carcinomas as well as the introduction of histopathologic grading of cancers promulgated cogent changes in therapy. Yet, with all the advances in the diagnosis and treatment of cancers, very little betterment could be demonstrated in the overall survival of patients, and by the end of the 1930s, cancer became the second most common cause of death in the United States.

A note from history: landmarks in history of cancer, part 3.

In the early 19th century, microscopy in pathology replaced gross descriptive pathology of the 18th century. Cells became known as the most important and distinct elements of benign and cancerous tissues. Thus, by the mid-1800s, a solid foundation had been laid for microscopy, and surgeons recognized that microscopic diagnosis by pathologists merited attention. In due course, preoperative microscopic diagnoses and classification of cancers in biopsy specimens were incorporated into choosing the most fitting surgical operation.

A note from history: landmarks in history of cancer, part 4.

In the second half of the 19th century, most cancer patients were cared for by surgeons who exerted ascesis and limited their operations to 1 or 2 specific areas. To assist surgeons and other physicians in caring for their patients, pathologists described newly discovered entities, refined the microscopic classification of tumors, and introduced the grading of cancers. The discoveries of Rontgen and the Curies revolutionized the diagnosis and treatment of cancers. The search for the cause of cancers extended to infectious organisms, chemicals, and radioactive materials. The 50 years covered in this review formed the groundwork for the coordinated, specialized care of cancer patients at institutions dedicated to render the most promising treatment.

Predictors of nipple-areolar complex involvement by breast carcinoma: histopathologic analysis of 787 consecutive therapeutic mastectomy specimens.

BACKGROUND: Breast-conserving therapy (BCT) is an accepted therapeutic option for most breast cancer patients. However, mastectomy is still performed in 30-50% of patients undergoing surgeries. There is increasing interest in preservation of the nipple and/or areola in hopes of achieving improved cosmetic and functional outcomes; however, the oncologic safety of nipple-areolar complex (NAC) preservation is a major concern. We sought to identify the predictive factors for NAC involvement in breast cancer patients. METHODS: We analyzed the rates and types of NAC involvement by breast carcinoma, and its association with other clinicopathologic features of the tumors in 787 consecutive therapeutic mastectomies performed at our institution between 1997 and 2009. RESULTS: Among these, 75 cases (9.5%) demonstrated NAC involvement. Only 21 (28%) of 75 of cases with NAC involvement could be identified grossly by inspection of the surgical specimen (seven of these had been clinically identified). NAC involvement was most significantly associated with tumors located in all four quadrants (P<0.0001), tumors>5 cm in size (P=0.0014 for invasive carcinoma and P=0.0032 for in-situ carcinoma), grade 3 tumors (P=0.0192), tumors with higher nuclear grades (P=0.0184), and tumors with HER2 overexpression (P=0.0137). CONCLUSIONS: On the basis of our findings, we have developed a mathematical model that is based on the extent and location of the tumor, HER2 expression, and nuclear grade that predicts the probability of NAC involvement by breast cancer. This model may aid in preoperative planning in selecting appropriate surgical procedures based on an individual patient's relative risk of NAC involvement.

A note from history: landmarks in history of cancer, part 2.

Events that took place in medicine during the 15th, 16th, and 17th centuries signaled the end of the Dark Ages. The Renaissance movement, spreading from Italy across Europe, ended the religious and public prohibitions that had prevented progress in medicine. Pioneer physicians and surgeons who gave their attention to discoveries in anatomy, physiology, and chemistry established the foundations for tumor pathology, surgical oncology, and medical oncology. This review is a summary of their accomplishments.

Relationship between nuclear grade of ductal carcinoma in situ and cell origin markers.

Ductal carcinoma in situ (DCIS) is a group of heterogeneous lesions genetically, morphologically, and biologically. Recently, breast epithelium in the terminal ductal lobular unit has been sub-classified based on the expression of several cytokeratin markers as stem cells (CK5/6 +), luminal cells (CK8, CK18 +), and basal cells (CK14, CK17 +). In this study we describe the relationship between DCIS of different nuclear grades (non-high grade and high grade) and these cell origin markers. Fifty-three cases of non-high grade and 46 cases of high grade DCIS were selected, and representative sections from each case were stained with antibodies to these cytokeratin markers. High grade DCIS showed significantly higher rates of expression with stem and basal cell markers compared with non-high grade DCIS (p <0.05). The majority of DCIS, both high grade and non-high grade, expressed luminal cell markers (67% to 91%) and single type of cell origin marker (72% to 87%). High-grade DCIS more frequently co-expressed all three types of cell origin markers compared with non-high grade DCIS (p <0.05). In summary, a subset of high grade DCIS frequently rises from stem or/and basal cell populations; the subset is associated with poor prognosis in invasive breast carcinoma. Thus, these markers may be used to identify a potentially more aggressive subgroup of breast carcinoma at its pre-invasive stage (DCIS), and to manage it accordingly. Second, most DCIS express luminal cell markers, suggesting that malignant transformation occurs relatively late along the cell differentiation pathway, contrary to the traditional belief that most neoplasms arise from a more primitive stem cell population. Third, the majority of DCIS exclusively express one type of progenitor marker, indicating that in most incidences they may arise from a single progenitor population. Last, triple expression of all types of cell origin marker is frequently associated with high grade DCIS, suggesting that more complicated pathways are involved in these more aggressive lesions. Further studies are needed to delineate the relationships of cell origin markers in DCIS and invasive carcinoma to the clinical outcome.

Sebaceous carcinoma of the lung: histologic and immunohistochemical characterization of an unusual pulmonary neoplasm: report of a case and review of the literature.

Sebaceous neoplasms, including carcinomas, are tumors most often seen around the eye and eyelid. Cases of extraorbital sebaceous tumors associated with skin adnexa are less common. The parotid gland may also be a source for sebaceous neoplasms, and cases associated with minor salivary gland tissue have also been reported. Once beyond the oropharynx, individual cases of pharyngeal and laryngeal sebaceous tumors are reported. The case of a patient with primary sebaceous carcinoma of the bronchus is presented. Our case is that of an endobronchial mass that has histopathologic features of a sebaceous carcinoma, with predominance of areas with morphologically classic sebaceous differentiation, confirmed by oil red O stain for lipid, analyzed by immunohistochemistry and evaluated ultrastructurally. This unique tumor extends the spectrum of extraocular, extracutaneous neoplasms with sebaceous differentiation from existing single reports in the hypopharyx and larynx to now include bronchus.

Pathologists who attained fame without using microscopy.

Morgagni, Baillie, and Rokitansky were three giants in pathology. They established the foundations for classification of diseases. Their combined contributions to clinical knowledge outweighed all that had been learned in medicine in the prior history of the human race. It is remarkable that their achievements were made without using microscopy.

Post-radiation angiosarcoma and bilateral mastectomy.

We report the occurrence of bilateral angiosarcoma after radiation therapy for breast carcinoma in a 64 yr-old woman. The first angiosarcoma developed 17 yr after radiation therapy to the right breast; the second angiosarcoma developed 1.5 yr after radiation therapy to the left breast. Recognizing angiosarcoma in radiated breast tissue is essential to appropriate therapy. The role of irradiation after surgery as adjuvant therapy is to be reviewed.

Incidental finding of mammary carcinoma in lumpectomy specimens.

More and more breast lumpectomies are being performed due to mammographic screening, and both in situ and invasive breast carcinomas are being detected earlier and smaller in size. The objective of this study was to determine the presence of incidental microscopic breast carcinoma in mammography-guided lumpectomy specimens. A prospective study was carried out by processing in surgical pathology approximately 9,000 breast lumpectomy specimens during a 2.5-yr period so that the entire specimens were embedded for microscopic examination. Excluded from the study were cases with grossly or microscopically identified carcinomas greater than 10 mm2, and non-invasive carcinomas diagnosed in association with invasive carcinoma. Cases with multifocal carcinomas, prior diagnosis of breast cancer, or prior history of breast biopsy were also excluded. Carcinomas present in the same tissue blocks as the clinically suspected lesions such as palpable nodules, microcalcification, or other mammographic abnormalities were excluded as well. Fifty cases of incidental microscopic mammary carcinoma were found including 8 infiltrating ductal carcinomas (IDC), 2 infiltrating lobular carcinomas (ILC), 21 intraductal carcinomas (DCIS), and 19 lobular carcinomas in situ (LCIS). All of the lesions were solitary, located in indistinct loosely arranged fibrous and adipose stromal tissues, and the majority of them were near or at the inked excisional margins. Physicians who care for patients with breast cancer should be aware of the existence of these minute breast carcinomas that are often near or at the surgical margins. The significance of these microscopic findings for therapeutic strategy and prognosis should be determined by long-term follow-up.