Juan Rosai: a metaphorical memoir

Time, the carpet of patterns, the web of relationships, the history of surgical pathology and Juan Rosai.

Michael C. Dugan, M.D. written July 2020

“In Eudoxia, which spreads both upward and down, with winding alleys, steps, dead ends, hovels, a carpet is preserved in which you can observe the city’s true form.?At first sight nothing seems to resemble Eudoxia less than the design of that carpet, laid out in symmetrical motives whose patterns are repeated along straight and circular lines, interwoven with brilliantly colored spires, in a repetition that can be followed throughout the whole woof.?But if you pause and examine it carefully, you become convinced that each place in the carpet corresponds to a place in the city and all the things contained in the city are included in the design, arranged according to their true relationship, which escapes your eye distracted by the bustle, the throngs, the shoving.?All of Eudoxia’s confusion, the mules’ braying, the lampblack stains, the fish smell is what is evident in the incomplete perspective you grasp; but the carpet proves that there is a point from which the city shows its true proportions, the geometrical scheme implicit in its every, tiniest detail.

It is easy to get lost in Eudoxia:?but when you concentrate and stare at the carpet, you recognize the street you were seeking in a crimson or indigo or magenta thread which, in a wide loop, brings you to the purple enclosure that is your real destination.?Every inhabitant of Eudoxia compares the carpet’s immobile order with his own image of the city, an anguish of his own, and each can find, concealed among the arabesques, an answer, the story of his life, the twists of fate….”

????????????????????????????????????????????????????????????????????????????-- Italo Calvino.?Invisible Cities [1]

In my last correspondence with Dr. Juan Rosai maybe 2 or 3 years ago I told him I was writing some short stories inspired by Invisible Cities, the work of Italo Calvino, an Italian author who had died in 1985.?Juan noted the coincidence that he was listening to an audiobook version of Calvino’s fascinating book as well and he remarked, “it is a shame he is not better known outside of Italy.”

Through an unlikely pairing, a twisted thread attached barely by the respect of one pathologist toward another, I had come to know “Dr. Rosai,” recommended to me by Dr. Tom Grogan at the U. of Arizona College of Medicine who suggested I consider interviewing at Yale, specifically because of him.?My residency interview was scheduled at Yale-New Haven Hospital on a late November Wednesday, but my meeting with him had been hastily rescheduled for Tuesday night after a train trip from Boston.?His assistant had indicated, calling my home phone and reaching my mother, that he was unavailable the next day, could she possibly relay a message to let me know he would like to interview me that night whenever I arrived??The train arrived about 9.?“Would not that be too late?” she asked.?His assistant indicated it would be fine.?I had called my mother on Tuesday afternoon to let her know how the interviews in Boston went and she relayed the message to get to the hospital as soon as possible.?My train was delayed, cell phones did not exist.?I showed up in the lobby well after 10 and apologized profusely when I placed the call from the information desk to his office.?He came down, shook hands, and led me upstairs to his office saying, “don’t worry, I am here every night late.” I said, “Oh really? How come?” He said, “I am working on the next edition of my book.”?“How late do you usually stay?” I asked.?“Often until midnight” he replied.

It is thought that when great mentors pass that they will live on in the ideas, memories and dreams of their students, perhaps living in many different cities, in different decades or lives, but connected forever by an intricate web of common shared experiences that defined who and what they were.?Those “students” must include all who have had the pleasure to listen intently to what they said, and perhaps only the tidbits that they could remember after so many years had passed.?It would be an understatement to say that anyone who was so lucky as to hear Juan Rosai speak on a topic, even briefly, would likely remember it the rest of their days.?So it is that when I heard of his passing I could recall not just this one story, not five or ten, but a series of descriptions and notations, a procession of questions and curiosities, a seemingly endless cascade of inquisitive piercing words in his distinctive Italian-Argentinian voice that would usher us--me and an handful of other fellow residents at Yale-New Haven Hospital during 1988-91 and others before and after--into the world of surgical pathology at a young impressionable age.

Dr. Juan Rosai or simply “Rosai” as we most often referred to him [though he preferred Juan once we graduated residency, or Dr. Rosai] was a giant in pathology, a Director of Anatomic Pathology at Yale, a Chair of Pathology at Memorial Sloan-Kettering, etc., but to himself perhaps just an earnest fellow who was lucky to have studied surgical pathology under Dr. Lauren V. Ackerman during the last year of his long tenure at Washington U. of St Louis.?It was Rosai who carried that giant’s namesake double volume textbook, Ackerman’s Surgical Pathology, forward from the fifth to its tenth edition.[2]?His latest 9th and 10th editions were published as Rosai and Ackerman’s Surgical Pathology, but much of the 5th and nearly all of the 6th, 7th and 8th without his name in the title were written entirely by Juan Rosai, except for a few chapters and parts, mostly concerning non-neoplastic diseases of just a few organs.?As noted in the preface to the 10th edition, moving with each edition several times in a career spanning several cities and institutions, his editions of the famous textbook each seemed a monumental, no…a Herculean effort.

The 10th edition published in 2011 filled over 2600 pages of text printed in a small font with thousands of illustrations and references.[2]?His scope of topics was not limited by the clinical subspecialties we commonly see today (GI, GU, Breast, Lung, etc.).?No, Rosai felt comfortable, one might say he felt compelled to know the details of every tissue, every organ and every cell, no matter its origin or eventual fate of a tumor destination.?Rosai, with his numerous fellows and residents, was a prolific author of papers that described many entities of many organs for the first time (e.g. sinus histiocytosis with massive lymphadenopathy, insular carcinoma of thyroid, follicular variant of papillary carcinoma of thyroid, mixed acinar neuroendocrine carcinomas of pancreas, etc.[3-6]?Others reviewed or solicited the input of experts to highlight the history of nomenclature and tumor classification or areas of common disagreement (e.g. atypical hyperplasia vs. carcinoma in site in breast).[7]

Not developed as an experimental pathologist, Rosai grew under the tutelage of Ackerman, a brief connection to him, to become the world’s greatest taxonomist and clinical anatomic detective of neoplasia, a true surgical pathologist.?Rosai was brilliant and engaging in his encyclopedic knowledge of tumors of bone, soft tissue, skin, lymph node and pancreas and their myriad clinical presentations and prognosis, and famed for his work defining criteria of thyroid neoplasia and characterizing other endocrine neoplasms.[8-11] But to those of us who studied with him he was perhaps better known for his weekly gross and microscopic resident conferences, question and answer sessions that would frequently delve into topics of morphologic mimics, the embryologic manifestations of tumors, divergent and mixed differentiation—mesenchymal, endothelial, epithelial, acinar, oncocytic, anaplastic, neuroendocrine, etc. and the various clinical and radiologic features related to their pathologic morphology.?

The clinically obscure presentation of a small cell tumor in the skin resembling metastatic lung cancer, but apparently derived from the skin [a Merkel cell tumor] would precipitate a discussion of cellular mimicry or divergent origins of the same.[12] At the time Rosai and colleagues first described this entity in 1980 it could only be distinguished based on electron microscopy.[12]?The endocrine manifestation of a tumor, such as hypophosphatemia and phosphoturia associated with mesenchymal tumors of bone or soft tissue, features described in 1985 and 1987 by Dr. Noel Weidner and colleagues at Brigham and Women’s Hospital in Boston, would elicit an historical review of hemangiopericytomas and osteoclast-like giant cells in various presentations which might have led confusingly to other diagnostic considerations.[13,14] Chondrosarcomas, atypical lipomas, mucinous adenomas and adenocarcinomas of the appendix—virtually any tumor considered was likely to be completely dissected of its historical descriptive precedents in 19th and early 20th century literature from Europe, or Asia or other parts of the globe.?Whether it derived from bone marrow, mesenchyme, epithelium or endothelial cells, Rosai would consider it in his differential and consider it fully, excluding the mundane, and elevating the rare, the obscure, the misunderstood threads to reach his destination.

Rosai did not simply “teach pathology” or provide “didactic lectures.”?Rather he forced us to study the ecology and evolution of the human form descended from the grotesque morphology of misshapen anatomy, tumors both huge and small, fatty and fibrous, calcified and necrotic, invasive or encapsulated.?These masses delivered or obtained by residents fresh from the operating room, were cut and dissected like archeological digs, carefully examined and photographed for all to see, their preciously examined museum pieces of tissue laid within selected cassettes, cut, stained and pinned to a glass slide.?From an awkward void of blood, lumps and uncertainty, his illustrations and dichotomous questions would plunge us into a microscopic world described in both present and historical derivatives of Latin, German, Italian, Spanish, Portuguese, English and any other languages he managed to speak or at least attempt to read.?For us it was a descent from black and white print—the domain of medical textbooks—and the haste of resident visits to ORs into a colorful, twisted, only slightly predictable world of fascinating splendor and complexity, easy to misread, simple to miscalculate, impossible to fully decipher, challenging to master, engaging without end.?The best of the best could be quickly humbled in the presence of Rosai, master of the neoplastic universe.

To fully recount his career and influence is impossible.?Rosai mentored dozens of residents and fellows and oversaw several departments of Surgical/Anatomic Pathology including the Univ. of Minnesota, Yale U., and Memorial Sloan-Kettering.?He served as editor in chief of the 3rd edition of the Armed Forces Institute of Pathology (AFIP) fascicles and authored with his wife, Maria Luisa Carcangiu and Ronald A. DeLellis, the definitive 3rd edition volume on Tumors of the Thyroid Gland, a title noteworthy for its historic anatomic reference to endocrine “glands” in an organ not containing ducts or exocrine cells.[8,9]?Rosai would have probably rather given that name to the pancreas with its well described dual exocrine and endocrine functions and anatomy described in numerous papers by Rosai, his former fellow David Klimstra and other notable pathologists far and wide around the globe.[6]

Rosai was a consummate historian of pathology and medicine.?He compiled and published with several contributors the 1997 book Guiding the Surgeon’s Hand which describes the history of surgical pathology as traced through many notable pathologists at several leading American institutions, among them Johns Hopkins, Columbia U, Cornell and Memorial Hospital (Memorial Sloan-Kettering), Harvard and Boston City Hospital, Children’s Hospital, Brigham and Woman’s Hospital and Massachusetts General Hospital, Washington University, St. Louis, the Mayo Clinic and the AFIP.?The book includes the autobiographic notes of Arthur Purdy Stout and Lauren V. Ackerman, both of which had been previously unpublished.[15,16] One photo from the book of Rosai and other fellows with Ackerman at Washington U-Barnes Hospital, St. Louis in 1973 is notable.[17]?It was Ackerman’s last year of two and half decades as the Director of Surgical Pathology, a period described in the book during which Surgical Pathology evolved dramatically under his leadership from an adjunct to surgery and a stepchild of anatomic (autopsy) pathology into a clearly demarcated clinical specialty, the “pathology of the living.”[17,18] In the later 20th Century it was Rosai, as much as anyone, who took this new clinical specialty to its most ambitious heights, training an army of residents and pathologists across his adopted country and around the globe, many of whom became department leaders and giants of their own generation, 20 to 30 years later.

Just before leaving Yale as Director of Surgical Pathology in the summer of 1991 to become Chair of Pathology at Memorial Sloan-Kettering, Rosai gave a commemorative last lecture, but not on pathology per se.?Rather he detailed the history of Florence’s Medici family.?“The House of Medici,” an Italian family beginning with the rise of Cosimo de’ Medici (or Cosimo the Elder), that ruled Florence, and later Tuscany, for most of an era extending from 1434 to 1737, were giants of commerce and banking, patrons of the arts and architecture, science and early medicine, who “transformed Florence into the cradle of the Renaissance, a cultural flowering rivaled only by that of ancient Greece.”[19,20] Fittingly, although he loved New York City and the American pathology training programs he had cultivated, Rosai, born and raised in Argentina to Italian parents, later returned to Milan Italy to become the Director of the Istatuto Nazionale dei Tumori (National Cancer Institute) and later continued his consultations at the Centro Diagnostico Italiano in Milan.

Famed internationally, Rosai was besieged with requests for consults and maintained arguably the largest and broadest consultation service in the world aside from numerous skin cases sent to other notable dermatopathologists.?His consultation service at Yale and MSK formed the basis for training numerous Rosai fellows including Dr. John KC Chan who arrived from Hong Kong, Dr. Giovanni Tallini from Italy, and many others who followed him.[21,22] When Rosai moved back to Italy his consultation service was logistically and administratively supported and professionally marketed by several commercial entities that pioneered reference laboratory services for surgical pathologists greatly expanding in the late 1990s and 2000s the then young fields of immunohistochemistry, flow cytometry and molecular diagnostics.?Rosai helped develop the first IHC reference laboratory in New York City.?Impath later expanded to a 2nd location in Los Angeles and was acquired in 2003 by Genzyme Corporation (Cambridge MA) to build their Genzyme Genetics business unit.[23]?During the late 2000s with Rosai as its most well-known pathologist, we grew this AP and molecular genetic reference laboratory to be the most prominent oncology and genetic reference laboratory nationally with over 30 pathologists.[23,24] In 2010 Genzyme Genetics was spun off and acquired by Laboratory Corporation of America.?Rosai remained affiliated with LabCorp for several years after they merged Genzyme Genetics with US Labs and it became Integrated Oncology.[24]

Having once been his fellow, to later serve as the head of Pathology Services at Genzyme and Integrated Oncology and hence be his dotted line “supervisor” for 4 years was ironic but not difficult.?My role was simply to support him and provide whatever he needed to continue his consultations.?We had a great deal of admiration for each other and much to share about the present and future of pathology.?Once previously at Yale in early 1991, the closing months of 3 years training with him, I had asked him or remarked about the various papers starting to mention p53.[25,26]?He said something like, “I don’t really know much about it, but it seems this molecular trend could take over pathology like immunohistochemistry.” I said to him, youthfully optimistic if somewhat temporally doubtful, “yes, it seems likely.” Our briefly shared sentiments seemed prophetic then and more so now.?

Rosai with MSK colleagues Enrique de Alava, Marc Ladanyi and William Gerald in 1995 helped define chimeric fusion gene transcripts associated with various soft tissue sarcomas.[27]?I went to Childrens Hospital Los Angeles in 1991 and later UCLA and Wayne State U./Detroit Medical Center and Children’s Hospital of Michigan to learn the molecular, cytogenetic and molecular cytogenetic techniques used to distinguish what were previously known as “small round blue cell tumors” as well as various acute leukemias in children and several leukemic or “blastic” lymphomas in adults.[27-29] Within 10 years of that conversation, molecular diagnostic tests were defining prognosis and survival in many solid tumors including those most deadly such as pancreatic cancer.[30-33] Within 20-25 years, molecular companion diagnostic tests such as KRAS, EGFR, BRAF and ALK were guiding first line targeted therapy choices and gene-expression based tests were being used to characterize tumors of unknown origin which could not be further classified by IHC and to guide first line conventional chemotherapy therapy.[34-37] Within 30 years short-read and then long-read Next-Generation Sequencing (NGS) was uncovering the molecular landscape of neoplasia in a distinctly encyclopedic, Rosai-like fashion supported by each of the largest commercial and academic pathology laboratories and many new ones which were introducing assays more tailored to particular clinical indications for use.[38-41]

In 2009 during USCAP’s annual meeting in Washington DC, Genzyme Genetics honored Juan Rosai to commemorate his career by hosting a dinner event.?He exclusively organized the content to review notable papers published by 5 of his residents or fellows each of which defined new entities described and characterized over his incredible career.[4,6,21,42,43] The historical recap, including Rosai’s tribute to the huge contributions of William Gerald, a Rosai fellow and faculty member at MSK who died prematurely of cancer in 2008, was a tour de force.[43-45] It was a quintessential display of Rosai’s depth, reach and influence across the field of surgical pathology, which shaped modern cancer classification, staging, treatment and medical care for many related entities (such as proliferative breast disease and autoimmune disorders of thyroid) in general.[7,10]

In 2014, several years after our Genzyme pathology connection, Rosai became affiliated with ARUP Laboratories in Salt Lake City UT to keep his still active consultation service going from Milan and for the occasion delivered one of his last and most intriguing public lectures in the US: Themes and Leit Motifs in Music and Pathology, examining how similar features can recur in tumors of disparate organs, sometimes recounting embryologic origins.[46] For Rosai, an fan of Italian opera, Leit Motifs, derived from the German word Leitmotiv [“leading motive”] are recurring themes appearing usually in operas but also in symphonic poems “used to reinforce the dramatic action, to provide psychological insight into the characters, and to recall or suggest to the listener extra-musical ideas relevant to the dramatic event. In a purely musical sense, the repetition or transformation of the theme also gives cohesion to large-scale works.”[47]

Once he had returned to Italy, most of us in the U.S. would only get to see Rosai at the annual USCAP meeting which he enjoyed attending with his wife, professional colleague and frequent co-author, Maria Luisa Carcangiu until recent years when he was unable to travel. In the spring of 2012, visiting Milan briefly on business, I had the pleasure to join him and Maria Luisa at a restaurant near the Duomo for dinner afterwards.?For the first time he mentioned his declining health and indicated it was getting more difficult to come to the USCAP Annual Meeting each year.?My thought then was, “What a shame. What would pathology be without Dr. Rosai?” It was just a moment of apprehension, a recognition of our mortality, the final page for all, fearing that he might one day be gone.?

Appreciating the incredible impact Rosai had on so many pathologists around the world, noting that as case slides would continue to come to him in consultation from cities on every continent and that his two volume textbooks recently published again would once more need to be updated though he might not be able to do it, I was honored that he would take the time to dine with me, happy to share more stories.?I was just a fellow traveler of the world, a young Marco Polo from a distant time and place, who met him, the great Kublai Khan, through a twist of fate, one late night in a city called New Haven or perhaps Eudoxia.?Rosai was fascinating and worldly then, but described aptly by Calvino, could eventually be recognized as nothing more than the weaver of an incredible thread, holding together and forming a fantastical carpet of pathology, an empire more detailed than an arabesque, one line tied to so many, a second father to an entire modern Medici family of surgical pathologists, each of whom became ensconced in the purple (and pink) enclosure of his world.

...

1.??????Italo Calvino, Invisible Cities [English translation of Le citta invisibili, c. 1972 by Giulio Einaudi Editore], Harcourt, Inc. [now Houghton Mifflin Harcourt Publishing Company, New York] 1974, pp. 96-97.

2.??????Juan Rosai. Rosai and Ackerman’s Surgical Pathology, 10th ed., Mosby-Elsevier, Edinburg, 2011, preface, pp. vii-viii.

3.??????Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7(1):19-73.

4.??????Carcangiu ML, Zampi G, Rosai J. Poorly differentiated ("insular") thyroid carcinoma. A reinterpretation of Langhans' "wuchernde Struma". Am J Surg Pathol. 1984;8(9):655-668. doi:10.1097/00000478-198409000-00005

5.??????Chem KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol. 1977;1(2):123-130. doi:10.1097/00000478-197706000-00003

6.??????Klimstra DS, Rosai J, Heffess CS. Mixed acinar-endocrine carcinomas of the pancreas. Am J Surg Pathol. 1994;18(8):765-778. doi:10.1097/00000478-199408000-00002

7.??????Rosai, Juan M.D. Borderline Epithelial Lesions of the Breast, The American Journal of Surgical Pathology. 1991; 15 (3): 209-221.

8.??????Rosai J, Carcangiu ML, DeLellis RA, Atlas of Tumor Pathology: Tumors of the Thyroid Gland [Third Series - Fascicle 5], Armed Forces Institute of Pathology, 1992

ISBN-10: 1881041034

ISBN-13: 978-1881041030

9.??????Rosai J, DeLellis RA, Cancangiu ML, Frable WJ, Tallini G., Atlas of Tumor Pathology: Tumors of the Thyroid and Parathyroid Glands [4th Series], Washington DC: American Registry of Pathology, 2014

10.??Rosai J, Kuhn E, Carcangiu. Pitfalls in thyroid tumour pathology. Histopathology. 2006; 49: 107-120.?https://doi.org/10.1111/j.1365-2559.2006.02451.x

11.??Rosai J. Papillary Thyroid Carcinoma: A Root-and-Branch Rethink. Am J Clin Pathol. 2008; 130: 683–686. https://doi.org/10.1309/AJCPBF63BWMCYSLW

12.??Sibley RK, Rosai J, Foucar E, Dehner LP, Bosl G. Neuroendocrine (Merkel cell) carcinoma of the skin. A histologic and ultrastructural study of two cases. Am J Surg Pathol. 1980;4(3):211-221. doi:10.1097/00000478-198006000-00001

13.??Weidner N, Bar RS, Weiss D, Strottmann MP: Neoplastic pathology of oncogenic osteomalacia/rickets. Cancer. 1985; 55: 1691-1705.

14.??Weidner N, Santa Cruz D: Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer. 1987; 59: 1449-1454.

15.??Stout AP, Notes on the Education of an “Oncological” Surgical Pathologist; the Autobiography of Arthur Purdy Stout, Ch 10, Guiding the Surgeon’s Hand: The History of American Surgical Pathology, Rosai J (ed.), Washington DC: American Registry of Pathology, Armed Forces Institute of Pathology, 1997: 197-274.

16.??Ackerman LV, Autobiographical Notes of Lauren V. Ackerman, Ch 11, ibid: 275-285.

17.??Dehner LP, Kissane JM. Surgical Pathology at the Washington University Medical Center and Barnes Hospital, Ch 7, ibid: 111-144.

18.??Boyd W. Surgical Pathology. Philadelphia: WB Saunders, 1925: 17-20.

19.??The Medici Family.?Florence Inferno.?https://www.florenceinferno.com/the-medici-family/#who-were-the-medici

20.??Strathern P. The Medici; Power, Money, and Ambition in the Italian Renaissance. New York: Pegasus Books, 2016.

21.??Chan JKC, Carcangiu ML, Rosai J: Papillary Carcinoma of Thyroid with Exuberant Nodular Fasciitis-like Stroma: Report of Three Cases. Am J Clin Pathol. 1991; 95 (3): 309–314. https://doi.org/10.1093/ajcp/95.3.309

22.??Tallini G, Carcangiu ML, Rosai J. Oncocytic neoplasms of the thyroid gland. Acta Pathol Jpn. 1992;42(5):305-315. https://doi:10.1111/j.1440-1827.1992.tb02879.x

23.??https://www.darkintelligencegroup.com/the-dark-report/anatomic-pathology/impath-has-a-buyer-genzyme-pays-215-mil/

24.??https://www.worldpharmanews.com/financial/1378-genzyme-announces-agreement-to-sell-genetic-testing-business-to-labcorp

25.??Hollstein M, Sidransky D, Vogelstein B, Harris CC, p53 mutations in human cancers. Science. 1991; 253: 49-53. https://doi.org/10.1126/science.1905840

26.??Lane D, p53, guardian of the genome. Nature. 1992; 358: 15–16. https://doi.org/10.1038/358015a0

27.??de Alava E, Ladanyi M, Rosai J, Gerald WL. Detection of chimeric transcripts in desmoplastic small round cell tumor and related developmental tumors by reverse transcriptase polymerase chain reaction. A specific diagnostic assay. Am J Pathol. 1995;147(6):1584-1591.

28.??Dockhorn-Dworniczak B, Sch?fer KL, Blasius S, et al. Assessment of molecular genetic detection of chromosome translocations in the differential diagnosis of pediatric sarcomas. Klin Padiatr. 1997;209(4):156-164. doi:10.1055/s-2008-1043964

29.??Vaishampayan UN, Mohamed AN, Dugan MC, Bloom RE, Palutke M. Blastic mantle cell lymphoma associated with Burkitt-type translocation and hypodiploidy. Br J Haematol. 2001;115(1):66-68. doi:10.1046/j.1365-2141.2001.03056.x

30.??Hruban RH, van Mansfeld AD, Offerhaus GJ, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143(2):545-554.

31.??Dugan MC, Dergham ST, Kucway R, et al. HER-2/neu expression in pancreatic adenocarcinoma: relation to tumor differentiation and survival. Pancreas. 1997;14(3):229-236. doi:10.1097/00006676-199704000-00003

32.??Dergham S, Dugan M, Sarkar F. et al. Molecular alterations associated with improved survival in pancreatic cancer patients treated with radiation or chemotherapy. J Hep Bil Pancr Surg. 1998; 5: 269–272. https://doi.org/10.1007/s005340050045

33.??Dergham ST, Dugan MC, Joshi US, Chen YC, Du W, Smith DW, Arlauskas P, Crissman JD. The clinical significance of p21WAF1/CIP‐1 and p53 expression in pancreatic adenocarcinoma.?Cancer. 1997; 80: 372-381. https://doi.org/10.1002/(SICI)1097-0142(19970801)80:3<372::AID-CNCR4>3.0.CO;2-U

34.??Agarwal A, Ressler D, Snyder G. The current and future state of companion diagnostics. Pharmgenomics Pers Med. 2015;8:99-110. Published 2015 Mar 31. doi:10.2147/PGPM.S49493

35.??Anderson S, Bloom KJ, Vallera DU, et al. Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed, paraffin-embedded tissue specimens of malignant melanoma. Arch Pathol Lab Med. 2012;136(11):1385-1391. doi:10.5858/arpa.2011-0505-OA

36.??Hainsworth JD, Rubin MS, Spigel DR, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol. 2013;31(2):217-223. doi:10.1200/JCO.2012.43.3755

37.??McVeigh TP, Kerin MJ. Clinical use of the Oncotype DX genomic test to guide treatment decisions for patients with invasive breast cancer. Breast Cancer (Dove Med Press). 2017;9:393-400. Published 2017 May 29. doi:10.2147/BCTT.S109847

38.??van Dijk EL, Jaszczyszyn Y, Naquin D, Thermes C. The Third Revolution in Sequencing Technology. Trends Genet. 2018;34(9):666-681. doi:10.1016/j.tig.2018.05.008

39.??Schmidt J, Blessing F, Fimpler L, Wenzel F. Nanopore Sequencing in a Clinical Routine Laboratory: Challenges and Opportunities. Clin Lab. 2020;66(6):10.7754/Clin.Lab.2019.191114. doi:10.7754/Clin.Lab.2019.191114

40.??Ou SI, Nagasaka M, Zhu VW. Liquid Biopsy to Identify Actionable Genomic Alterations. Am Soc Clin Oncol Educ Book. 2018;38:978-997. doi:10.1200/EDBK_199765

41.??Schrock AB, Ouyang C, Sandhu J, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019;30(7):1096-1103. doi:10.1093/annonc/mdz134

42.??Argani P, Erlandson RA, Rosai R. Thymic Neuroblastoma in Adults: Report of Three Cases With Special Emphasis on Its Association With the Syndrome of Inappropriate Secretion of Antidiuretic Hormone, Am J Clin Pathol. 1997; 108: 537–543. https://doi.org/10.1093/ajcp/108.5.537

43.??Gerald WL, Rosai J. Case 2. desmoplastic small cell tumor with divergent differentiation. Pediatr Pathol. 1989; 9: 177-183.

44.??Gerald WL, Miller HK, Battifora H, Miettinen M, Silva EG, Rosai J. Intra-abdominal desmoplastic small round-cell tumor. Report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol. 1991; 15: 499-513

45.??Ladanyi M. In Memoriam; William L. Gerald, M.D., Ph.D., 1954-2008. J Mol Diag. 2009; 11: 1-3. https://doi.org/10.2353/jmoldx.2009.080139

46.??https://www.globenewswire.com/news-release/2014/02/27/614151/10070506/en/ARUP-Laboratories-Introduces-New-Medical-Director-Dr-Juan-Rosai-at-USCAP-2014.html

47. https://www.britannica.com/art/leitmotif