Pathology Grand Rounds April 9., 2026: Edi Brogi, MD, PhD

Transcript

• 00:00Good afternoon, everybody. It gives
• 00:02me great pleasure
• 00:03to
• 00:04introduce doctor Eddie Brogi for
• 00:06her,
• 00:08lecture
• 00:09on
• 00:10the WHO six breast tumors
• 00:12classification,
• 00:13what's new and noteworthy
• 00:15for the pathology grand rounds.
• 00:17And she's internationally
• 00:19very well known to all
• 00:20the people
• 00:21practicing breast pathology, needs no
• 00:23introduction. I'll keep it brief.
• 00:26Doctor Brodie got her, she's
• 00:28currently director of the breast
• 00:30pathology service in Memorial Sloan
• 00:32Kettering Cancer Center and has
• 00:34been the director there for
• 00:36close to twenty years.
• 00:38And she got her MD
• 00:39from the University of Florence
• 00:40in Italy
• 00:42and then,
• 00:44completed her PhD
• 00:45from the Italian Ministry of
• 00:48University and Research,
• 00:49and she then moved to
• 00:51Boston where she was a
• 00:52postdoctoral fellow
• 00:54and then,
• 00:55did her residency in anatomic
• 00:57pathology
• 00:58at
• 00:59MGH and followed by a
• 01:01fellowship in cytopathology
• 01:03and then moved as an
• 01:05attending to MIMO MSKCC
• 01:07in two thousand from where
• 01:09she's been there and is
• 01:10now professor
• 01:11in,
• 01:12Cornell Medical College.
• 01:14And
• 01:15she she received an award
• 01:17for her graduation thesis,
• 01:20during her MD and more
• 01:21recently got the Larry Norton
• 01:23excellence in pathology award by
• 01:25the International Society of pet
• 01:28breast pathology.
• 01:29I'm not listing all the
• 01:31awards. This is just the
• 01:32top. And then she has,
• 01:34been a CME,
• 01:36course director for the breast
• 01:38section of the surgical pathology
• 01:40of neoplastic diseases offered by
• 01:43MSKCC
• 01:43every year, and this has
• 01:45been for decades. And she
• 01:47served as president
• 01:48of the International Society of
• 01:50Breast Pathology, served on ASCAP
• 01:53and other leading societies,
• 01:55and
• 01:57authored more than two hundred
• 01:58peer reviewed publication
• 02:01publications,
• 02:02chapters, book chapters, reviews,
• 02:05mentored
• 02:06multi multiple
• 02:09fellows in breast, including our
• 02:11own faculty,
• 02:12doctor Lorraine
• 02:13Kronkartegena.
• 02:15And,
• 02:17and
• 02:18she's on the editorial she's
• 02:20an editorial board member of
• 02:22the WHO
• 02:23classification of breast tumors, the
• 02:25fifth and the sixth edition.
• 02:26So without further ado, I
• 02:28will
• 02:29hand it over to you.
• 02:35Good afternoon, everyone. Thank you
• 02:37very much, doctor Krishnamurti for
• 02:39the kind introduction. It's a
• 02:41pleasure to be here with
• 02:42you today,
• 02:44and I had a great
• 02:45morning. I spent interacting with
• 02:47the the staff, the residents,
• 02:51reviewing cases. It's really a
• 02:52very dynamic
• 02:54breast pathology
• 02:55service and I really enjoyed
• 02:58and it's nice to meet
• 02:59friends, make new ones. So
• 03:01I'm really happy to be
• 03:02here.
• 03:04My topic
• 03:05is,
• 03:06on the educational
• 03:08side, very focused on breast
• 03:10pathology,
• 03:11of course.
• 03:13And, I, as you all
• 03:14know, why do we need
• 03:22nomenclature that can be adopted
• 03:24worldwide,
• 03:25is evidence based, provides a
• 03:27standardized framework to for categorization
• 03:30of tumors
• 03:32so that everybody can render
• 03:34the right diagnosis
• 03:36using a similar terminology.
• 03:39Therefore,
• 03:40we can guide the therapeutic
• 03:41strategies,
• 03:42inform research,
• 03:45and enable also the precise
• 03:48epidemiological
• 03:49data collection,
• 03:51by cancer registries.
• 03:53In fact, in this
• 03:55optic,
• 03:56the sixth edition series differs
• 03:58from the prior because obviously
• 04:00it provides update, but also
• 04:02has included oncology,
• 04:04radiology, molecular,
• 04:06genetics,
• 04:07expert. And
• 04:08also
• 04:09as included the pathologists
• 04:12that practice in low and
• 04:13middle
• 04:14income countries
• 04:15so that, it can really
• 04:17be used, you know, the
• 04:19classification can be really,
• 04:23used worldwide
• 04:24and,
• 04:26contribute
• 04:26to the management of patients
• 04:29all over the world.
• 04:30This is the first picture
• 04:32that was taken when we
• 04:34first met for the first
• 04:35editorial board meeting in October
• 04:37second.
• 04:38On October second twenty twenty
• 04:40four in Lyon, France. There
• 04:42was a subsequent
• 04:44in person meeting in February.
• 04:46During this time, October to
• 04:48February,
• 04:49we were supposed to revise
• 04:51and rewrite
• 04:52the WHO classification.
• 04:54It was an intense
• 04:55writing and rewriting period.
• 04:59The classification is not out
• 05:01yet because after we met
• 05:03the second time,
• 05:05we also had to discuss
• 05:07a few points,
• 05:08but I think it will
• 05:09be published hopefully this year,
• 05:12very soon this year.
• 05:15And,
• 05:16what is different compared to
• 05:18the prior classification?
• 05:19Well, first of all, there
• 05:21is a lot of preparatory
• 05:23work that went into,
• 05:25this classification.
• 05:27And there were many subcommittees
• 05:29that met
• 05:30that dealt with the specific,
• 05:32points
• 05:33that could facilitate a more
• 05:35precise classification.
• 05:37I was also member of
• 05:39the two more clarification
• 05:40and refining
• 05:42committee. So we all had
• 05:43a preparatory
• 05:44work. We met many times
• 05:46online.
• 05:47So to identify
• 05:49specific
• 05:51that
• 05:52needed to be
• 05:54addressed
• 05:55by the upcoming
• 05:56classification.
• 05:58And of course, everything had
• 05:59to be evidence based. Basically,
• 06:01I think. These are the
• 06:02various chapters in the
• 06:05classification. I don't know. Someone
• 06:07is probably I understand.
• 06:09Can you please mute your
• 06:10butt your microphone? Thank you.
• 06:13Thank you so much.
• 06:15And, these are the various
• 06:18chapters in the upcoming classification.
• 06:20So I'll focus on comparing
• 06:23what is different and new
• 06:24and noteworthy
• 06:25between the fourth and the
• 06:27sixth edition.
• 06:28Of course, I cannot,
• 06:30discuss all the various changes
• 06:32because
• 06:33it would take not one
• 06:34hour but maybe one month,
• 06:36but I'll focus on some
• 06:38specific information.
• 06:40First of all, the general
• 06:41introduction that was extremely long
• 06:43in the original
• 06:44In the fifth edition has
• 06:46been shortened
• 06:47and the the information that
• 06:49pertains to specific tumor has
• 06:50been included in small introduction
• 06:53in each tumor specific chapter.
• 06:56There is a section also
• 06:57known small diagnostic
• 06:59sample, fine needle aspiration,
• 07:00core needle biopsy,
• 07:02how,
• 07:03it should be reported. They
• 07:05should be reported
• 07:07with a standardized
• 07:08system. In particular, there is
• 07:10an emphasis on the b
• 07:12coding system that is used
• 07:14in the UK
• 07:15mainly for categorizing
• 07:17breast corneal biopsy finding,
• 07:20emphasis on the clinical
• 07:22triple assessment,
• 07:23combining ideology, pathology, and also
• 07:26clinical interpretation.
• 07:28And there is an information
• 07:30about the use of digital
• 07:32pathology and artificial intelligence
• 07:34that is really coming up
• 07:36on on the horizon
• 07:38in many departments.
• 07:40Then the section on epithelial
• 07:43tumor has been split into
• 07:44two parts. The first part
• 07:46basically deals with the,
• 07:50all intraductal
• 07:51proliferation ranging from benign
• 07:54to malignant,
• 07:55the DCIS.
• 07:56And then in this section,
• 07:58there are also
• 07:59epithelial, my epithelial tumors that
• 08:01can be invasive
• 08:02and also some papillary neoplasm
• 08:05that can be invasive. So
• 08:06not everything
• 08:08in this
• 08:09part,
• 08:10one is really
• 08:12within the dots.
• 08:14I'll start with adenomyopiteloma,
• 08:16malignant adenomyopiteloma.
• 08:19They are included in the
• 08:20section on epithelial and myepithelial
• 08:23tumors. As you all know,
• 08:24adenoid cystic carcinoma is also
• 08:26an epithelial myepithelial carcinoma, but
• 08:28is discussed
• 08:30under rare and salivary gland
• 08:31type tumors.
• 08:33There was, you know, adenomy
• 08:35epithelioma from a histopathology
• 08:37point of view, where low
• 08:38power has typically this multilobulated
• 08:41contour with central sclerotic area,
• 08:43fibrous septae.
• 08:45The WHO six edition,
• 08:47group,
• 08:49has agreed that finding small
• 08:51satellite
• 08:52nodules
• 08:53at the periphery of the
• 08:55main tumor should not be
• 08:56over interpreted
• 08:58as indicative of malignancy.
• 09:00So you can find the
• 09:01smaller nodules
• 09:03at the periphery of the
• 09:04tumor. This is a tumor
• 09:06that is
• 09:08composed of two cell layers
• 09:11forming tightly just opposed to
• 09:14small glands. So the epithelial
• 09:15cells align the glands. The
• 09:17my epithelial cells form the
• 09:19outer cell layer. The epithelium
• 09:21often has apocrine feature, may
• 09:23show focal sebaceous or squamous
• 09:26metaplasia.
• 09:27Focal myxoid stroma is possible.
• 09:29Actually, we saw a case
• 09:31today,
• 09:32this morning,
• 09:33that had extensive
• 09:34myxoid
• 09:35stroma
• 09:36and almost mimicked pleomorphic
• 09:38adenoma. And that was actually
• 09:40the differential diagnosis, but was
• 09:42in adenomyopithelioma.
• 09:44The my epithelial cells are
• 09:45actually the most
• 09:47important cells in another myepithelioma,
• 09:50and they can have a
• 09:51variety of morphologic
• 09:53appearances,
• 09:54clears
• 09:55glycogen rich cytoplasm,
• 09:58spindle so prominent that they
• 10:00can mask the,
• 10:02glandular component, can look myoid
• 10:05or plasmacytoid.
• 10:07Adenomy epithelioma was first described
• 10:09in nineteen seventy by Herwig
• 10:12Hamper, a very stern looking
• 10:15German pathologist.
• 10:16Other pathologists
• 10:17wrote about adenomy epithelial lesions
• 10:20in the late,
• 10:22eighties,
• 10:23early nineties.
• 10:25But the first mention of
• 10:26adenomy epithelioma
• 10:28was only in the third
• 10:29edition of the WHO classification,
• 10:33blue book in two thousand
• 10:35and three where it was
• 10:36included in the chapter on
• 10:38my epithelial tumors.
• 10:40In the fourth edition, it
• 10:41had a dedicated chapter but
• 10:43both adenomyopiteloma
• 10:45and malignant
• 10:46adenomyopiteloma
• 10:48or as it was called,
• 10:49adenomyopiteloma
• 10:50with carcinoma
• 10:51were described together in just
• 10:53one
• 10:54chapter, and it was difficult
• 10:56to keep them apart.
• 10:57In the ninth in the
• 10:59fifth edition two thousand nineteen,
• 11:01they were separated. Each one
• 11:03gets its own chapter.
• 11:04Adenomy epithelioma
• 11:06is classified as classic adenomyopathyloma.
• 11:09It's recognized that it can
• 11:11be mitotically active and difficult
• 11:13to distinguish from, a malignant
• 11:16adenomyopathyloma.
• 11:17And also that there are
• 11:19reports that it can be
• 11:20occasionally metastatic
• 11:22even though it looks totally,
• 11:25benign appearing.
• 11:26And
• 11:27it was suggested that maybe
• 11:29it should be regarded as
• 11:30a neoplasm of low malignant
• 11:33potential.
• 11:33For malignant adenomyepithelioma,
• 11:36it was defined as adenomyepithelioma
• 11:38with carcinoma.
• 11:40The malignancy could arise from
• 11:42epithelium, my epithelial or
• 11:44both components.
• 11:46And if both components were
• 11:47malignant,
• 11:48one could use the term
• 11:50epithelial my epithelial carcinoma.
• 11:53There was also information about,
• 11:55the molecular activation. I'll come
• 11:57back to that later. And
• 11:59it was indicated that staging
• 12:01should be according to the
• 12:02invasive component.
• 12:04Now all these diagnostic criteria
• 12:06in the fifth edition were
• 12:08interesting,
• 12:09but nothing was precisely specified.
• 12:12And really how did we
• 12:13go from adenomyopathy
• 12:15to a malignant adenomyopathy?
• 12:17There was a missing link
• 12:19of atypical adenomyopathy.
• 12:22A group led by Doctor.
• 12:24Ima Dragaka, a very famous
• 12:26and very productive breast pathologist,
• 12:29proposed
• 12:30a new classification
• 12:31in twenty twenty one where
• 12:33they classified
• 12:34adenomyopathy leoma into benign, atypical
• 12:37and malignant,
• 12:38including a malignant
• 12:40in situ
• 12:42and invasive
• 12:45carcinoma arising
• 12:47in adenomyopithelioma.
• 12:50This classification
• 12:52actually separated nicely atypical and
• 12:54malignant
• 12:55and actually provided the cutoff
• 12:58for mitotic activity that the
• 13:00author suggested should be only
• 13:03in the my epithelial cells.
• 13:05We thought very hard about
• 13:08adopting this classification
• 13:10for in the sixth edition
• 13:12of the WHO book,
• 13:15but,
• 13:16did not,
• 13:18eventually
• 13:18decided that there was not
• 13:20enough evidence to support
• 13:22the use of a classification
• 13:24that was not yet validated.
• 13:26And so it has,
• 13:28we haven't changed anything.
• 13:30And we still have classic
• 13:32adenomyopiteloma
• 13:34and malignant adenomyopiteloma.
• 13:36However, the classic is now
• 13:38subdivided
• 13:39into benign, that is,
• 13:41has no atypia, no necrosis
• 13:43up to one point five
• 13:44mitosis per square millimeter
• 13:47or three in ten high
• 13:48power fields.
• 13:50And then,
• 13:51there is an atypical adenomyepithelioma
• 13:53that will have mild to
• 13:55moderate atypia in epithelium, my
• 13:57epithelium or both.
• 13:59Can have more mitosis up
• 14:01to two point five per
• 14:02square millimeters.
• 14:04Can have focal necrosis.
• 14:06Can also have a substantial
• 14:08epithelial atypia
• 14:09in so much that you
• 14:11can diagnose DCIS in adenoma
• 14:14epithelioma.
• 14:15Our recommendation has been that
• 14:17you should be reported as
• 14:18such and managed as DCIS.
• 14:21And there are also some
• 14:22rare reports of atypical AME
• 14:26developing lymph node metastasis.
• 14:28But at this point, there
• 14:29is no routine recommendation for
• 14:31sentinel lymph node biopsy.
• 14:33Here is an example of
• 14:35an atypical adenomyepithelioma
• 14:37with mild to moderate atypia
• 14:39in epithelium, my epithelium or
• 14:41both.
• 14:42And also it has been
• 14:43noted that, adenomyopiteloma
• 14:46have an unusual staining pattern.
• 14:49High molecular weight cytokeratin
• 14:51will stain, paradoxically,
• 14:53the luminal cells of the
• 14:55gland and not the myoepithelial
• 14:58cells
• 14:58while the myoepithelial
• 15:00markers can stain variably different
• 15:02parts of the tumor that
• 15:04nonetheless look myoepithelial.
• 15:07So there is a discrepancy
• 15:09there.
• 15:10If we have an atypical
• 15:12adenomyopathy loma, how do we
• 15:13separate from a malignant adenomyopathy
• 15:16loma? You can still find
• 15:17a typical, if you find
• 15:18a typical mitosis in an
• 15:20atypical adenomyopathy
• 15:21loma, of course, there is
• 15:23a high level of suspicion
• 15:25for malignant transformation.
• 15:27But, mitotically
• 15:29active adenomy epithelioma that have
• 15:31some also cytological tibia can
• 15:33be difficult to separate
• 15:35still,
• 15:37with a new criteria
• 15:39difficult to separate from a
• 15:40malignant adenomy epithelioma.
• 15:42And if you have an
• 15:43AME with mild to moderate
• 15:45cytological tpia or as many
• 15:47as two point five mitosis
• 15:49per square millimeter,
• 15:51then, you don't have other
• 15:53features of malignancy,
• 15:55then you can still call
• 15:56it atypical adenoma epithelioma.
• 15:59The main differential diagnosis of
• 16:01adenoma epithelioma
• 16:03listed here, touch on two.
• 16:05One is intraductal papilloma
• 16:07that morphologically
• 16:08looks very similar to adenomyopiteloma,
• 16:11can have areas with prominent
• 16:14my epithelial
• 16:15cells very
• 16:18evident throughout the glance
• 16:20but it's definitely in an
• 16:22excision specimen will be entirely
• 16:24confined within a duct while
• 16:26AME is going to be
• 16:28a more solid proliferation
• 16:30within nodular proliferation
• 16:32within,
• 16:33the breast parenchyma.
• 16:35Nonetheless, it can be difficult
• 16:37to separate the two in
• 16:38a core biopsy.
• 16:40And, in the core biopsy,
• 16:41actually this differential had substantial
• 16:44management implication. At our institution,
• 16:46for example, we no longer
• 16:48excise red path concordant papillomas,
• 16:51diagnose on cord, needle biopsy,
• 16:54while a classic AME always
• 16:57needs to be excised.
• 16:59The recommendation is to look
• 17:01at the my epithelial
• 17:02cells.
• 17:03If they are more numerous,
• 17:05plumper, larger,
• 17:06then you're dealing with an
• 17:08adenomyopithelioma
• 17:09rather than in interductor papilloma
• 17:12or a normal lobules or
• 17:13nodular adenosis.
• 17:14So this is easier said
• 17:16than done. And I say,
• 17:17I still find it
• 17:19quite challenging.
• 17:20Yeah. The differential is a
• 17:22typical AME with adenoid cystic
• 17:25carcinoma of conventional morphology
• 17:27because you can still have
• 17:29CD one seventeen positivity,
• 17:32focal MIB positivity.
• 17:33However, there is no MIB
• 17:35amplification
• 17:36in these tumors
• 17:37and in particular
• 17:39this one,
• 17:40this tumor that looks,
• 17:42could be interpreted as adenoid
• 17:45cystic carcinoma
• 17:46actually harbored
• 17:48a typical,
• 17:49HGAS Q61R
• 17:51mutation
• 17:52that is regarded as diagnostic
• 17:54of adenoma epithelioma. So a
• 17:56lot of overlap.
• 17:58And, but the staining for
• 18:00MIB tends to be very,
• 18:02very focal in
• 18:04AME. And, if you do
• 18:06molecular,
• 18:08study, you will not find
• 18:10MIB amplification.
• 18:12In terms of behavior,
• 18:14AME usually has a benign
• 18:16clinical course and surgical excision
• 18:18is curative.
• 18:19It may record locally if
• 18:21there are satellite nodules or
• 18:23a prominent intraductor papillary component.
• 18:27But, these done METs from
• 18:29an AME that didn't have
• 18:31any atypia or increased cell
• 18:33proliferation
• 18:34have been reported.
• 18:35And, for that reason, the
• 18:37WHO recommends
• 18:39that, classic AME
• 18:41is best regarded not truly
• 18:43as a benign entity
• 18:45but a neoplasm of uncertain
• 18:47malignant potential.
• 18:50For malignant adenoma epithelioma,
• 18:52it is defined as AME
• 18:55with carcinoma.
• 18:56And And again, the malignancy
• 18:57may arise from epithelium, my
• 18:59epithelium or both.
• 19:01It used to be called
• 19:02epithelio my epithelial carcinoma,
• 19:04not anymore. That terminology
• 19:06has been eliminated
• 19:08as well as adenomyepithelial
• 19:10carcinoma. You can call it
• 19:12AME with invasive carcinoma.
• 19:15In these cases,
• 19:16you should
• 19:17be still be able to
• 19:18recognize the underlying
• 19:21adenomyopithelial
• 19:22tumor
• 19:23on with in addition, there
• 19:25will be cytological
• 19:26tibia, mitosis, necrosis in the
• 19:29malignant component.
• 19:31When you have a malignant
• 19:32transformation
• 19:33predominantly
• 19:34in the epithelial component,
• 19:36you may get an invasive
• 19:38breast carcinoma
• 19:39of no special type or
• 19:40other special types including globular.
• 19:43If the malignant transformation
• 19:45affects the my epithelial component,
• 19:48then you have overgrowth of
• 19:50spindle epithelioid, my epithelial cells
• 19:53with nuclear gatipia and mitosis.
• 19:56Not uncommonly, actually, the invasive
• 19:58carcinoma that arises
• 20:00in
• 20:01adenoma epithelioma
• 20:02is a metaplastic
• 20:03carcinoma. Spindle cell,
• 20:05squamous cell, logated adenosquamous
• 20:08matrix producing
• 20:09have all been reported.
• 20:11And in these cases,
• 20:13you should sample the tumor
• 20:15and see if you can
• 20:16identify an AME component.
• 20:19And, in terms of staging,
• 20:21you report the size of
• 20:23the invasive component.
• 20:25Here example of a metaplastic
• 20:27spindle cell carcinoma arising in
• 20:29an adenoma epithelioma.
• 20:31And here is a fibromatosis
• 20:33like carcinoma also arising in
• 20:36an adenoma epithelioma.
• 20:38From a genetic
• 20:40standpoint of view, these lesions,
• 20:43they seem to vary depending
• 20:45on the ER status. The
• 20:47ER positive tumors, adenomy epithelioma,
• 20:50tend to have PIK3CA
• 20:51or AKT1
• 20:53mutations
• 20:54similar to those, hotspot mutation
• 20:57you find in papillomas.
• 21:00While the ER negative or
• 21:02ER low adenomyopathy
• 21:04leomas
• 21:05tend to harbor an HRASQ61,
• 21:09mutation
• 21:10combined with PIK3CA
• 21:12and they may have also
• 21:14homozygous deletion of CDK
• 21:17N2A
• 21:18that encodes P16.
• 21:20And it seems that actually
• 21:22this is how
• 21:25from this second group of
• 21:26ER negative tumors, we have
• 21:28the development of the malignant
• 21:30adenoma epithelioma
• 21:32that are usually triple negative
• 21:34and harbor the same molecular
• 21:35alteration
• 21:38as the atypical
• 21:39ER negative adenomy epithelioma.
• 21:42Other mutations
• 21:43in HRSA have also been
• 21:45reported both in atypical and
• 21:47malignant adenomy epithelioma.
• 21:49There is only one case
• 21:51where the same gain of
• 21:52function of AKT1
• 21:53variant was found
• 21:55in AME and malignant
• 21:57AME. So this would be
• 21:58an exception.
• 22:00In general, AKT1 mutation are
• 22:02more in keeping with
• 22:04benign
• 22:05ER positive adenomyopiteloma
• 22:07or intraductor papilloma. Maybe the
• 22:10two are the same thing.
• 22:11Right?
• 22:12And then,
• 22:13p fifty three mutations
• 22:15are generally not observed. There
• 22:17is only one case report.
• 22:19And there are no BB
• 22:20two u amplification,
• 22:22at least in a series
• 22:24from our institution of forty
• 22:26two cases.
• 22:27And actually, if you have
• 22:29there is an immunoistochemical
• 22:33stain that can be used
• 22:34to detect the HRS q
• 22:36sixty one
• 22:37R mutated
• 22:39altered protein
• 22:40and it's positive only in
• 22:42the tumor that harbor this
• 22:44alteration
• 22:46and not,
• 22:48you know, it's negative only
• 22:49in the tumor with this
• 22:50alteration,
• 22:51well, it will,
• 22:53I am sorry. It's,
• 22:55it doesn't stain tumors that
• 22:57do not have the mutation,
• 22:59but it stains only the
• 23:01tumors
• 23:02that harbor this alteration. So
• 23:03alteration. So it has a
• 23:05possible diagnostic
• 23:07value, but it's
• 23:08probably present in fifty to
• 23:10sixty percent of, malignant
• 23:12adenomyopithelioma.
• 23:13So it's not that frequently,
• 23:17positive.
• 23:18The other entity that has
• 23:20been discussed
• 23:21and somewhat modified is encapsulated
• 23:24papillary carcinoma together with invasive
• 23:26papillary carcinoma.
• 23:28Encapsulated papillary carcinoma typically occur
• 23:31in postmenopausal
• 23:33women, usually in the seventh
• 23:34decade,
• 23:35and can present with a
• 23:37nipple discharge,
• 23:38typically forms this silk inscribed
• 23:41greater or subariolar mass
• 23:43that is solid and cystic,
• 23:46by ultrasound.
• 23:47And, it's characterized by the
• 23:49absence
• 23:50of my epithelial cells all
• 23:52throughout the tumor and most
• 23:54importantly,
• 23:55around the tumor at the
• 23:57interface with the normal breast
• 23:59cancer and chemo. Therefore,
• 24:01technically speaking, this is an
• 24:03invasive carcinoma but it has
• 24:05a very blunt
• 24:07front of invasion
• 24:09and clinically behaves in a
• 24:11very
• 24:12indolent manner.
• 24:14So to, it's important in
• 24:16these cases to sample extensively
• 24:18the periphery of the tumor
• 24:19with a rim of adjacent
• 24:21tissue
• 24:21because sometimes you may find
• 24:23outside the encapsulated papillary carcinoma
• 24:27an invasive,
• 24:28frankly invasive component,
• 24:30which is present in about
• 24:31twenty to sixty percent of
• 24:33the cases.
• 24:34Usually, the presence of invasion
• 24:37is unrelated
• 24:38to the size of the
• 24:39EPC,
• 24:40but the majority of these
• 24:42tumors, about seventy percent, are
• 24:43well differentiated invasive ductile. You
• 24:46can find also
• 24:47other special subtypes such as
• 24:49mucinous tubular, invasive cribriform.
• 24:52And the majority are going
• 24:53to be very small tumor,
• 24:55PT1,
• 24:57two PT one a or
• 24:59b,
• 25:00that are ER positive, HER2
• 25:02negative.
• 25:03Now if there is no
• 25:04frank invasion,
• 25:07this tumor for many years
• 25:09was actually
• 25:10regarded and managed as DCIS,
• 25:13not even recognized,
• 25:14classified
• 25:15just as DCIS.
• 25:17And indeed, that's a very
• 25:18good
• 25:19prognosis.
• 25:20And generally speaking, in the
• 25:22absence of invasion,
• 25:24EPC
• 25:25is staged as in cytocarcinoma
• 25:28because
• 25:29as a behavior
• 25:30similar to that of DCIS.
• 25:34When the previous
• 25:35edition of the WHO was
• 25:37published, there was only one
• 25:39series of twelve
• 25:41EPC like carcinomas
• 25:42of high nuclear grade without
• 25:44frank invasion and one of
• 25:46the ten patients with follow-up
• 25:48had died of disease.
• 25:50So at that point,
• 25:51it was decided that the
• 25:53diagnosis
• 25:54of EPC
• 25:55should be restricted to tumors
• 25:57with low or intermediate nuclear
• 25:59grade. And if the EPC
• 26:01like carcinoma had high nuclear
• 26:04grade or HER2 positive,
• 26:07profile,
• 26:08it should be classified as
• 26:09an invasive papillary carcinoma.
• 26:11That is back in twenty
• 26:13nineteen.
• 26:14We fast forward to twenty
• 26:16twenty six, this is no
• 26:18longer true. There is still
• 26:20one series only of EPC
• 26:22like carcinoma of high nuclear
• 26:24grade. And this was thought
• 26:26to be not sufficient evidence
• 26:28to classify
• 26:29EPC like carcinoma of high
• 26:31nuclear grade as invasive.
• 26:34So in the absence of
• 26:35crank invasion, the editorial board
• 26:38recommends that EPC like carcinoma
• 26:40of high nuclear grade of
• 26:42HER2 positive be categorized as
• 26:44EPC
• 26:45and staged as DCIS.
• 26:47Remember, they don't have my
• 26:48epithelial cells
• 26:50with a comment enumerating the
• 26:52unusual features.
• 26:54In these cases,
• 26:55it is recommended to do
• 26:57a thorough histological examination
• 26:59of the specimen
• 27:01and maybe submit additional section
• 27:03to exclude the possibility
• 27:05of a high grade invasive
• 27:06carcinoma
• 27:07with pseudopapillary
• 27:09growth secondary to central necrosis.
• 27:11I have here an example
• 27:13of a case that clearly
• 27:15looks invasive, but it appears
• 27:17that the margin is relatively
• 27:19well circumscribed.
• 27:21It has a papillary architecture
• 27:23secondary
• 27:24to extensive tumor necrosis. So
• 27:27these cases may mimic EPC
• 27:29of high nuclear grade. Beware
• 27:31of these cases.
• 27:33And if you are convinced
• 27:35that you're dealing with an
• 27:36EPC only
• 27:38with high nuclear grade, the
• 27:39patient will be managed and
• 27:41staged and managed as having
• 27:43a DCIS.
• 27:44This remains a controversial
• 27:46issue. We'll see what happens.
• 27:48If there is no definite,
• 27:50DCIS,
• 27:52then it's also important in
• 27:53these cases to rule out
• 27:55metastasis
• 27:56and metastatic carcinoma from another
• 27:58site. You can use,
• 28:00epithelial,
• 28:01you know,
• 28:02breast specific markers such as
• 28:04GATA, SOGSTANT, TRPS1
• 28:06in the appropriate
• 28:08panel to demonstrate that the
• 28:10tumor is indeed of breast
• 28:11origin.
• 28:13The second section on epithelial
• 28:15tumors deals with a variety
• 28:17of issue. Nuclear pleomorphism
• 28:20is always a question
• 28:22how,
• 28:23what's the minimum proportion of
• 28:25tumor nuclei
• 28:26that should be,
• 28:28should show marked nuclear tibia
• 28:30before score three is allocated.
• 28:33This remains not well defined
• 28:35and finding an occasional and
• 28:37larger bizarre nucleus should not
• 28:39be used to give a
• 28:41score three rather than a
• 28:42score two.
• 28:45Tumor infiltrating lymphocytes,
• 28:47it is recognized that they
• 28:49can be prognostically,
• 28:52can be incorporated in the
• 28:53pathology report as prognostic
• 28:55factor, but there is no
• 28:58mandate
• 28:58to do so.
• 29:00And,
• 29:01if you want to report
• 29:02TEOS, use use the the
• 29:04standardized
• 29:06protocol by the International
• 29:08Biomarket Working Group on Breast
• 29:09Cancer.
• 29:10For HER2, it is recognized,
• 29:13same as the CAP guidelines,
• 29:16that, HER2 can be three
• 29:18plus, two plus, one plus,
• 29:19and then zero or zero
• 29:21plus.
• 29:22That should be reported. It's
• 29:23not necessary to say low
• 29:26and ultra low terminology.
• 29:28And basically we are all
• 29:30pretty much used to this
• 29:32by now, right?
• 29:33One big change I think
• 29:35is regards microinvasive
• 29:37carcinoma. It's still defined as
• 29:39invasive breast carcinoma
• 29:40less up to one millimeter
• 29:42in size,
• 29:43But it has been decided
• 29:45that if they are closely
• 29:46associated,
• 29:47the foci of micro invasion,
• 29:49that are
• 29:51within the five millimeter
• 29:53range, they should be submitted
• 29:55and staged according to the
• 29:57overall size.
• 29:59Here is actually an example
• 30:00of a case that we
• 30:01received from an outside institution
• 30:03where there was micro invasion
• 30:05in each of these,
• 30:08TDLUs
• 30:09and, the outside pathologists had
• 30:11reported the four separate foci
• 30:13of microinvasion,
• 30:15but we did span the
• 30:17entire thing and they became
• 30:18four millimeter in size. So
• 30:21this is an application of
• 30:22that rule. Let's see how
• 30:25will that
• 30:26adopt because many times the
• 30:28amount of microinvasive
• 30:30carcinoma is very, very scant.
• 30:32So we'll see how it
• 30:34goes.
• 30:35Invasive lobular
• 30:36should be graded based on
• 30:38Nottingham grading system.
• 30:40We also have to report
• 30:41the cytomorphology,
• 30:43the architectural
• 30:44patterns,
• 30:45as mentioned here.
• 30:47The patterns can be classic,
• 30:49trabecular,
• 30:50solid, alveolar.
• 30:52There is also a recent
• 30:54variation,
• 30:55that of the solid pattern
• 30:56that is solid papillary
• 30:59that should,
• 31:00be recognized to avoid confusion
• 31:03with other papillary lesions.
• 31:05The new kid on the
• 31:06block is ILC with extracellular
• 31:08mucin
• 31:09that has recently been described,
• 31:12is often associated with lymphoid
• 31:14metastasis,
• 31:16and often has features unusual
• 31:18for invasive lobula. Grade three,
• 31:20tumor necrosis,
• 31:21HER2 positivity.
• 31:23And, also the extracellular
• 31:25mucin may be focal,
• 31:27but it should be,
• 31:29separated.
• 31:30It has a poor prognosis,
• 31:32so it should be separated
• 31:33from true mucinous
• 31:35carcinoma that has a favorable
• 31:37prognosis.
• 31:38There is some nomenclature
• 31:40issue related to tubulobular
• 31:42carcinoma. A term that I
• 31:43personally rarely use because I
• 31:46find it very,
• 31:48you know,
• 31:49ambiguous.
• 31:50In the past has been
• 31:51used for tumors with combined
• 31:53invasive lobular and small
• 31:55well formed glands morphology.
• 31:58There was a suggestion to
• 31:59say, okay, let's do icadigin.
• 32:01Icadigin
• 32:02positive, we call it docile.
• 32:04Icadirin negative, we call it
• 32:05lobula. There is no evidence
• 32:07to support that. At present,
• 32:09it is recommended to call
• 32:11it tubular lobula
• 32:13if there is no icadirin
• 32:14expression. But if you have
• 32:16a mix invasive lobula and
• 32:18tubular carcinoma,
• 32:20then they,
• 32:22you call it as such
• 32:23if the invasive lobular elements
• 32:25are icadigin negative and those
• 32:28that look more tubular are
• 32:29icadigin positive. I'm not sure
• 32:32how much this helps but
• 32:34the invasive cribriform carcinoma
• 32:36needs to be called as
• 32:38such invasive to avoid confusion
• 32:40with cribriform
• 32:42carcinoma.
• 32:44Mucinous carcinoma
• 32:45has been,
• 32:47is defined as having low
• 32:49to intermediate nuclear grade
• 32:51and it needs to be
• 32:52ER positive, HER2 negative
• 32:55or composed of this, cluster
• 32:57of epithelial cells floating in
• 32:59mucin.
• 33:00Should not be confused with
• 33:01the cancer with
• 33:03mucin,
• 33:04but high nuclear grade or
• 33:06HER2 positivity
• 33:07because those tend to have
• 33:09a more aggressive behavior.
• 33:10Shouldn't be confused with the
• 33:11mediplastic carcinoma with chondromicoid
• 33:14matrix that is going to
• 33:16be negative
• 33:17and not to be confused
• 33:19with ILC with extracellular
• 33:21amusing that also has a
• 33:23worse prognosis.
• 33:25A clinic cell carcinoma
• 33:27has been renamed as a
• 33:29clinic cell like carcinoma because
• 33:31in the breast, the so
• 33:33called synic cell carcinoma does
• 33:35not have the molecular activation
• 33:38that are characteristic
• 33:40of a synic cell carcinoma
• 33:41of salivary gland and pancreas.
• 33:44Actually looks more like,
• 33:46triple negative carcinoma
• 33:48and, or
• 33:50especially the carcinoma rising
• 33:52in association with MGA.
• 33:54Polymorphous,
• 33:56adenocarcinoma
• 33:57was there for many additions,
• 33:59but has finally been removed.
• 34:01There are, like, five or
• 34:03six cases reported all by
• 34:05the same people, and there
• 34:06is not enough evidence that
• 34:08this is a tumor that
• 34:09does exist.
• 34:11An issue is regarding
• 34:13neuroendocrine
• 34:14neoplasms.
• 34:16And,
• 34:17you know, they show breast
• 34:18cancer and neuroendocrine
• 34:19differentiation has been debated for
• 34:21many years. In nineteen sixty
• 34:23three,
• 34:24neuroendocrine
• 34:25differentiation in breast cancer was
• 34:27first described by two German
• 34:29pathologists again.
• 34:31In nineteen seventy seven, two
• 34:33pathologists from Memorial Sloan Kettering,
• 34:35Doctor. Woodruff and Kubila,
• 34:38report described the so called
• 34:40primary carcinoid tumor of the
• 34:42breast.
• 34:43This was a very debated
• 34:45publication.
• 34:46And at the time, neuroendocrine
• 34:48differentiation
• 34:49was at first demonstrated
• 34:51using silver stain and
• 34:54EM and neurosecretory
• 34:56granules.
• 34:56After eighty five, immunohistochemistry
• 34:59for neuroendocrine
• 35:00markers was introduced,
• 35:02chromo, synapto.
• 35:03But really, this was a
• 35:05very nebulous
• 35:07type of,
• 35:08topic.
• 35:10It was only in two
• 35:11thousand and three, the third
• 35:13edition of the WHO, that
• 35:15the neuroendocrine tumors
• 35:17were first,
• 35:19recognized
• 35:20to occur in the breast.
• 35:21They have morphology
• 35:23similar to
• 35:24neuroendocrine
• 35:25tumors
• 35:26in GI,
• 35:27tract, and lung.
• 35:28And they it was,
• 35:31they were supposed to express
• 35:32neuroendocrine
• 35:33marker
• 35:34in greater than fifty percent
• 35:35of the cells.
• 35:37And,
• 35:38although there was evidence that
• 35:40the neuroendocrine differentiation
• 35:42was present also in other
• 35:44invasive breast carcinoma, they were
• 35:46classified as solid neuroendocrine carcinoma,
• 35:49small cell carcinoma, large cell
• 35:51carcinoma.
• 35:53In twenty twelve, fourth edition
• 35:56of the WHO classification,
• 35:59they are still similar to
• 36:01the
• 36:01GI tract and lung tumors.
• 36:04They express neuroendocrine
• 36:06market to a greater or
• 36:07lesser degree. It's not given
• 36:09a specific cutoff.
• 36:11And,
• 36:12also this
• 36:14designation
• 36:14of neuroendocrine
• 36:15features
• 36:16in carcinoma with neuroendocrine features
• 36:19included
• 36:20the new
• 36:21carcinomas
• 36:22with very specific
• 36:23morphology
• 36:25such
• 36:26as mucinous and solid papillary
• 36:28carcinoma that showed the neuroendocrine
• 36:30differentiation.
• 36:31And then we move on,
• 36:34to twenty eighteen
• 36:36when, there was an effort
• 36:38to harmonize
• 36:39the nomenclature
• 36:41of neuroendocrine
• 36:42neoplasm
• 36:43across organ systems. So a
• 36:45group was convened,
• 36:47a group of experts convened,
• 36:49and they agreed to classify
• 36:51neuroendocrine
• 36:52neoplasm
• 36:53throughout the body as well
• 36:55or poorly differentiated
• 36:57using the terminology that is
• 36:58used for pulmonary and gastrointestinal
• 37:01neuroendocrine
• 37:02neoplasm.
• 37:03This was adapted to the
• 37:04breast. So in the twenty
• 37:06nineteen
• 37:08WHO book,
• 37:09neuroendocrine
• 37:10neoplasm
• 37:11were separated from invasive breast
• 37:13cancer with neuroendocrine
• 37:15features
• 37:17that had less than ninety
• 37:19percent,
• 37:21neuroendocrine
• 37:21marker expression.
• 37:24And,
• 37:25the tumors
• 37:26that were regarded as neuroendocrine
• 37:28neoplasm
• 37:30had more than
• 37:31ninety percent neuroendocrine
• 37:33differentiation,
• 37:34excluding
• 37:35solid papillari,
• 37:37and mucinous carcinoma.
• 37:39They were classified as neuroendocrine
• 37:41tumor carcinoma,
• 37:43small cell carcinoma, or large
• 37:45cell neuroendocrine
• 37:46carcinoma.
• 37:47However,
• 37:49time passes and we recognize
• 37:51there are limitations
• 37:53to this classification.
• 37:54First of all, nobody has
• 37:56ever demonstrated the existence
• 37:58of benign neuroendocrine
• 37:59cells in the breast.
• 38:02There are many new neuroendocrine
• 38:04markers. Which one should we
• 38:06use
• 38:07to determine if there is
• 38:08a neuroendocrine
• 38:09differentiation?
• 38:10And what's most important, what
• 38:12is the clinical significance of
• 38:14neuroendocrine
• 38:15differentiation
• 38:16in breast tumors?
• 38:18It's really it remains debated
• 38:21and unknown.
• 38:22And actually, the breast neuroendocrine
• 38:24tumors that have a very
• 38:26low grade usually are
• 38:28quite ER, strongly positive. It
• 38:31can be managed,
• 38:32accordingly.
• 38:33And it's really unclear
• 38:35what is the prognostic and
• 38:37treatment implication of neuroendocrine
• 38:39breast carcinomas
• 38:41defined as such. Like a
• 38:43small cell carcinoma at our
• 38:44institution,
• 38:45patient receive
• 38:47platinum based
• 38:48chemotherapy,
• 38:50but
• 38:50not everywhere
• 38:52else, not everywhere in the
• 38:53world. So there is really
• 38:55a lot of uncertainty.
• 38:57So the WHO six edition
• 38:59tried to address these limitations
• 39:02and has proposed
• 39:04the diagnostic
• 39:05algorithm
• 39:06for the identification of invasive
• 39:08breast carcinoma with neuroendocrine
• 39:10morphology.
• 39:11If you have a mucinous
• 39:13or a solid papillary carcinoma
• 39:15or if the tumor is
• 39:16invasive
• 39:17of no special type and
• 39:19is negative for neuroendocrine
• 39:20marker, you call it as
• 39:22such. On the other, and
• 39:23here is an example.
• 39:25This is a solid papillary
• 39:26carcinoma,
• 39:28very strongly positive for ISNM1
• 39:30synapto, much less so for
• 39:32CHROMO. You still call it
• 39:34solid papillary carcinoma
• 39:36regardless of neuroendocrine
• 39:38markers. You don't even need
• 39:39to do them.
• 39:41On the other end of
• 39:41the spectrum, if you have
• 39:43a small cell carcinoma,
• 39:44then you can call it
• 39:45as such. This is exceptionally
• 39:48rare as a pure entity.
• 39:50Metastasis
• 39:51from the lung should be
• 39:52ruled out,
• 39:53but sometimes it can coexist
• 39:56as a component
• 39:58associated with an invasive breast
• 40:00carcinoma
• 40:01or other morphology.
• 40:02And then there are the
• 40:04tumors in between. Right? You
• 40:06have neuroendocrine differentiation
• 40:09demonstrated
• 40:10by
• 40:11immunosochemical
• 40:12stains with neuroendocrine
• 40:14markers.
• 40:15If it is only focal
• 40:16and weak, just call it
• 40:18invasive
• 40:19breast carcinoma.
• 40:21If it is,
• 40:22a little bit,
• 40:24moderate to strong, so evident,
• 40:27or is diffusely
• 40:29diffuse even though weak but
• 40:31unequivocal,
• 40:33you call it invasive breast
• 40:34carcinoma
• 40:35with neuroendocrine differentiation.
• 40:37And the group of large
• 40:39cell neuroendocrine
• 40:40carcinoma
• 40:41has been moved here.
• 40:43We have some preliminary evidence
• 40:46that maybe
• 40:47there is really a large
• 40:48cell neuroendocrine
• 40:49carcinoma of the breast,
• 40:51but, you know, we haven't
• 40:53published yet. So this is
• 40:55what the WHO
• 40:57is recommending.
• 40:58And then, if you have
• 41:00a typical neuroendocrine
• 41:02morphology
• 41:03and the neuroendocrine
• 41:04marker expression is strong and
• 41:07diffuse,
• 41:08you may be dealing with
• 41:09a true neuroendocrine
• 41:11tumor of the breast, which
• 41:12is going to be exceptionally
• 41:14rare,
• 41:15ER positive. If it is
• 41:17ER negative,
• 41:18consider the possibility
• 41:20of a metastasis
• 41:22and work it up accordingly.
• 41:25So this is the entire
• 41:26diagnostic
• 41:27algorithm.
• 41:29And then, I think I'll
• 41:30conclude talking about phylloidis tumor,
• 41:32another,
• 41:33debated
• 41:34topic.
• 41:35This is a table
• 41:37for the grading of phylloidis
• 41:39tumor according to the fifth
• 41:41edition of the WHO.
• 41:43We were supposed to score
• 41:44two more borders, stromal cellularity
• 41:46at stromal atypia, mitotic activity,
• 41:49stromal overgrowth, and then assess,
• 41:52the presence of malignant at
• 41:54the oligosomelements.
• 41:56And if all those five
• 41:57parameters, tumor borders, stromal cellularity,
• 42:01stromal tibia,
• 42:02mitotic activity,
• 42:04or stromal overgrowth were present
• 42:06end of the malignant
• 42:08level,
• 42:09then we could call the
• 42:10tumor malignant.
• 42:12This approach
• 42:14using the five diagnostic criteria
• 42:16was also endorsed by the
• 42:18cap.
• 42:20If they were malignant
• 42:22elements except well differentiated
• 42:25liposarcoma,
• 42:26then you could still call
• 42:27it a malignant filoides tumor.
• 42:30However, there has been a
• 42:31study from,
• 42:32Emory
• 42:33University
• 42:35where,
• 42:36a group of sixty five
• 42:37malignant filoides tumor
• 42:39were, re reviewed and reclassified
• 42:42using the
• 42:43WHO fifth edition
• 42:45diagnostic
• 42:46criteria
• 42:47and, all margins were negative
• 42:49for phylloidis tumor
• 42:51but
• 42:52with on follow-up twenty patients
• 42:54developed decent metastasis
• 42:57and actually seven
• 42:58died of disease.
• 43:00This is a difficult table
• 43:02to see, a lot of
• 43:03information.
• 43:04The important thing is, you
• 43:05know, not every case had
• 43:07marked stromal atypia.
• 43:09Some had moderate atypia.
• 43:11Some cases,
• 43:12had the majority marked stromal
• 43:14cellularity, but some had moderate
• 43:17stromal cellularity.
• 43:18Not every case had more
• 43:19than ten mitosis per ten
• 43:21amp hour fields.
• 43:23In some cases, there was
• 43:24no stromal overgrowth, meaning
• 43:26not all the features were
• 43:27present in this
• 43:29phylloidous tumor that indeed developed
• 43:33this metastasis
• 43:34proving to be malignant.
• 43:37And also if you look
• 43:38specifically at the seven patients,
• 43:40the filoidous tumor in the
• 43:42seven patients who died of
• 43:43disease,
• 43:44well,
• 43:46they,
• 43:47not all of them had
• 43:48a permeative border. The somal
• 43:50cellularity
• 43:51was not always marked.
• 43:53The same for somal atypia.
• 43:55Mitotic activity, somal overgrowth was
• 43:58also absent.
• 43:59None of these cases had
• 44:01malignant
• 44:02heterologous element.
• 44:03So it was concluded
• 44:04that,
• 44:05you know, these criteria are
• 44:07just too strict,
• 44:08and they need to be
• 44:09redefined.
• 44:11And, actually, the investigators
• 44:14propose
• 44:14a combination
• 44:16of criteria
• 44:17with stromal overgrowth with one
• 44:19of three additional features
• 44:21used to diagnose malignant phylloidis
• 44:24or mark stromal overgrowth
• 44:26with one or more of
• 44:27three additional features listed here
• 44:30to could be used as
• 44:32an alternative.
• 44:33And they use these criteria
• 44:35to reclassify
• 44:37a series of hundred and
• 44:38thirty six filoides tumor borderline
• 44:41and malignant
• 44:42with follow-up information.
• 44:44And they if you use
• 44:46the WHO fifth edition criteria,
• 44:49ninety four of these tumors
• 44:51were classified as borderline, but
• 44:53nearly ten percent developed distant
• 44:55METs. And the malignant
• 44:57forty two cases, fifty percent
• 44:59developed distant METs.
• 45:01While if they used the
• 45:02refined criteria,
• 45:04only the malignant phylloidis tumor
• 45:06developed distant metastasis,
• 45:09in with a metastasis
• 45:11rate of forty percent.
• 45:13There are limitations also to
• 45:15this study.
• 45:16Retoceptive series, multi institutional, probably
• 45:20different,
• 45:21sampling,
• 45:22different treatment.
• 45:24Local recurrence rate in this
• 45:26series was very low compared
• 45:28to the distant metastasis
• 45:30rate that is extremely
• 45:31high. Normally, in malignant phylloidis
• 45:34tumor in other cities,
• 45:36you know, a distant metastasis
• 45:38rate of twenty percent,
• 45:40ten, sixteen percent.
• 45:42But this is extremely
• 45:44high
• 45:45no matter how you look
• 45:46at this. So there are
• 45:48there is some suspicion.
• 45:49However,
• 45:51it was recognized that indeed,
• 45:53these,
• 45:54five criteria are too restrictive
• 45:56and the
• 45:58panel of experts,
• 46:00you know, wrote
• 46:02a consensus paper
• 46:04stating that,
• 46:05it,
• 46:06strict criteria
• 46:07may underdiagnose
• 46:08filoides tumor that do have
• 46:11metastatic potential
• 46:12and,
• 46:14therefore, it is recommended to
• 46:16redefine malignant phylloidis
• 46:18as cases that have at
• 46:20least four of the five
• 46:22WHO criteria.
• 46:24And, so this is what
• 46:26the WHO six edition will
• 46:28recommend
• 46:29to use four of the
• 46:31five malignant criteria.
• 46:33If you have malignant heterologous
• 46:35elements except well differentiated
• 46:37liposarc,
• 46:38you can still call it,
• 46:40a malignant phylloidis.
• 46:42So how do you equate
• 46:43the phylloidis tumor,
• 46:45that sometimes don't fit neatly
• 46:47in diagnostic
• 46:48category?
• 46:49If there is a benign
• 46:51versus borderline
• 46:52and predominantly
• 46:53looks benign,
• 46:54but there are one or
• 46:55two features of borderline.
• 46:57You favor, you should favor
• 46:59a benign phylloides
• 47:01and mention the borderline features
• 47:03in a note.
• 47:04If, is unquestionable
• 47:06borderline, you call it as
• 47:07such. In the other differential
• 47:09between borderline and malignant,
• 47:12if it is predominantly
• 47:14borderline but some features, one
• 47:16or two are malignant,
• 47:18you say favor borderline and
• 47:20you mention the malignant features
• 47:22in a note.
• 47:23Three malignant features only, definitely
• 47:25a borderline.
• 47:27Four or five malignant features
• 47:29is definitely malignant, and you
• 47:31can call it malignant also
• 47:33if there is, there are
• 47:34malignant
• 47:36element. Again, except this well
• 47:38differentiated
• 47:39liposarcoma.
• 47:41And this is a final
• 47:42table that is going to
• 47:44be,
• 47:46will appear in
• 47:47the WHO six edition
• 47:50that also lists of fibroadenoma.
• 47:51I don't have time to
• 47:53mention additional studies
• 47:55that, with regard to fibroadenoma,
• 47:57have identified the presence of
• 47:59focal peripheral infiltration.
• 48:02So occasional fibroadenoma
• 48:03may have slightly
• 48:05irregular
• 48:06interface with the adjacent stroma.
• 48:08And also mitotic activity
• 48:10usually
• 48:11is absent,
• 48:12but can be low and,
• 48:15especially in younger patients,
• 48:18with increased thromal cellularity and
• 48:21also increased mitosis.
• 48:23For benign filoides tumor, occasionally,
• 48:26the margin may not be
• 48:28so circumscribed,
• 48:30but slightly
• 48:31irregular. But you still call
• 48:33it benign if the other
• 48:34features,
• 48:36are of benign grade. And
• 48:37as I said, for the
• 48:38malignant,
• 48:40the presence,
• 48:42you need to have at
• 48:43least four of the five
• 48:45criteria to call it malignant
• 48:47and the presence
• 48:48of these famous malignant heterologous
• 48:51elements
• 48:52except
• 48:53well differentiated
• 48:54liposarc
• 48:55will allow malignant categorization.
• 48:58All this is going to
• 48:59be summarized
• 49:00also in a
• 49:02review article that is, impressed
• 49:05in histopathology
• 49:07that, highlights
• 49:08some of these changes I
• 49:10just mentioned to you.
• 49:12There are many other subtle
• 49:14changes. I didn't have I
• 49:15don't have the time to
• 49:17go over them,
• 49:18but I want to thank
• 49:19you very much for your
• 49:21attention. I know it's a
• 49:22very breast focused
• 49:24lecture.
• 49:25I hope you enjoyed it,
• 49:26and it's clear and, useful
• 49:29in your practice. Thank you
• 49:30very much.
• 49:36Thank you for that wonderful
• 49:38experience of what's all coming
• 49:40up. And I
• 49:42like I don't know if
• 49:43Yeah. I
• 49:44like and look forward that,
• 49:45you know, it's no longer
• 49:46a requirement for the full
• 49:48house, which is too stringent.
• 49:50But is there any,
• 49:52mention or weightage given to
• 49:54different
• 49:56like, is,
• 49:57a permeator border weighted heavier
• 49:59than
• 50:00any of the other features
• 50:02like cellularity?
• 50:03Because right now, it's all
• 50:04equal weightage to all of
• 50:05them.
• 50:06Oh, yeah. You can keep
• 50:07it. I think, it's a
• 50:09great question.
• 50:10And, that's what actually the
• 50:12MRE group has tried
• 50:14to develop, you know, to
• 50:16give more emphasis to stroma,
• 50:19overgrowth,
• 50:20or marked nucleotypsya.
• 50:21But in reality,
• 50:24this is their experience.
• 50:27There is no study that
• 50:28has
• 50:30established
• 50:31the weight of all these
• 50:33different parameters.
• 50:35And actually in that publication
• 50:36that I
• 50:38showed,
• 50:39where there was a consensus
• 50:41group
• 50:42of experts,
• 50:44people were asked what is
• 50:45the most important feature and
• 50:47there was no agreement. So
• 50:49it's really difficult to to
• 50:50establish.
• 50:51Yes.
• 50:53Another question
• 50:55there.
• 50:57I I speak really loud.
• 50:58I can hear you. Oh,
• 50:59thank you.
• 51:03Thank you so much. That
• 51:04was an amazing presentation and
• 51:06so practical, incredibly practical
• 51:09for breast pathologists in particular.
• 51:11Thank you very much. I
• 51:12I have a question with
• 51:13regards to the assessment of
• 51:15micro invasion
• 51:17as we we all suffer
• 51:19with how to
• 51:20objectively measure these areas.
• 51:25Now is clearly more objective,
• 51:27which we really appreciate.
• 51:29My question is, do you
• 51:30think that
• 51:31the differences in measurement
• 51:33that will be implemented will
• 51:35resort result in more chemotherapy
• 51:39treatment for patients?
• 51:42I don't know, but definitely
• 51:45I have mixed feelings about
• 51:47this in the case I
• 51:48showed where, you know, there
• 51:50were four
• 51:51different TLUs
• 51:53and, we measured
• 51:55all across
• 51:56because and we felt very
• 51:58strongly about that.
• 51:59But the original pathologist felt
• 52:01very strongly too that those
• 52:03were separate foci.
• 52:05I think it will result
• 52:07in a little bit of
• 52:08over,
• 52:10you know, staging
• 52:11of these cases.
• 52:13You showed me a case
• 52:14of microinvasive
• 52:15lobular where there were tiny
• 52:17little single cells
• 52:19scattered throughout
• 52:20a focus of, I think
• 52:22was either flogid or pleomorphic
• 52:24LCIS.
• 52:26There were like five cells
• 52:27here, three cells there, but
• 52:29if you did span the
• 52:31entire length, that becomes a
• 52:34half a centimeter
• 52:35focus of invasion. And I
• 52:37think
• 52:38there will be issues also
• 52:39related to that.
• 52:41The
• 52:42point is that if you
• 52:43have a DCIS
• 52:45with
• 52:46extensive DCIS,
• 52:47mass forming,
• 52:49and you find micro invasion
• 52:50in one focus and then
• 52:52another one and another one.
• 52:54Most likely there is a
• 52:55lot of invasion that is
• 52:57only limitedly
• 52:59sampled
• 53:00and that's what prompted,
• 53:02that decision.
• 53:03And it's actually the application
• 53:05of the CAP guidelines
• 53:07where two tumors
• 53:09that are
• 53:10separated
• 53:11five millimeters apart,
• 53:13they are regarded as separate,
• 53:15but within
• 53:16five millimeter, they are measured
• 53:18together.
• 53:19So it's an extension of
• 53:21that.
• 53:22What if all about
• 53:25I mean,
• 53:26we measure something as four
• 53:27millimeters, but the one to
• 53:29itself is going to be
• 53:30low. And how accurate would
• 53:32be our
• 53:33biomarkers? And then if they
• 53:35start, like, in
• 53:36a lobular or in a
• 53:37deco knife
• 53:39on that, that's going to
• 53:40be Yeah. I I agree.
• 53:43Some of these
• 53:44topics
• 53:45were very discussed,
• 53:47and there was,
• 53:49this is a consensus statement.
• 53:51This is, we're going to
• 53:53use this for for some
• 53:55time.
• 53:56Also some discussion regarding
• 53:59EPC with high nuclear grade
• 54:02to call it DCIS.
• 54:04There was discussion also about
• 54:06that, but, you know,
• 54:09for the phylloidis tumor using
• 54:12four criteria,
• 54:13the five criteria were introduced
• 54:15in the prior WHO edition
• 54:17because it was thought that
• 54:18the criteria were too lax
• 54:20and people were diagnosing
• 54:22malignant phylloidis tumor too often.
• 54:25So, you know, we need
• 54:27to find a way to
• 54:29give us different weight probably
• 54:31to these different criteria.
• 54:33You have a question? Thank
• 54:35you so much for the
• 54:36wonderful talk. I think it's
• 54:37really, really helpful for the,
• 54:39daily practice.
• 54:41So I have two questions.
• 54:43First one is about EPC.
• 54:44As you mentioned, like, the
• 54:46EPC is in dolent
• 54:47invasive
• 54:48cancer,
• 54:49carcinoma,
• 54:50but behave like a DCIS.
• 54:52That's why we kinda, stated
• 54:54as a PTIS,
• 54:55DCIS.
• 54:56But I do encounter a
• 54:58few cases in the past,
• 55:00at least two cases.
• 55:01It's beautiful, beautiful like EPC,
• 55:03low to intermediate grade, a
• 55:05year positive,
• 55:06totally
• 55:07fine. But we see a
• 55:09couple of positive notes.
• 55:10So in that scenario we
• 55:12kind of like, uh-oh, so
• 55:13how should we do that?
• 55:14Because we cannot ignore,
• 55:16this is a positive note.
• 55:17So in that situation,
• 55:19I believe we kind of
• 55:21push over to the invasive
• 55:23cancers to be consistent to
• 55:25combine a finding a note.
• 55:27But somehow I feel like
• 55:29in that kind of scenario,
• 55:30it's very it's unusual, real
• 55:33situation.
• 55:34What's your, recommendation
• 55:36when we're dealing with the
• 55:37case?
• 55:39Thankfully they are rare, but
• 55:41I understand
• 55:42the the issue.
• 55:43You know,
• 55:45in reality, EPC is an
• 55:47invasive carcinoma. We choose to,
• 55:50classify it as in situ
• 55:52but,
• 55:53it is possible
• 55:55that in Focali may have
• 55:57metastasized.
• 56:00Or there is another focus
• 56:01of invasion
• 56:02anywhere else, somewhere else in
• 56:04the breast that has not
• 56:06been sampled.
• 56:08Or even in the sections
• 56:09that we put through, in
• 56:11the deeper section, there could
• 56:12be a focus of frank
• 56:14invasion that has not been
• 56:16put on the glass. So,
• 56:18yeah, we report whatever we
• 56:20have
• 56:21and, you know, the patient
• 56:23will be
• 56:25it's a hard it's a
• 56:27hard one. I think the
• 56:29one cannot ignore
• 56:30the positivity
• 56:31of the lymph nodes and
• 56:33probably
• 56:34considering that in this case,
• 56:37the we know that
• 56:38this is a tumor that
• 56:40is by convention
• 56:41in situ, but in reality
• 56:43is invasive. One can write
• 56:44a nice note
• 56:46and maybe send it for
• 56:47oncotype DX
• 56:49where they,
• 56:51you know, they can give
• 56:52some additional information.
• 56:54I have to say
• 56:55I don't have the time,
• 56:57but
• 56:59to I remove the slide.
• 57:00I have seen
• 57:02at least two cases with
• 57:03distant metastasis.
• 57:05One case was from a
• 57:06forty four year old woman,
• 57:08seventeen years later developed a
• 57:11bone mat.
• 57:12She had a bilateral
• 57:13mastectomy
• 57:15so the breast was gone
• 57:17but,
• 57:18and she was part of
• 57:19a study we did. And
• 57:20the second case
• 57:22is,
• 57:23a case from a man
• 57:25with EPC in the breast
• 57:28and he can, of course,
• 57:29a man and
• 57:30he developed
• 57:32the LungMet
• 57:33a few years later. I
• 57:35don't remember the time exactly.
• 57:37So I'm always very suspicious
• 57:39of EPC
• 57:40in young women
• 57:42because the information we have
• 57:44is about older women.
• 57:46But this woman was forty
• 57:47four, still pretty young, right,
• 57:50long life,
• 57:52left ahead of her, and
• 57:54also in men. I'm a
• 57:55little bit more suspicious based
• 57:57on this experience I've had.
• 57:59And they are invasive carcinoma,
• 58:02but they are classified as
• 58:04in situ. We'll see what
• 58:05happens now that we'll call
• 58:07also
• 58:08high nuclear grade lesions,
• 58:12in situ
• 58:13without any myopithelial cells. Obviously,
• 58:16you may gather I was
• 58:17not too much in favor
• 58:18of it, but,
• 58:36But now it doesn't matter.
• 58:38But I actually tried to
• 58:40get cases
• 58:42to put together a series
• 58:43of,
• 58:44EPC like carcinomas with high
• 58:46nuclear grade or HER2 positive.
• 58:48They've all been treated
• 58:50as invasive carcinomas.
• 58:52So,
• 58:54it's hard also to to
• 58:56get, you know, events
• 58:58in this in this patient.
• 59:00Sure. Great.
• 59:02So second question is about
• 59:03the mucinous carcinoma.
• 59:05So mucinous is like a
• 59:06hypocellular
• 59:07and a hypercellular.
• 59:10So when I issued a
• 59:11report say,
• 59:12mucinous carcinoma,
• 59:14hypercellular
• 59:15type,
• 59:16And then I got, like,
• 59:17communication from oncologist.
• 59:19They are not happy about
• 59:20this way because maybe for
• 59:23insurance building issue, they are
• 59:24not able to send out
• 59:25the oncotype.
• 59:27And then I
• 59:29since then, I'm a kind
• 59:30of try to learn, or
• 59:31try to be more,
• 59:34change the way I sign
• 59:35out the IDC with immune
• 59:36system differentiation.
• 59:37But I do some research
• 59:39to, to,
• 59:41to look at literature to
• 59:42compare the mucinous carcinoma
• 59:44hypercellular
• 59:45versus IDC with, with hype,
• 59:48with the mucinous differentiation.
• 59:50They do show some similar,
• 59:52overlapping things. So I don't
• 59:54know.
• 59:55So so I don't know
• 59:57what I should stick to,
• 59:58say, mucinous carcinoma, hypersolar type,
• 01:00:02or just, like, be general
• 01:00:03to say, IDC was mucinous
• 01:00:05differentiation.
• 01:00:07So if it is a
• 01:00:08mucinous carcinoma and you are
• 01:00:10convinced, I personally, I don't
• 01:00:13use hyper or hypocellular
• 01:00:15I see. Qualification.
• 01:00:18There are two morphologic
• 01:00:20appearances,
• 01:00:21but both qualify as,
• 01:00:23new sinus carcinoma. Their hypercellular
• 01:00:26variant
• 01:00:27is oftentimes associated with solid
• 01:00:30papillary carcinoma
• 01:00:32and, can even show neuroendocrine
• 01:00:35differentiation
• 01:00:36just like a solid papillary
• 01:00:38carcinoma can do. But it
• 01:00:40it has a very,
• 01:00:43if it is properly class
• 01:00:45you know,
• 01:00:45diagnosed, it's,
• 01:00:47a mucinous carcinoma.
• 01:00:49I wouldn't call it invasive
• 01:00:52breast carcinoma
• 01:00:54of,
• 01:00:56you know, NOS, NOS, NOS,
• 01:00:57NOS, NOS, NOS, NOS, NOS,
• 01:00:59NOS, NOS, NOS, NOS, NOS,
• 01:01:01NOS, NOS, NOS, NOS, NOS,
• 01:01:02NOS, NOS, NOS, NOS, NOS,
• 01:01:02NOS, NOS, NOS, NOS, NOS,
• 01:01:04NOS, NOS, N
• 01:01:08at this qualification
• 01:01:09that,
• 01:01:11according to the sixth edition,
• 01:01:12it shouldn't be ER positive
• 01:01:15or HER2 sorry. Shouldn't be,
• 01:01:18of high nuclear grade
• 01:01:20or HER2 positive. If you
• 01:01:22find that,
• 01:01:24don't call it mucinous.
• 01:01:26Yeah. Yeah. Thank you so
• 01:01:28much. It's really helpful.
• 01:01:30Alright.
• 01:01:31Any questions online?
• 01:01:37Oh, I don't know where
• 01:01:38is the chat. Unmute unmute
• 01:01:41the disabled.
• 01:01:44Once you
• 01:01:51I'm not seeing anything.
• 01:01:57I'm not seeing. Good. Okay.
• 01:01:59No. Thank you so much.
• 01:02:00Thank you. Thank you all
• 01:02:01for your attention.
• 01:02:03Thank you.