Ebook Sarcoma of the female genitalia (Vol 1): Part 2

The subject matter of volume 1 of the 2-volumes-handbook focusses on leiomyosarcoma, low-grade and high-grade endometrial sarcoma and undifferentiated uterine sarcoma of the whole female genitalia. The book aims to identify and provide diagnostic and therapeutic guidance. The listed tumor entities also constitute a particular diagnostic challenge for pathologists that contains numerous pitfalls and difficulties.

3 Endometrial stromal tumors – endometrial

stromal nodule, endometrial stromal tumor

with sex cord-like elements (ESTSCLE),

uterine tumor resembling ovarian sex-cord tumor (UTROSCT) and similar tumors

Introduction

The current WHO Classification (36) divides EST and similar neoplasms into ESN, ESS, HG-ESS and UUS UTROSCT also belong to the EST family of tumors ESN arebenign stromal tumors There are special forms of EST with different types of differ-entiation, like the endometrial stromal tumor with endometrioid glands, mixed en-dometrial stromal tumors and smooth muscle tumors as well as endometrial stromaltumors with sex cord-like elements (ESTSCLE), and uterine tumors resembling ovariansex-cord tumor (UTROSCT) Uterine stromal sarcomas (LG-ESS, HG-ESS, UUS) belong

LG-to the family of pure homologous sarcomas and are discussed in separate chapters(Chapters 4 and 5)

3.1 Endometrial stromal nodule

3.1.1 Uterine endometrial stromal nodule

General, pathogenesis, pathological-anatomical features

ESN is a benign EST with histological features unambiguously reminiscent of trial stroma in the proliferation phase Overall, ESN are only very rarely diagnosed,accounting for only 3 % of all EST in the DKSM database (25) ESN have been ob-served to arise in women aged 23–86 The majority of patients are premenopausal,with a median and mean age of 47 resp 53 years It can already be deduced from thisage distribution that ESN share an epidemiologic relationship with LG-ESS, which, ac-cording to the DKSM data, arise in patients aged 18 to 80 years Median age of patientswith LG-ESS is 46 years, suggesting that, like ESN, the majority of such tumors arise

endome-in premenopausal women (25) These two types of neoplasm endome-in fact share clear genetic commonalities On the one hand, the differences between the two in terms

patho-of their microscopic features are more gradual than abrupt Both LG-ESS and ESN hibit t(7;17) translocations and consecutive fusions of the JAZF1 and SUZ12 (previously:JJAZ1) genes as well as t(6;7) translocations (JAZF1/SUZ12 gene fusion) (26) The t(7;17)(p15;q21) translocation is regarded as an early genetic aberration in the development

ex-of ESN and LG-ESS Interestingly, this translocation can also be observed in ESN thatexhibit focal smooth muscle differentiation, which allows the conclusion that suchtumors originate from a progenitor cell (35), and could also serve to explain why ESNand LG-ESS so frequently arise within the myometrium LG-ESS, ESN and CLM ex-press common immunohistochemical markers (CD10, SMA, WT-1), another factor thatsupports the notion that stromal and myogenic tumors might derive from the same pre-cursor cells (48) What is rather conspicuous from an epidemiologic perspective is thatESN account for only a very small proportion of all EST Subtle analyses have revealedthat, when ESN and LG-ESS are summed together, the latter account for a substantiallylarger share (84 %) than the former (16 %) (45) Given the fact that microscopicallydifferentiating between LG-ESS and ESN is very difficult, this can essentially only beexplained by the fact that a non-negligible number of ESN (for example such withlimited infiltration or myogenic differentiation) are probably classified or diagnosed

as LG-ESS just to be “on the safe side” That could also help to explain why there is somuch variation in terms of the propensity of such tumors to recur The situation mightactually be very similar to that of STUMP and LMS

Endometrial stromal nodules are rare benign endometrial stromal tumors that predominantly arise

in premenopausal women They are regarded as a precursor of low-grade endometrial stromal coma.

sar-Similar to LM, ESN are usually situated intramurally Their intramural growth serves

to visibly compress the surrounding myometrium, and potentially the endometrium

as well The tumor is thus well-circumscribed ESN have a yellowish, tan, occasionallyalmost white color on the predominantly smooth, fleshy cut surface Sometimes cysticstructures, necrosis and focal hemorrhages can be visible in the cut-open specimen.Nodular or polypoid growth into the cavum uteri is not uncommon ESN are usuallyconsiderably softer than LM Their size can range from only a few mm to 22 cm, with

a mean diameter of 5–7 cm Multiple ESN can develop simultaneously

Microscopy also very frequently reveals that ESN are situated entirely withinthe myometrium Myometrial compression caused by the tumor’s strong displacinggrowth is usually easy to see, and can appear to resemble an actual capsule in somecases The densely packed, diffusely growing small oval to spindle cells stronglyresemble the endometrial stromal cells of the proliferative endometrium The cellscontain scant cytoplasm and usually have unclear margins The oval to spindle,relatively uniform nuclei are practically void of pleomorphism, have unsuspiciousnucleoli and exhibit a prominent coloration that often makes them appear deep blue

in histological specimens

The cells often focally whorl around the vessels (1) Virtually all ESN contain ple uniform vessels (15) reminiscent of endometrial spiral arterioles The vessels canoccasionally be thick-walled and hyalinized, but are usually situated within areas ofsmooth muscle differentiation in such cases

am-Densely cellular tumors are predominant (roughly 80 %), while 20 % are lular with fibrous, hyalinized, myxoid or edematous sections (15) ESN with an abun-dance of epithelioid cells have also been described in the literature (33) Occasionalareas consisting of foam cells within the tumor are another noticeable feature (31).There are no entirely cytologic criteria that can be drawn on to differentiate ESN fromLG-ESS Hyalinized areas, cystic degeneration and necroses occur in both of thesetypes of tumors, and are thus not suitable specific DD criteria (1).

hypocel-In microscopy, the tumor is usually sharply delineated from the myometrium due

to the absence of infiltration (Fig 3.1.1 (A))

Fig 3.1.1:Histological findings of an endometrial stromal nodule and diagnostic differentiation from cellular leiomyoma; (A) a clear, sharp margin between the stromal nodule (top left) and the myometrium (bottom right) constitutes an important characteristic feature, the stromal cells with scant cytoplasm morphologically correspond to those of low-grade endometrial stromal sarcoma; (B) cellular leiomyoma can have a very similar appearance and needs to be ruled out via immunohis- tochemical testing.

The tumor margins can also be slightly irregular or poorly defined as a result of

tongue-or finger-like protrusions of the main tumtongue-or up to 3 mm deep into the btongue-ordering ometrium Even the presence of small individual nodules located no further than 3 mmaway from the tumor does not serve to exclude such cases from being diagnosed asESN Tumors in such cases are referred to as ESN or EST with limited infiltration (15,

my-49, 51) or LG-ESS with limited infiltration (1) VI and LVI are absent by definition mors in which the infiltrations or satellite masses extend beyond 3 mm or in whichthere is VI will be LG-ESS In some cases, tumors with focal margin irregularities thatextend up to 9 mm beyond the main border of the tumor still do not have to be classi-fied as LG-ESS (15) Such infiltrations usually only occur focally and should be limited

Tu-to three localizations in order Tu-to fulfill the ESN criteria (1) These criteria must indeedappear vague even to non-pathologists, and constitute a substantial reason why ESNand LG-ESS share such overlap in a diagnostic “gray area”

Smooth muscle differentiations are far from the exception in ESN, and are present

in up to 50 % of cases (15) At times, the smooth muscle cells can also appear to semble epithelioid cells Tumors in such cases are referred to as ESN with smoothmuscle differentiation, regardless of the extent of the smooth muscle component (32)

re-In the past, tumors in which the smooth muscle tissue accounted for > 30 % weretermed stromal myoma Today, these tumors constitute a special subgroup of ESTcalled mixed endometrial stromal smooth muscle tumors (see below) Larger sections

of smooth muscle differentiation can be “interlocked” with stromal cells in a cog- orphalanx-like fashion, a situation that can be misinterpreted as myometrial infiltration

by stromal cells and thus result in a misdiagnosis as LG-ESS Larger areas of smoothmuscle differentiation can thus cause differential diagnostic problems, especially incurettage specimens (see below) Besides fibrous elements, 24 % of tumors also con-tain focal visible degrees of sex cord-like differentiation arranged in cords/bundles in

a glandular epithelioid structure (15) These tumors are further subdivided into twosubtypes along the lines of the extent of sex cord-like differentiation in the tumor –ESTSCLE and UTROSCT (in which sex cord-like differentiation is predominant) (seebelow)

The majority of ESN exhibit no mitotic activity or MI < 3 M/10 HPF MI of up to

15 M/10 HPF have been described in the literature (49), but only 10 % of ESN have

> 5 M/10 HPF (15) MI is not relevant for the diagnostic context and has no impact onprognosis Cysts resulting from cystic degeneration as well as infarct-type necroses areobserved in 24 and 68 % of ESN, respectively (15, 17)

Regarding IHC, ESN virtually always express ER and PGR, vimentin and CD10.Pure ESN without further differentiation are usually negative for desmin and h-caldesmon (34) The corresponding lead markers can be found in cases in whichtumors exhibit additional morphologic differentiations, for instance: desmin and h-caldesmon when there is smooth muscle differentiation; inhibin, calretinin, CD99and O-13 when there is sex cord-like differentiation; myogenin when there is skeletalmuscle differentiation CD10 constitutes the most reliable and most characteristicmarker for endometrial stromal cells, and thus for ESN and LG-ESS CD10 is typicallydiffusely expressed and strongly positive in both ESN and LG-ESS (see also the table

on p XXVI) In ESN, areas with smooth muscle differentiation also stain with CD10.ESN usually show strong and diffuse positive immunoreactive staining for the WT-1antibody (48)

Endometrial stromal nodules can barely be macroscopically discerned from leiomyoma or grade endometrial stromal sarcoma, also in terms of their localization Endometrial stromal nod- ules are noticeably soft and of a conspicuously yellow color.

low-The only real histological difference between endometrial stromal nodules and low-grade dometrial stromal sarcomas is the absence of infiltration in cases of the former It consists of very densely packed small cells with low levels of pleomorphism that are reminiscent of proliferative endometrial stroma Endometrial stromal nodules typically express CD10 Smooth muscle and sex cord-like differentiations with corresponding immunophenomena are possible.

en-Clinical presentation, diagnostics, imaging, differential diagnostics, screening

Like LG-ESS, ESN are often incidental findings made on the basis of specimens tained via HE Uterus enlargement, menorrhagia and possibly AUB in the form ofadditional bleeding are the central clinical symptoms Patients occasionally also com-plain of abdominal pains when there is uterine enlargement The noticeable softness

ob-of such tumors ob-often becomes apparent either during gynecologic examination orintraoperatively Overall, at the latest during surgery, ESN or LG-ESS should be con-sidered as possible diagnoses when a tumor is soft and appears very smooth andyellowish on the cut surface In principle, symptoms largely correspond to those of

LM and can thus also be entirely absent Accordingly, and analogous to LG-ESS, theyare usually operated on under the diagnosis LM

Diagnostics primarily involve sonography, and also include HSC in combinationwith targeted biopsy or curettage when there is AUB The problems pertaining tocurettage are discussed at greater length in the chapter on LG-ESS (Chapter 4) Theaforementioned diagnostic steps are often not taken when LM is assumed Similar tosmooth muscle tumors and LG-ESS, the hysteroscopic picture usually only reveals asmooth bulge in the endometrium caused by a displacing tumor (Fig 3.1.2)

Fig 3.1.2:Hysteroscopic findings of an dometrial stromal nodule, differentiation from leiomyoma is barely possible on gross observa- tion.

en-An irregular surface or polypoid structures are also possible features The cut face usually has a conspicuous yellowish color The tumor appears softer than LM

sur-in biopsy The diagnostic flowchart can be drawn on sur-in ambiguous or uncertasur-in cases(cf Chapter 6)

Symptoms, findings and clinical diagnostics all largely correspond to those of leiomyoma or grade endometrial stromal sarcoma Hysteroscopy and curettage are indicated when there is ab- normal uterine bleeding.

low-Given the rarity of ESN, only very few data are available that can give insight intotheir imaging characteristics Sonography does not yield findings that are specific to

ESN, but typically reveals a well-circumscribed heterogeneous tumor that is largelyhypoechoic (38) While the presence of anechoic structures (cysts or necroses) is not

a finding that is specific to ESN, they can nonetheless be suggestive of ESN whenthe tumor in which they are situated is hypoechoic Large ESN also appear as well-circumscribed heterogeneous hypoechoic masses with cystic/necrotic and solid parts(17) (Fig 3.1.3 (A), (B))

Fig 3.1.3:(A) endometrial stromal nodules with predominantly cystic structures in sonography; (B) the tumor also appeared to be cystic in uterus-sparing surgery, the findings were later patho- logico-anatomically characterized as pseudocysts within the tumor.

Since the only microscopic and macroscopic difference between ESN and LG-ESS isthe absence of myometrial and VI in the former, it cannot be realistically expectedthat these two types of neoplasm will exhibit greatly differing imaging-related fea-tures Assessing the margins of the tumor with a view to identifying infiltrations can,however, be helpful

Cases of ESN that are isoechoic to the myometrium or to LM have been reported (8).Accordingly, as is also the case with LG-ESS, the majority of ESN are classified as LM insonography Findings similar to those for ESN and LG-ESS have also been described forLMS and DLM Overall, the sonographic picture merely serves to suggestively indicatethe presence of an unusual mesenchymal mass

CT reveals unspecific tumor enlargement with occasionally discernible cysts Thetumor shows heterogeneous enhancement in CECT that is absent in the cystic sections

CT is not an appropriate tool for reaching a specific diagnosis (41)

T1W-MRI usually reveals a tumor with SI that is isointense to the myometrium (38).Administration of gadolinium shows homogeneous to inhomogeneous enhancementthat can be lower than or identical to that of normal myometrium Cystic structuresremain hypointense (41) In one case (38), only the areas on the margins of the tumorshowed enhancement, while the rest of the tumor did not The non-enhancing areasapparently corresponded to hemorrhagic degeneration T2W reveals a heterogeneoustumor that is intermediately intense to hyperintense SI is slightly higher than that of

the myometrium and skeletal musculature (18) Hypointense bands within the tumor,

a typical feature of LG-ESS (cf Chapter 4), are absent in T2W (38) These features serve

to distinguish ESN from LM rather well Cystic structures that appear hypointense inT1W are hyperintense in T2W Analogous to LG-ESS that exhibit worm- or tongue-likeinvasion, T2W should also reveal hypointense bands in ESN with more pronouncedsmooth muscle differentiation LG-ESS with little or no certain myometrial invasionare typically separated from the myometrium by a narrow hypointense rim (cf Chap-ter 4) This rim might well serve as a criterion for differentiation from DLM and LG-ESSwith diffuse infiltration (18)

It is generally assumed that ESN cannot be reliably differentiated from LG-ESSwith limited or little infiltration in MRI (18)

Endometrial stromal nodules have no specific sonographic criteria or features They typically present as well-circumscribed masses with heterogeneous hypoechoicity, sometimes with cystic structures In T2W-MRI endometrial stromal nodules are heterogeneously intermediate to hyper- intense Signal intensity is slightly higher than that of normal myometrium, and tumors are usually surrounded by a hypointense rim These characteristics and features are well suited for differen- tiating endometrial stromal nodules from leiomyoma Differentiation from low-grade endometrial stromal sarcoma is often not possible.

From a clinical perspective, ESN and LG-ESS are often mistaken for LM, both eratively and intraoperatively In fact, the majority of both of these types of neoplasmare subjected to surgery under the indication LM, and such tumors are thus oftenincidental findings (cf Chapter 4) Intramurally localized ESN are only exception-ally accessible to curettage, as is also the case with other intramural mesenchymaltumors ESN are, however, usually softer than LM on palpation and are usually soli-tary Cut-open ESN have a yellowish-brown color, a smooth cut surface and lack a clearpseudo-capsule, making them relatively easy to discern macroscopically from LM withtheir more whitish color and whorled structures DD from CLM, which are also rathersoft (Fig 3.1.1 (A), (B)), is particularly challenging from a clinical and pathological-anatomical perspective Discerning between CLM and ESN is practically impossibleusing purely clinical methods CLM and STUMP can be similar to ESN in terms of colorand consistency, and can also contain cystic structures and necroses Polypoid protru-sion or “bulging” into the cavum militates against a diagnosis of LM, CLM or STUMP.LG-ESS constitutes the most important DD in terms of microscopic and macro-scopic features ESN cannot be discerned from LG-ESS solely on the basis of cytology

preop-A tumor can only be definitively and reliably diagnosed as ESN when the entirety ofthe tumor’s margins is observable/assessable A reliable diagnosis of ESN cannot bereached when the tumor borders are incomplete following curettage, morcellation orenucleation, but the clinician might nonetheless have to settle for that diagnosis, eventhough LG-ESS cannot be ruled out Differentiating ESN with limited infiltration fromLG-ESS is very difficult even when the margins of the tumor are all clearly assessable,

but also has prognostic consequences The same applies for intraoperative frozen tions, whose value is already limited as it is (see below).

sec-In histological tissue specimens, the uniformity of the cells, dense cellularity,strong staining in the nucleoli and the fact that they are typically well-delineatedfrom the myometrium are all factors collectively suggestive of CLM The latter, how-ever, are characterized by relatively large, thick-walled vessels and narrow clefts in thetumor The clefts possibly correspond to compressed vessels (34) Thick-walled arteri-oles are occasionally also found in ESN, but are usually situated at the periphery/nearthe margins of the tumor in such cases (15) Performing frozen sections without IHCanalysis (Fig 3.1.1 (B)) is thus greatly prone to error for this group of neoplasms, andmust be regarded critically by clinicians In contrast to CLM, ESN exhibit strong anddiffuse CD10 expression With the exception of ESN with smooth muscle differenti-ation, and in contrast to CLM, ESN do not stain positively for desmin H-caldesmonappears to be the most important differential diagnostic marker as it virtually nevershows staining in ESN (48) Since CD10 can also be traceable in 20–55 % of CLM,the latter can best be discerned from ESN by drawing on a combination of desmin,h-caldesmon and CD10 (cf Tab 4.1.1) (10, 34) However, it should be noted that LMScan also be CD10 positive and h-caldesmon negative (4, 42) Assessing CD10 is gen-erally not enough for safely and reliably distinguishing between ESN and smoothmuscle neoplasms

Extensive smooth muscle differentiations with interposed stromal elements canserve to mimic invasion and subsequently result in overdiagnosis as LG-ESS Relatedproblems tend to arise in cases in which extensive morcellation has been performedleaving many small pieces of tissue ESN with epithelioid cells with ample eosinophiliccytoplasm (33) can be confused with PEComa in microscopy Effort must be devoted

to differentiating ESN from ESTSCLE (see below) and UTROSCT (see below) when sexcord-like elements are found to be present

Stromal endometriosis constitutes a further differential diagnostic challenge, anomenclature used to describe endometriosis with sparse or no glandular differenti-ation, sometimes also referred to as stromatosis Stromal endometriosis is sometimesobserved to arise after long-lasting or highly-dosed progestin therapy (29) Stromal en-dometriosis usually arises on the surface of the peritoneum in the vicinity of other ar-eas of endometriosis and does not develop actual tumors as such (7) Cyclic changes orolder hemorrhages with hemosiderin can be recognizable in the stromal endometrio-sis Stromal endometriosis occasionally arises in the cervix (12), where it can also beconfused with ESN or LG-ESS An AS can be overlooked in specimens obtained viabiopsy or curettage when no glands are visible in the small amount of tissue available.ESN with focal endometrioid glandular differentiation are usually endometrialstromal tumors with endometrioid glands There is also an LG-ESS equivalent to suchneoplasms AS must also be considered from a DD perspective whenever glands arepresent However, cuff-like accumulations of stromal cells around the vessels make

AS generally easy to recognize as such (cf Chapter 6, Vol 2)

There is no particular screening that we are aware of Nor is such a screening essary due to the rarity of such tumors and the fact that they are benign The low rate

nec-of cellular atypia also serves to rule out incidental detection nec-of ESN in the context nec-ofcytological screenings for cervical carcinoma

Low-grade endometrial stromal sarcoma and common leiomyoma are the most important clinical differential diagnoses Microscopically differentiating endometrial stromal nodules from cellular leiomyoma can be very difficult without applying additional immunohistochemical methods, espe- cially in frozen sections The same applies for rarer differential diagnoses, like PEComa, ESTSCLE and UTROSCT.

There is no specific screening for endometrial stromal nodules, nor is such screening necessary given the rarity and benignity of such tumors.

Course, prognosis, primary surgery, adjuvant and additive radio-,

chemo-and hormone therapy

ESN are benign tumors that do not recur or metastasize (49) Accordingly, prognosis

is good so long as the tumor margins are well-circumscribed and open to assessment.Such assessment is largely based on tumors that have been removed via THE Noreliable prognostic assessments can be made concerning the application of conser-vative surgery to ESN since case numbers are so low Among the few cases that havebeen recounted in the literature, none have recurred (15, 43, 49) From a pathological-anatomical perspective, it is assumed that limited myometrial invasion of up to 3 mmdepth is unlikely to impact unfavorably on prognosis This notwithstanding, a case isrecounted in the literature in which a uterine ESN with limited invasion exhibited ex-trauterine dissemination, though the lesion in question was probably in fact very earlyLG-ESS (24) A case has been reported in which an ESN with more than three perme-ations not exceeding 3 mm metastasized (47) Due to a lack of data, the prognosticimpact of the presence of tumor margin irregularities of 3 to 10 mm depth remains un-certain (15, 52) For practical purposes, it is therefore recommended that such tumorsalso be classified as LG-ESS, and that it is pointed out independently that the degree

of infiltration at hand is far lower than is usually observed in LG-ESS (1) In cases inwhich tumors are subjected to morcellation or RX resection, or in which the tumorborders cannot be assessed in their entirety, pathologists must unequivocally pointout that the tumor in question may also be LG-ESS

Endometrial stromal nodules are benign tumors that neither recur nor metastasize This statement only applies when all tumor margins are reliably observable or assessable.

There is currently no alternative to adopting a primarily surgical approach to therapy,not least because ESN need to be regarded as a precursor for LG-ESS Since LG-ESS gen-erally cannot be ruled out whenever an ESN is suspected – neither clinically, nor in

imaging or via HSC or curettage – the tumor should be approached as though it wereLG-ESS THE is therefore the therapeutic method of choice, because the tumor mar-gins can only really be reliably assessed when the uterus remains intact For the samereasons, morcellation, SLH or clamping the tumor with sharp instruments should beavoided, not least because injuring the tumor or the uterus has a negative impact

on prognosis for LG-ESS LAVH or TLH can be opted for so long as the integrity ofthe uterus and the tumor is not endangered Given the difficulty associated with suc-cessfully differentiating from LG-ESS, indications for SAH and SLH should be subject

to strict criteria when a diagnosis of EST is known prior to or during surgery BSO

is not necessary in premenopausal patients The regular expression of ER and PGRnotwithstanding, there are no data which suggest that sparing the ovaries facilitates

or promotes recurrence

As a precaution, an approach analogous to that which would be adopted for anLG-ESS should be opted for in cases in which the resection margins cannot be reliablyassessed following morcellation or other tumor injuries

Uterus-sparing TE can be considered for young women who urgently wish topreserve their fertility (15, 43, 49) The removed specimen should have a wide margin

of myometrial tissue so as not to miss any infiltrations In light of the fact that ESNconstitutes a precursor of LG-ESS, a certain risk of recurrence needs to be reckonedwith, especially when there is limited infiltration, and indications for organ-sparingsurgery need to be subject to very strict criteria or be made analogous to STUMP.The central problem, however, lies in the fact that the diagnosis “ESN” is usuallynot known prior to surgery, and that most ESN are subjected to surgery under thediagnosis “LM” Against this backdrop, subjecting LM to laparoscopic intracapsular

ME (as is recommended by some) (50) constitutes a real prognostic risk In the casepresented in Fig 3.1.3 (A), (B), the patient delivered a mature and healthy child viacesarean section within one year of laparoscopic surgery, and there was no evidence

of any recurrence of disease Further detail is presented in Chapter 8, Vol 2 ESN thathave been resected leaving unclear margin status should be subjected to reresection

so as to be able to reach a definitive diagnosis Postoperative HT should be considered

in cases in which reresection is not possible for whatever reason

Regarding the surgical treatment of primarily advanced tumors that are fined to the pelvis and the abdominal cavity, only one case has been reported ofsynchronous spread of an ESN with limited infiltration into structures of the lesserpelvis (24) Complete tumor resection constitutes the therapeutic measure of choice

con-in any case HT can be attempted con-in cases of con-inoperability

Since endometrial stromal nodules and low-grade endometrial stromal sarcomas are so closely related and difficult to differentiate from each other, the surgical approach should always be de- signed as though the tumor at hand were low-grade endometrial stromal sarcoma Total hysterec- tomy thus constitutes the therapeutic option of choice Any injury to the tumor and the uterus

should be avoided Vaginal, laparoscopy-assisted vaginal or total hysterectomy can only be opted for when it can be guaranteed that the tumor or the uterus shall not be injured in the process There

is no reliable indication for removing the adnexa following adequate hysterectomy in pausal patients Tumor extirpation is possible when patients desire to preserve their fertility Such extirpation needs to leave disease-free (i.e R0) resection margins outside of the pseudo-capsule consisting of compressed tumor tissue Cases of expansive disease require maximal cytoreductive surgery.

premeno-There is no indication for adjuvant and/or additive RT and/or CHT

In principle, applying adjuvant HT could be an adequate approach given that ESNare virtually always ER and PR positive With the exception of one case of ESN withlimited infiltration (24), there are no known cases in which ESN subjected to THE or

TE leaving R0 resection margins have developed recurrences and/or metastases sequently, there is no justifiable indication for applying adjuvant HT The literatureprovides no applicable accounts of ESN that have been subjected to morcellation orthat have been suboptimally resected Against the backdrop of the fact that ESN areregarded as precursors for LG-ESS, and that potential tumor residuals might be prob-lematic if an LG-ESS has been overlooked, the potential risk of recurrence needs to bediscussed with the patient The lack of relevant data notwithstanding, analogous toLG-ESS, adjuvant ablative or additive HT would be a feasible option in these specialcases in RX or R1 situations Such therapy would be best achievable via BSO, thoughthis option is obsolete when patients desire to preserve their fertility Additive pro-gestin therapy can also be considered in such cases There are no data that can givesome insight into the duration that such treatment should be applied for Drawing onwhat is known for other receptor-positive tumors, HT should last for at least 2 and up to

Con-5 years Administering AI instead of progestin therapy is an option for postmenopausalwomen In principle, the same approach can be adopted as for LG-ESS Particularitiesare presented in the respective Chapter 4

There is no indication for adjuvant radio or chemotherapy for endometrial stromal nodules ogous to LG-ESS, adjuvant ablative or additive hormone therapy can be considered when tumor margins are unclear or in RX/R1 situations.

Anal-Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability

Independent of the fact that the majority of ESN are only postoperatively diagnosed

as such, there are no known applicable definitive primary medication-based or terventional therapeutic options Analogous to premenopausal LG-ESS, administer-ing progestins or GnRH analogues with a view to achieving tumor shrinkage can beconsidered for patients who urgently desire to preserve their fertility One such caseinvolving the application of GnRH analogues has been described in the literature (43)

in-The central problem in this regard lies in the fact that reliable diagnoses cannot beachieved via biopsy or curettage (see above) Consequently, there will always be therisk that such treatment is administered to an LG-ESS that has not been identified

as such Applying GnRH therapy in order to effect tumor shrinkage in cases in whichconservative therapy has been opted for due to a desire to preserve fertility constitutes

a risk that is difficult to calculate or pinpoint In any case, HT should only be appliedupon having (re)assessed HR status Analogous to LG-ESS, HT must be regarded ascontraindicated when patients are postmenopausal, unless surgery is not an optionwhatever the reason Such cases should be approached in the same fashion as LG-ESSwould be in such situations (cf Chapter 4)

Hormone therapy can only be applied when there is a contraindication for surgery and the ence of hormone receptors has been verified Hormone therapy can be drawn on exceptionally as

pres-a mepres-ans for pres-achieving tumor shrinkpres-age prior to plpres-anned conservpres-ative surgicpres-al procedures.

Aftercare, recurrences, metastases and their treatment

Patients with ESN who have undergone THE require no specialist or specific follow-up

or aftercare In light of the ambiguous or insecure data situation, clinical oriented follow-up and aftercare should be rendered analogous to that for LG-ESSwhen patients have undergone conservative operations and/or in cases of ESN withlimited infiltration, and should be combined with TVS Whether or not surgery should

symptom-be completed via THE once the patient’s desire to have children has symptom-been fulfilled mains unsubstantiated by reliable data If, following conservative surgery, the pathol-ogist can only opt for a diagnosis of EST (which does not exclude LG-ESS), follow-

re-up should be designed analogous to that recommended for LG-ESS, and performingfollow-up LSC within 3–6 mo should be considered

With the exception of two unclear cases (24, 47), there have been no accounts

of recurring or metastasizing ESN, and recurrence/metastases are highly unlikely tooccur following THE without injury to the tumor Tumors that have been subjected tomorcellation and/or that have not been subjected to reliable R0 resection thus have

an elevated risk of recurring Recurrences or metastases that do occur are very likely

to be LG-ESS, making it advisable to proceed in accordance with the criteria relevant

to recurrent and metastasized LG-ESS (cf Chapter 4)

Oncologic symptom-oriented aftercare and follow-up are only necessary following conservative surgery or when margin status is not clear Recurrences and metastases need not be reckoned with when endometrial stromal nodules have been subjected to adequate surgery and have been unambiguously histologically verified as such.

3.1.2 Extrauterine endometrial stromal nodules

Extrauterine ESN are the exception In one reported case, the tumor in question waslikely in fact a metastasis of an ESN with limited infiltration, or potentially even avery early LG-ESS (24) A further case study describes an account of an extrauterineESN with the typical IHC profile in the vicinity of the sigmoid colon (33) The well-circumscribed, yellow, fleshy mass contained ample epithelioid cells among otherfeatures The origin of this tumor remained unclear, while development from an en-dometriosis is a thinkable option Intrauterine counterparts need to be searched forwhenever an extrauterine ESN is identified Therapy does not differ from that envis-aged for other EST primarily localized in the pelvis A treatment attempt via individu-alized HT can be applied in cases in which surgery is contraindicated, for any reason,analogous to the approach adopted for HT in cases of advanced or metastasized LG-ESS (cf Chapter 4) Stromal endometriosis in the lesser pelvis should be ruled outbeforehand

3.2 Special variants of endometrial stromal tumors

3.2.1 Endometrial stromal tumor with endometrioid glands

Endometrial stromal tumors with endometrioid glands are benign and contain ithelial components usually in the form of endometrioid glands These can constitutedifferent epithelial differentiations or so-called entrapped endometrial glands that –since the tumor does not infiltrate the endometrium – are most likely to be persistentglands of a pre-existing endometriosis Endometrial stromal tumors with endometri-oid glands are thus usually small tumors incidentally discovered in postmenopausalwomen An expansive adenomyosis is another possible DD (31)

ep-Endometrial stromal tumors with endometrioid glands are benign endometrial tumors containing epithelial elements usually in the form of glands.

3.2.2 Mixed endometrial stromal and smooth muscle tumor,

combined stromal-smooth muscle

EST are classified as mixed endometrial stromal and smooth muscle tumors whenmore than 30 % of their total volume is accounted for by smooth musculature LikeESN, such tumors are usually diagnosed incidentally The histologic characteristics

of their smooth muscle differentiation correspond to those of LM Central prominenthyalinizations reminiscent of an exploding star can often be observed (Fig 3.2.1 (A)).The isles of smooth muscle differentiation are predominantly sharply/well-delineated

▸ Fig 3.2.1:Microscopic characteristics of combined stromal-smooth muscle tumors (A) microscopic image showing the typical hyalinizations; (B) analogous to endometrial stromal nodules, this type

of neoplasm, too, can be highly cellular ((A), (B) HE staining); (C)–(E) the smooth muscle cells press the corresponding markers SMA (C), desmin (D) and caldesmon (E); (F), (G) in the stromal component, the CD10 positive cells are more densely or loosely bundled depending on the number

ex-of stromal cells; the reverse image for the muscle markers (C)–(E) is clear and leads to the correct diagnosis; (G), (H) the same applies to the estrogen receptors.

from the stromal cells, but can also transition into them rather inconspicuously Highcellularity is not an uncommon feature (Fig 3.2.1 (B)) Notwithstanding, the tumor isstill unambiguously of stromal origin with smooth muscle elements that have devel-oped metaplastically (31, 52) There is also an account in the literature of an ESN withsmooth muscle and striated muscle elements (28)

EST in which cells with smooth muscle differentiation account for 30 % of the totaltumor volume, and which also exhibit LVI and/or VI or myometrial invasion, are clas-sified as stromal sarcomas with mixed endometrial and smooth muscle differentiation(cf Chapter 4) (30) Analogous to ESN and LG-ESS, tumor aggressiveness is dependent

on the presence or absence of infiltration Accordingly, classification either as ESN or

as LG-ESS is based on these criteria The IHC of the stromal cells corresponds to that

of ESN (Fig 3.2.1 (F)) The smooth muscle components show strong positive stainingfor SMA, desmin and h-caldesmon (Fig 3.2.1 (C)–(E)) Analogous to EST and LG-ESS,there is also strong ER expression (Fig 3.2.1 (G), (H)) Diagnostics and therapy corre-spond to those for ESN or LG-ESS, respectively In MRI, T2W images are most likely toyield findings suggestive of this type of tumor

Endometrial stromal tumors in which cells with smooth muscle differentiation account for 30 %

of the total tumor volume are classified as mixed endometrial stromal and smooth muscle tumors Such tumors are in turn classified as stromal sarcomas with mixed endometrial and smooth muscle differentiation when they exhibit myometrial or lymphovascular invasion.

3.2.3 Uterine tumor with sex cord-like elements type I

(ESTSCLE, endometrial stromal tumor with sex cord-like elements)

Uterine tumors with sex cord-like elements can occur as two different entities, or ants Type I tumors encompass EST in which > 10 but < 50 % of the tumor’s volume iscomprised of epithelioid structures that are reminiscent of ovarian sex cord stromaltumors They are also referred to as uterine tumors with sex cord-like elements type I,

vari-or ESTSCLE (13, 52) Type II tumvari-ors (UTROSCT) are discussed in mvari-ore detail in the nextsubsection Despite this differentiation, ESTSCLE should be classified as a variant ofEST, a relationship that is also suggested by the fact that ESTSCLE contain JAZF-SUZ12(prev.: JJAZ1) fusion genes (2, 11, 44, 52) Type I tumors account for roughly 11 % ofall tumors of both entities (5) Discussion pertaining to the genesis of both type I and

(A) (B)

type II tumors has focused around a potential origin from stromal cells, adenomyosis,stromal myosis, endometriosis as well as from pluripotent myometrial cells Around

50 % of such tumors cannot be exactly classified as type I or II (5)

Virtually all women with ESTSCLE have given birth Average patient age is 46 yearsand an association with exposure to tamoxifen has been described (5) ESTSCLE have

a macroscopic appearance largely reminiscent of UTROSCT Fifty percent of type I and28.6 % of type II tumors exhibit nuclear pleomorphism Atypia can be found in 61 and

31 % of type I and II tumors, respectively, while necroses are found in 25 resp 7 %(5) The sex cord-like cells usually grow in cords or fascicles in a trabecular, occasion-ally tubular fashion (31) In contrast to UTROSCT, ESTSCLE only express one sex cordmarker, usually calretinin or CD99 (5, 13) Furthermore, ESTSCLE show constant re-activity to vimentin, ER and PGR as well as varying degrees of positive reactivity forCD10, keratin, actin and desmin (5, 27) Sixty-six percent of ESTSCLE are ER positive,and 100 % are PGR positive (5) Sex cord-like elements can also be found in LG-ESS,but they have no influence on the tumor’s behavior per se Focal masses with circum-scribed margins are benign, while tumors with infiltrating margins exhibit the prog-nostic behavior of LG-ESS Risk of recurrence, frequency of cervical involvement andfrequency of peritoneal dissemination are all higher for ESTSCLE than for UTROSCT(see below) Their behavior corresponds to the differing cytological criteria as well

as to the fact that 50 % of type I, but only 6.7 % of type II tumors exhibit LVI (5).From a clinical perspective, both entities should therefore be regarded as tumors withuncertain behavior or with low malignant potential (13) Further data pertaining toprognosis are described in the section on type II below Clinical features, diagnosticsand therapy all largely correspond to those of ESN, LG-ESS or UTROSCT The sameapplies for RX and R1 resections and potential adjuvant therapy Further detail is pro-vided in the section on UTROSCT One key problem is that diagnosis is usually onlyreached postoperatively Clinical symptom-oriented oncologic follow-up and aftercareanalogous to that provided or recommended for LG-ESS (cf Chapter 4) should be ren-dered at least in cases in which patients have undergone conservative surgery and/or

in which surgery has left RX or R1 margin status This also includes endoscopic

follow-up when there is a corresponding indication Special imaging-diagnostic techniquesneed not be performed in the course of follow-up, with the exception of TVS whennecessary

The treatment of recurrences and metastases should also be conducted analogous

to ESN and LG-ESS

Endometrial stromal tumors that contain sections with characteristics and features of ovarian sex cord stromal tumors are referred to as endometrial stromal tumors with sex cord-like elements (ESTSCLE) if the sex cord-like elements account for more than 10 but < 50 % of the tumor’s total vol- ume These tumors derive from the endometrial stroma and are also referred to as uterine tumors with sex cord-like elements type I In contrast to type II tumors, type I tumors only immunohisto-

chemically express one sex cord marker They should be clinically and prognostically classified as tumors with uncertain behavior Surgical therapy is thus largely guided by the criteria for low-grade endometrial stromal sarcoma Adjuvant therapy is not indicated when such tumors have been sub- jected to adequate surgery.

3.2.4 Uterine tumors with sex cord-like elements type II (UTROSCT, uterine tumors resembling ovarian sex-cord tumors)

Uterine tumors than consist entirely or more than 50 % of sex cord-like elements arealso referred to as uterine tumors with sex cord-like elements type II, or UTROSCT(uterine tumors resembling ovarian sex-cord tumors) (13) Type II tumors accountfor about 39 % of both subtypes combined (5) UTROSCT occur in patients aged be-tween 10 and 69 years, usually in premenopausal i.e pubescent patients (mean age42–52 years) (5, 22) Seventy-five percent of patients are nulliparous As is also thecase for ESTSCLE and other uterine mesenchymal tumors, numerous sources report

an association between UTROSCT and exposure to tamoxifen (5, 20, 39) Cytogeneticanalyses suggest that UTROSCT do not belong to the EST family of tumors, not leastdue to the fact that the JAZF1-SUZ12 fusion genes (typical for EST) are not trace-able in UTROSCT (27, 35, 52) Therefore, despite numerous commonalities, UTROSCTand ESTSCLE should be regarded as independent entities The morphologic andimmunohistochemical features and findings are also supportive of the assumption

of independent sex cord differentiation from pluripotent mesenchymal uterine cells.Since their origin has yet to be fully resolved, the WHO classifies UTROSCT under thecategory of mesenchymal tumors – endometrial stromal and related tumors (36).Like ESN, the usually well-circumscribed whitish to yellowish tumors (Fig 3.2.2(A)) are predominantly localized in the uterine wall, and sometimes in the endome-trium (2, 51) They can also present as polypoid, sometimes cystic lesions and reachdeep into the cavum as pedunculated tumors Type II tumors can also develop inthe endometrium, remain there or exhibit wide/ample growth into the myometrium.Type II tumors have a mean size of 6–7 cm, but lesions with diameters of up to 27 cm inthe largest dimension have also been described (2, 9, 22) Like ESN, ESTSCLE and LG-ESS, they are virtually always primarily diagnosed as LM and subjected to surgeryunder that indication A small handful of cases has been covered in the literature

in which tumors exhibited myometrial or VI (2, 22, 44) Analogous to ESTSCLE, thetumor cells are arranged in a trabecular fashion, in cords or nests, or form tubuli.Cells reminiscent of Sertoli or granulosa cells can also be found The stroma can beendometrioid or fibrous and usually account for less than 50 % of total tumor vol-ume The nucleoli are small, inconspicuously round or oval and exhibit only littlepleomorphism Fifty percent of type I and 28.6 % of type II tumors exhibit nuclearpleomorphism (5) Nuclear pleomorphism is negatively correlated with ER expressionand positively correlated with CD10 expression (5) Epithelioid cells that do not stain

▸ Fig 3.2.2:UTROSCT in macroscopy and microscopy (A) parts of a UTROSCT subjected to lation Maturation was apparently associated with a production of steroid hormones or similar substances This assumption is supported by the observed vacuolization (F) of the cells and the bright yellow color reminiscent of a yellow body or the adrenal cortex; (B) Due to the tumor’s high cellular density, in low magnification it looks reminiscent of a stromal nodule or cellular leiomyoma,

morcel-or a low-grade endometrial stromal sarcoma when pomorcel-orly circumscribed; (C) staining with desmin reveals a prognostically more favorable smooth muscle differentiation; (D) CD10, as an endometrial stroma marker, could not be verified here; (E) the presence of small trabecular cell accumulations that gradually go over into nests of finely vacuolized cells with ample cytoplasm is a decisive diag- nostic feature The latter cells are reminiscent of lutein cells from the ovary or even adrenal cortex cells; (F) findings from (E) under stronger magnification; (G)–(J) cells depicted in (E), (F) express markers that are typical for such tissues in varying degrees, for instance cytokeratins (G), inhibin- alpha (H), melan-A (I) and calretinin (J), allowing them to be classified as maturing sex cord-tissue cells.

with CD10 can also be present (50) MI is typically 3 M/10 HPF or lower (5, 52), but canalso reach 9 M/10 HPF Necrosis and hemorrhages are uncommon

UTROSCT are often positive for cytokeratins and EMA, almost always positive forCD10 and vimentin, and virtually without exception positive for ER and PGR (2, 5, 50).Nearly all UTROSCT express 1 or 2 smooth muscle markers like for instance actin,caldesmon and desmin According to another source, caldesmon shows no reaction inthis type of tumor (2) Tumors are reactive to actin and desmin only when there are sec-tions with smooth muscle differentiation Calretinin, inhibin, CD99 and melan-A arethe most important IHC markers for sex cord cells (5, 13, 14, 22, 40, 52) Positivity forcalretinin as well as at least one of the other aforementioned markers is enough to jus-tify a diagnosis of UTROSCT (Fig 3.2.2 (B)–(I)) (13, 40) There is an interesting account

of a case in which a patient presented with elevated prolactin levels and galactorrhea

at the time of primary and recurrent diagnosis The prolactin values returned to mal levels following primary surgery and surgery on recurrent disease (37)

nor-ESTSCLE, LG-ESS with sex cord-like elements, epithelioid LM, endometrioid cinoma with sex cord-like elements, and metastasized ovarian sex cord tumors areregarded as the most important DD Cases have been reported of AS with a predomi-nating UTROSCT component that exhibited the typical histologic and immunohisto-chemical features of both of these entities (cf AS Chapter 6, Vol 2) (46) UTROSCTlocalized in the cervix can clinically mimic adenocarcinoma The absence of signifi-cant cellular atypia and mitotic activity, the characteristic pattern in which the cellsare arranged, and the IHC features are however strongly suggestive of UTROSCT (23).UTROSCT largely exhibit the same clinical behavior as ESN and ESTSCLE, includ-ing heavy menstrual bleeding or postmenopausal bleeding (51) Clinical diagnosticsand further clinical DD are thus identical to those of ESN and ESTSCLE The frequentlyreported presence of epithelioid cells should give rise to also considering PEComasand epithelioid smooth muscle tumors in the DD context UTROSCT can be differen-tiated from ESTSCLE by measuring the JAZF1-SUZ12 gene fusion, which is present in

Fig 3.2.3:Slightly heterogeneous tumor that is roughly isoechoic to normal myometrium; the irregular but relatively smooth margins are an important factor suggestive of an abnormal or unusual mesenchymal tumor.

ESTSCLE but not in UTROSCT (51) Only very little is known regarding the sonographiccharacteristics of UTROSCT (Fig 3.2.3)

UTROSCT are usually benign and less aggressive than ESTSCLE, another factor infavor of regarding these two types of neoplasms as independent entities Since occur-rences of LVI, nodal positivity, recurrences and metastasization as well as peritonealdissemination have been described in the literature (4, 5, 6, 37, 51), UTROSCT, too,are defined as tumors with uncertain behavior or low malignant potential (13) Recur-rence correlates with infiltrative borders, VI, frequent mitotic figures, cytologic atypiaand serosal rupture (40) One meta-analysis (5) identified five variables that are statis-tically associated with poorer DFS, including: pelvic pains at the time of diagnosis;type I disease (ESTSCLE); tumor diameter > 10 cm; cervical or extrauterine spread;and LVI The same publication registered four cases of recurrence and one death of

a patient with metastasized UTROSCT in a median follow-up period of 15 mo Mediantime to relapse was 24 mo One-year, 2-year and 5-year DFS after resection were 97, 92.7and 69.7 %, respectively Corresponding 1-year, 2-year and 5-year OS was 97 % Strat-ification according to type I, type II and non-specifiable tumors revealed significantdifferences between 2-year and 5-year DFS, at 23.8 vs 100 % (type I), 100 vs 100 %(type II) and 50 vs 81.8 % (not specified)

ESTSCLE and UTROSCT are not covered in the NCCN Recommendations THE stitutes the therapeutic method of choice, not least because their behavior and malig-nant potential is uncertain (13, 40) While the tumors usually express ER and PGR,there is no evidence to suggest that the ovaries should be removed In the cases oftype I and II tumors covered in a meta-analysis, 65 % were subjected to TAH with BSO,

con-19 % of patients only underwent TAH, and about 15 % underwent TE There is oneaccount in which a patient underwent TE and later had a successful pregnancy eventhough the tumor margins had been infiltrative (21) Since the behavior of such tumors

is uncertain, the tumor should not be injured during surgery, analogous to other plasms with uncertain malignant potential Accordingly, morcellation or SLH should

neo-be avoided According to the meta-analysis cited above (5), BSO has no impact on

prognosis, neither for type I nor for type II tumors, and thus need not be routinelyperformed Conservative surgery leaving R0 resection margins appears to be a viableoption in cases in which patients wish to preserve their fertility (2, 3, 19, 21), but shouldremain the exception Conservative surgical procedures can be opted for if the follow-ing criteria are fulfilled: not ESTSCLE, no LVI, no distant metastases, tumor diameter

< 10 cm (5)

The main problem lies in the fact that UTROSCT, too, are virtually always tally diagnosed as such postoperatively In general, surgical management of UTROSCTshould be guided by the surgical criteria for STUMP (cf Chapter 1)

inciden-Adjuvant therapy is not deemed necessary for both tumor types, and no specificmodes thereof are in fact known (5) In light of the fact that such tumors regularlyexpress HR, applying adjuvant ablative or additive HT could be adequate following

RX or R1 resections Conservative surgery has been followed up with adjuvant gestin therapy in some reported cases No recurrences were reported (2) Subjecting aUTROSCT that had been clinically diagnosed as LM to treatment with GnRH analoguesonly achieved temporary remission of symptoms (51) Applying HT should, therefore,only be regarded as a “therapy attempt”, rather than recommended or standard prac-tice In this context, these cases should be approached analogous to ESN or ESTSCLE.Providing clinical symptom-based oncologic follow-up and aftercare appears to

pro-be sensible at least when conservative surgery has pro-been performed and/or in cases of

RX or R1 margin status With the exception of TVS, special imaging-diagnostic sures are not required Analogous to LG-ESS and STUMP, performing follow-up LSCafter 3–6 mo is advisable in such cases (cf Chapter 4)

mea-Recurrences and metastases should best be surgically removed Reference cangenerally be made to the criteria and specifications in place for LG-ESS (cf Chapter 4)

in this regard According to a meta-analysis (5), all cases of recurrence observed todate have been subjected to resection, sometimes multiply HT can be opted for first

in cases in which HR are positive and surgery is not an option There is one report of asuccessful remission being achieved under AI therapy (6) In one case, a patient whounderwent extensive surgery on a recurrent type II tumor was subsequently subjected

to CHT using bleomycin, etoposide and cisplatin The patient developed no further currences within one year (37), though it remains unknown whether this course was

re-a result of the re-applied CHT

Another publication recounts a case in which a patient with metastasized OSCT underwent CHT consisting of ifosfamide plus carboplatin as well as cyclophos-phamide, vincristine, doxorubicin plus dacarbazine Said therapy failed to achieve aremission (16)

UTR-Uterine tumors that consist entirely of sex cord-like elements, or such in which sex cord-like ements account for more than 50 % of total tumor volume, are termed UTROSCT (uterine tumors resembling ovarian sex-cord tumors) or as uterine tumors with sex cord-like elements type II These

el-tumors exhibit the same clinical behavior and imaging-diagnostic features as endometrial stromal nodules, but do not derive from them In contrast to type I tumors, they immunohistochemically ex- press multiple sex cord markers UTROSCT are prognostically classified as tumors with uncertain behavior Total abdominal hysterectomy without injuring the uterus is regarded as the therapeutic method of choice Organ-sparing surgery can be opted for when patients desire to preserve their fertility Providing follow-up and aftercare analogous to that for low-grade endometrial stromal sarcoma should be considered when conservative procedures have been opted for There is no indication for adjuvant therapy when adequate surgery has been performed.

(3) Berretta R, Patrelli TS, Fadda GM, Merisio C, Gramellini D, Nardelli GB Uterine tumors bling ovarian sex cord tumors: a case report of conservative management in young women Int J Gynecol Cancer 2009; 19: 808–810

resem-(4) Biermann K, Heukamp LC, Büttner R, Zhou H Uterine tumor resembling an ovarian sex cord tumor associated with metastasis Int J Gynecol Pathol 2008; 27: 58–60

(5) Blake EA, Sheridan TB, Wang KL, Takiuchi T, Kodama M, Sawada K, Matsuo K Clinical teristics and outcomes of uterine tumors resembling ovarian sex-cord tumors (UTROSCT): a systematic review of literature Eur J Obstet Gynecol Reprod Biol 2014; 181: 163–170

charac-(6) Blinman P, Tattersall MH A case of uterine tumour resembling ovarian sex cord tumour sponding to second-line, single agent anastrazole Intern Med J 2009; 39: 617–619

re-(7) Boyle DP, McCluggage WG Peritoneal stromal endometriosis: a detailed morphological sis of a large series of cases of a common and under-recognised form of endometriosis J Clin Pathol 2009; 62: 530–533

analy-(8) Cacciatore B, Lehtovirta P, Wahlström T, Ylöstalo P Ultrasound findings in uterine mixed rian sarcomas and endometrial stromal sarcomas Gynecol Oncol 1989; 35: 290–293

mülle-(9) Carta G, Crisman G, Margiotta G, Mastrocola N, Di Fonso A, Coletti G Uterine tumors bling ovarian sex cord tumors A case report Eur J Gynaecol Oncol 2010; 31: 456–458

resem-(10) Chu PG, Arber DA, Weiss LM, Chang KL Utility of CD10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: an immunohistochemical comparison of

34 cases Mod Pathol 2001; 14: 465–471

(11) Clement PB, Scully RE Uterine tumors resembling ovarian sex-cord tumors A clinicopathologic analysis of fourteen cases Am J Clin Pathol 1976; 66: 12–525

(12) Clement PB, Young RH, Scully RE Stromal endometriosis of the uterine cervix A variant of endometriosis that may simulate a sarcoma Am J Surg Pathol 1990; 14: 449–455

(13) Czernobilsky B Uterine tumors resembling ovarian sex cord tumors: an update Int J Gynecol Pathol 2008; 27: 229–235

(14) de Leval L, Lim GS, Waltregny D, Oliva E Diverse phenotypic profile of uterine tumors bling ovarian sex cord tumors: an immunohistochemical study of 12 cases Am J Surg Pathol 2010; 34: 1749–1761

resem-(15) Dionigi A, Oliva E, Clement PB, Young RH Endometrial stromal nodules and endometrial mal tumors with limited infiltration: A clinicopathologic study of 50 cases Am J Surg Pathol 2002; 26: 567–581

stro-(16) Di Vagno G, Cormio G, Resta L, Colucci GA, Provenzano L, Selvaggi L Uterine tumour sembling an ovarian sex-cord tumour presenting with spontaneous haemoperitoneum in pregnancy Aust N Z J Obstet Gynaecol 1996; 36: 213–215

re-(17) Fdili Alaoui FZ, Chaara H, Bouguern H, Melhouf MA, Fatemi H, Belmlih A, Amarti A dometrial stromal nodule: report of a case Case Report Med 2011; 2011: 260647 doi: 10.1155/2011/260647

En-(18) Furukawa R, Akahane M, Yamada H, Kiryu S, Sato J, Komatsu S, Inoh S, Yoshioka N, Maeda E, Takazawa Y, Ohtomo K Endometrial stromal sarcoma located in the myometrium with a low- intensity rim on T2-weighted images: report of three cases and literature review J Magn Reson Imaging 2010; 31: 975–979

(19) Garuti G, Gonfiantini C, Mirra M, Galli C, Luerti M Uterine tumor resembling ovarian sex cord tumors treated by resectoscopic surgery J Minim Invasive Gynecol 2009; 16: 236–240 (20) Giordano G, Lombardi M, Brigati F, Mancini C, Silini EM Clinicopathologic features of 2 new cases of uterine tumors resembling ovarian sex cord tumors Int J Gynecol Pathol 2010; 29: 459–467

(21) Hillard JB, Malpica A, Ramirez PT Conservative management of a uterine tumor resembling an ovarian sex cord-stromal tumor Gynecol Oncol 2004; 92: 347–352

(22) Irving JA, Carinelli S, Prat J Uterine tumors resembling ovarian sex cord tumors are typic neoplasms with true sex cord differentiation Mod Pathol 2006; 19: 17–24

polypheno-(23) Kabbani W, Deavers MT, Malpica A, Burke TW, Liu J, Ordoñez NG, Jhingran A, Silva EG Uterine tumor resembling ovarian sex-cord tumor: report of a case mimicking cervical adenocarci- noma Int J Gynecol Pathol 2003; 22: 297–302

(24) Kim KR, Jun SY, Park IA, Ro JY, Nam JH Endometrial stromal tumor with limited infiltration and probable extrauterine metastasis: report of a case Ann Diagn Pathol 2005; 9: 57–60.

(25) Köhler G, Belau, A, Dennis K, Hesse J, Köller M, Krichbaum J, Kühnast M, Lehnhoff H,

Lehr A, Linke L, Müller S, Riechmann C, Schädler J, Schalitz S, Ständer C, Simon J, Spring P, Trojnarska D, Wilcke S, Witte, N, Zygmunt M.: Deutsches klinisches Kompetenzzentrum für genitale Sarkome und Mischtumoren an der Universitätsmedizin Greifswald (DKSM) und Kooperationspartner VAAO Deutschland und FK Frankfurt/Sachsenhausen Datenbank und Promotions- und Forschungsgruppe genitale Sarkome, Greifswald 2016, http://www2.medizin uni-greifswald.de/gyn/forschung/dksm/

(26) Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Dal Cin P, Fletcher JA, Sklar J Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors Proc Natl Acad Sci USA 2001; 98: 6348–6353

(27) Krishnamurthy S, Jungbluth AA, Busam KJ, Rosai J Uterine tumors resembling ovarian sex-cord tumors have an immunophenotype consistent with true sex-cord differentiation Am J Surg Pathol 1998; 22: 1078–1082

(28) Lloreta J, Prat J Endometrial stromal nodule with smooth and skeletal muscle components simulating stromal sarcoma Int J Gynecol Pathol 1992; 11: 293–298

(29) Löning, T Funktionelle Morphologie und Pathologie des Myometriums In: Löning T, Riethdorf L (eds.) Pathologie der weiblichen Genitalorgane III – Pathologie des Uterus der Vagina und Vulva Springer, Berlin–Heidelberg–New York 2001; 652–704

(30) Moinfar F, Azodi M, Tavassoli FA Uterine sarcomas Pathology 2007; 39; 55–71

(31) Nucci MR, Quade BJ Uterine mesenchymal tumors In: Crum PC, Nucci MR, Lee KR (eds.) nostic Gynecologic and Obstetric Pathology 2nd edn Elsevier-Saunders, Philadelphia 2011; 582–639

Diag-(32) Oliva E, Clement PB, Young RH, Scully RE Mixed endometrial stromal and smooth muscle mors of the uterus: a clinicopathologic study of 15 cases Am J Surg Pathol 1998; 22: 997–1005 (33) Oliva E, Clement PB, Young RH Epithelioid endometrial and endometrioid stromal tumors: a report of four cases emphasizing their distinction from epithelioid smooth muscle tumors and other oxyphilic uterine and extrauterine tumors Int J Gynecol Pathol 2002; 21: 48–55

tu-(34) Oliva E, Young RH, Amin MB, Clement PB An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: a study of 54 cases emphasizing the impor- tance of using a panel because of overlap in immunoreactivity for individual antibodies Am J Surg Pathol 2002; 26: 403–412

(35) Oliva E, de Leval L, Soslow RA, Herens C High frequency of JAZF1-JJAZ1 gene fusion in trial stromal tumors with smooth muscle differentiation by interphase FISH detection Am J Surg Pathol 2007; 31: 1277–1284.

endome-(36) Oliva E, Caracangiu ML, Carinelli SG, Ip P, Loening T, Longacre TA, Nucci MR, Prat J, Zaloudek CJ Mesenchymal tumors In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH (eds.) WHO Clas- sification of Tumors of Female Reproductive Organs 4th edn IARC: Lyon 2014; 135–152 (37) O’Meara AC, Giger OT, Kurrer M, Schaer G Case report: Recurrence of a uterine tumor resem- bling ovarian sex-cord tumor Gynecol Oncol 2009; 114: 140–142

(38) Ozaki K, Gabata T Magnetic resonance imaging of an endometrial stromal nodule J Obstet Gynaecol Res 2016; 42: 99–102

(39) Oztekin O, Soylu F, Yigit S, Sarica E Uterine tumor resembling ovarian sex cord tumors in a patient using tamoxifen: report of a case and review of literature Int J Gynecol Cancer 2006; 16: 1694–1697

(40) Pradhan D, Mohanty SK Uterine tumors resembling ovarian sex cord tumors Arch Pathol Lab Med 2013; 137: 1832–1836

(41) Reinhold C, Zand KR Endometrial stromal sarcoma In: Hricak HH, Akin O, Sala E, Ascher SM, Levine D, Reinhold C (eds.) Diagnostic Imaging Gynecology Amyrsis 2007, 2-162–2-166 (42) Rush DS, Tan J, Baergen RN, Soslow RA h-Caldesmon, a novel smooth muscle-specific anti- body, distinguishes between cellular leiomyoma and endometrial stromal sarcoma Am J Surg Pathol 2001; 25: 253–258

(43) Schilder JM, Hurd WW, Roth LM, Sutton GP Hormonal treatment of an endometrial stromal nodule followed by local excision Obstet Gynecol 1999; 9: 805–807

(44) Staats PN, Garcia JJ, Dias-Santagata DC, Kuhlmann G, Stubbs H, McCluggage WG, De lis M, Kommoss F, Soslow RA, Iafrate AJ, Oliva E Uterine tumors resembling ovarian sex cord tumors (UTROSCT) lack the JAZF1-JJAZ1 translocation frequently seen in endometrial stromal tumors Am J Surg Pathol 2009; 338: 1206–1212

Nicto-(45) Stemme S, Ghaderi M, Carlson JW Diagnosis of endometrial stromal tumors: a logic study of 25 biopsy specimens with identification of problematic areas Am J Clin Pathol 2014; 141: 133–139

clinicopatho-(46) Stolnicu S, Balachandran K, Aleykutty MA, Loghin A, Preda O, Goez E, Nogales FF Uterine adenosarcomas overgrown by sex-cord-like tumour: report of two cases J Clin Pathol 2009; 62: 942–944

(47) Su TF, Chao TK, Lee HS, Perng CL, Nieh S Malignant potential of an endometrial stromal tumor with limited infiltration: a case report Int J Surg Pathol 2014; 22: 559–563

(48) Sumathi VP, Al-Hussaini M, Connolly LE, Fullerton L, McCluggage WG Endometrial stromal neoplasms are immunoreactive with WT-1 antibody Int J Gynecol Pathol 2004; 23: 241–247 (49) Tavassoli KL, Norris HJ Mesenchymal tumors of the uterus A clinicopathological study of 60 endometrial stromal nodules Histopathology 1981; 5: 1–10

(50) Tinelli A, Hurst BS, Hudelist G, Tsin DA, Stark M, Mettler L, Guido M, Malvasi A Laparoscopic myomectomy focusing on the myoma pseudocapsule: technical and outcome reports Hum Reprod 2012; 27: 427–435.

(51) Umeda S, Tateno M, Miyagi E, Sakurai K, Tanaka R, Tateishi Y, Tokinaga A, Ohashi K, Furuya M Uterine tumors resembling ovarian sex cord tumors (UTROSCT) with metastasis: clinicopatho- logical study of two cases Int J Clin Exp Pathol 2014; 7: 1051–1059

(52) Zaloudek C, Hendrickson MR, Soslow RA Mesenchymal tumors of the uterus In: Kurman RJ, Ellenson LH, Ronnet M (eds.) Blaustein’s Pathology of the Female Tract 6th edn Springer 2011; 453–527

Image references

Andergassen U Klinikum Universität München, Campus Innenstadt, Klinik Frauenheilkunde und Geburtshilfe, München Fig 3.1.3 (A), (B)

Evert M, Evert K Universitätsmedizin Greifswald, Institut für Pathologie, Greifswald.

Fig 3.1.1 (A), (B); 3.2.1 (A)–(H); 3.2.2 (A)–(J)

Job H Theresienkrankenhaus und St Hedwig-Klinik, Gynäkologisch geburtshilfliche Abteilung, Mannheim Fig 3.1.2

Niesel A, Klinik Preetz, Abt Gynäkologie, Preetz Fig 3.2.3

4 Low-grade endometrial stromal sarcoma

4.1 Uterine low-grade endometrial stromal sarcoma

4.1.1 General, epidemiology, etiology, pathogenesis, staging

LG-ESS is a pure homologous sarcoma Endometrial stromal sarcomas had originallybeen divided into LG-ESS and HG-ESS This differentiation was primarily based on thenumber of M/10 HPF Tumors with < 10 M/10 HPF were categorized as LG-ESS, whilesuch with ≥ 10 M/10 HPF were termed HG-ESS It had, however, already been known forsome time that prognosis did not always correlate with mitotic count (69) Accordingly,the categorization of tumors into LG- and HG-ESS along the lines of MI was abandonedsome years ago Instead, stromal sarcomas were pathologico-anatomically differenti-ated into endometrial stromal sarcomas (ESS) and undifferentiated endometrial sar-comas (UES) on the basis of cytologic pleomorphism, the degree of nuclear atypia andthe presence of TCN These two entities also differed in terms of their immunologic andcytogenetic profiles (98), a difference that could be drawn on in cases of uncertaintywhen having to discern between the two Under this classification, ESS (optionally ESSlow-grade) constituted the more differentiated and prognostically more favorable tu-mor, while UES was comparably less differentiated and clearly the more aggressive ofthe two According to the criteria of the time, tumors with an MI of ≥ 10 M/10 HPF could

be ESS, and tumors with an MI < 10 M/10 HPF could be classified as UES tion between the two was thus guided by cytologic/nuclear properties and features.Already at the time, the change in classification and the often still lacking differ-entiation between the two tumor entities served to compromise the validity or weight

Differentia-of numerous studies

The current WHO Classification of 2014 (172) has returned to the distinction intoLG-ESS and HG-ESS, but now also includes UUS Tumors previously categorized asUES need to be stratified into HG-ESS with an intermediate but nonetheless poor prog-nosis on the one hand, and UUS with the worst prognosis on the other

While not many data have been gathered from randomized studies thus far, scale retrospective SEER analyses have been conducted that provide a lot of meaning-ful information The current NCCN Guidelines – Uterine Neoplasms (160) are definitelyalso a helpful resource, notwithstanding the fact that they are almost entirely based

larger-on “lower-level evidence” due to the lack of available experience, research and tigation

inves-According to DKSM data, in Germany, LG-ESS account for 65 % of all sarcomasthat originate from the endometrial stroma, with UUS and HG-ESS accounting for theremainder They account for 18.1 % of all uterine sarcomas when CS are included,and 26.4 % when CS are excluded (115) In a Norwegian cohort of similar size, they

accounted for 20 % of all uterine sarcomas excluding CS (2) They have an incidence

of 0.23 per 100,000 women in southern European countries (146), and about 0.3 per100,000 women in northern Europe, where it is at its highest in women aged between

45 and 49 years Incidence increases most steeply during the fourth decade of life, andremains largely stable/constant during and as of the fifth decade (117)

According to various sources, the age of affected women ranges from 15 to 96 years.Median age is 42–52 years; 50 to 88 % of LG-ESS patients are premenopausal (18, 36,237) The age range in Germany is 18–80 years according to DKSM data (115), medianage is 46 years, and only 18 % of presenting women are postmenopausal LG-ESS thuspredominantly arise in young to middle-aged women Disease in women aged 20 to

30 is by no means the exception Correspondingly, LG-ESS occur at a considerablyyounger age than HG-ESS and UUS do (see also Tab 6.1.1) (36, 115, 128, 199, 207) Blackwomen are said to be affected more frequently than white women (140)

A look at age distribution reveals an epidemiologic correlation between LG-ESSand ESN – the latter arise in patients aged between 23 and 86 years, and 75 % ofpatients are premenopausal (241) LG-ESS and ESN also share clear pathogenetic com-monalities On the one hand, the microscopic differences between these two tumortypes are gradual rather than abrupt or clear-cut On the other hand, both LG-ESSand ESN exhibit t(7;17) translocations and consecutive fusions of the JAZF1 and SUZ12(previously: JJAZ1) genes as well as t(6;7) translocations (JAZF1/PHF1 gene fusion)(119, 166) Interestingly, this translocation of the former can also be observed in ESNand LG-ESS that exhibit focal smooth muscle differentiation, which allows the con-clusion that such tumors originate from a pluripotential mesenchymal precursor cell(progenitor cell) (166, 171) The putative localization of such a progenitor cell withinthe myometrium could help to explain why LG-ESS and ESN both predominantly arisethere But according to recent research, not all LG-ESS exhibit LG-ESS related gene fu-sions (see also subchapter DD) (151) Both LG-ESS and ESN express common immuno-histochemical markers (CD10, SMA, WT-1), another factor that supports the notion thatstromal and myogenic tumors might derive from the same precursor cell (220) BothLG-ESS and ESN are usually DNA diploid, cytogenetically speaking (26)

Regarding epidemiology, it is interesting to note that, compared to LG-ESS, ESNare only rarely described In the DKSM database, LG-ESS and ESN have a ratio of only

100 to 3 (115) Subtle analyses have revealed that, when ESN and LG-ESS are summedtogether, the latter account for a substantially larger share (84 %) than the former(16 %) (218) Given the fact that microscopically differentiating between LG-ESS andESN is very difficult, this can essentially only be explained by the fact that a non-negligible number of ESN (for example such with limited infiltration, cf Chapter 3)are probably classified or diagnosed as LG-ESS just to be “on the safe side” (19) Thiscould also serve to explain why so many LG-ESS take very good courses The situationhere might well be similar to the one involving STUMP and LMS (cf Chapters 1 and 2).There is an assumed epidemiologic association between these neoplasms and hy-perestrogenic states, including gestation, endometriosis, assisted reproduction and

the administration of xenoestrogens Xenoestrogens have actually been found to bepresent within tumors themselves Aromatase expression has also been found in LG-ESS tissues (187) Furthermore, it is also known that variations in the CYP19 gene canpromote estrogen production via aromatases The sum of all data including the ex-pression of ER and PGR give strength to the assumption that estrogens are involved

in the etiology, pathogenesis and progression of LG-ESS (186, 187, 188, 189, 190, 191).Average parity is 1.9, and 22 % of women have given birth to < 2 children (199, 237)

It is also highly probable that LG-ESS can develop directly from an endometriosis,not least because LG-ESS are often associated with the latter (56, 148) and becausearomatase can also be present in endometriotic plaque (219) However, since LG-ESSare also found in extragenital endometriosis, this observation also allows the conclu-sion to be drawn that the precursor cells are also situated in the endometrial stroma,and not only in the myometrium

The role of HRT is highly debated, at least regarding epidemiology In a largerFinnish study, exposure to HRT for longer than five years was accompanied by signif-icant risk elevations for all uterine sarcomas (97) More recent extensive northern Eu-ropean data sources, in contrast, suggest that HRT has no impact on the incidence ofstromal sarcomas (117) In general, anamnestic or ongoing tamoxifen or toremifen in-take is regarded as an (albeit rare) etiologic factor for all uterine sarcomas that shouldnot be underestimated (16, 87, 89, 105) The pathogenetic mechanism at play is said to

be a mutagenic effect rather than the inherent estrogeneous effect, not least becausethe prognostically unfavorable non-endometrial ER negative EC are almost twice asfrequent compared to the normal population when patients have previously been sub-jected to or are still receiving tamoxifen treatment (161) Such tamoxifen associationalso applies to CS, HG-ESS, UUS, LMS and heterologous sarcomas (16) At least for

CS, experimental studies have shown that the tumorigenesis provoked by tamoxifen

is not dictated by the ER (9) Accordingly, it can occasionally so happen that EC andLG-ESS occur simultaneously following tamoxifen treatment (35) and thus constitutethe preconditions for the development of CS via collision, at least theoretically

A medical history of pelvic irradiation is also said to constitute a risk factor forLG-ESS (240)

Since 2009, new FIGO staging and UICC TNM classification have been in placefor LMS and stromal sarcomas (76, 182, 214) (see also Tab 2.1.1) All pelvic and para-aortic LN are defined as regional LN Simultaneous LG-ESS of the uterine corpus andthe ovaries or the pelvis in association with ovarian or pelvic endometriosis should beclassified as independent primary tumors

One problem lies in the fact that the results from numerous studies cannot besimply transferred or said to apply to the new staging For example, in the old stagingsystem, stage II included such tumors that are confined to the uterus but extend to thecervix The current stage II, by contrast, refers to disease that has spread beyond theuterus yet only to the pelvis Stage III has experienced a dramatic adaptation Tumorsthat now belong to stage III had previously been categorized as stage IV Therapeutic

recommendations that had in the past applied to stages II and III can thus not simply

be adopted for current FIGO and UICC stage II and III In the monograph at hand, theold data have been adapted to the new classification where necessary

Low-grade endometrial stromal sarcomas are pure homologous uterine sarcomas that nantly arise in premenopausal patients They need to be clearly distinguished and delineated from high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas It is very likely that endometrial stromal nodules are a precursor for low-grade endometrial stromal sarcoma The JAZF1-SUZ12 gene fusion is the most important genetic criterion of both low-grade endometrial stromal sarcomas and stromal nodules Tamoxifen exposure plays a role in terms of etiology The impact of hormone replacement therapy on tumorigenesis is subject to debate New FIGO staging and UICC TNM classification for leiomyosarcomas and stromal sarcomas have been in place since 2009.

predomi-4.1.2 Macroscopic and microscopic features

LG-ESS predominantly have the appearance of an intramural nodulated tumor withstrong similarities to an LM or the rare ESN (Fig 4.1.1 (A)) Submucously localizedtumors can also be pedunculated, prolapse/protrude from the cervix upon furthergrowth (Fig 4.1.1 (B)–(E)) and thus appear to resemble, or mimic, pedunculated LM

or polyps

Accordingly, between 69 and 75 % of LG-ESS are subjected to primary surgery der a diagnosis of LM (18, 115, 199, 237) LG-ESS have a median size of 5.5–5.8 cm(82, 115) Compared to LM, LG-ESS almost always have a softer consistency, butthey are considerably more solid than common fibroglandular mucosal polyps.However, this feature is often only discovered during surgery Larger tumors canentirely displace the uterine cavity (Fig 4.1.1 (B)) Like LM, the cut surface may ex-hibit whorled structures, but is usually significantly smoother (Fig 4.1.1 (A), (B)) LikeESN, the opened tumor often has a yellowish to yolk-yellow (Fig 4.1.2 (A)), tan-yellowand sometimes light reddish appearance On gross examination, intramural tumorscan appear well-circumscribed and can displace the surrounding myometrium andendometrium Compressed tumor and surrounding tissue can form a kind of pseudo-capsule (Fig 4.1.2 (A)) Analogous to the results from microscopy, infiltrations intothe musculature are sometimes already visible to the naked eye as cords, small nod-ules or trabeculae Macroscopically visible finger-, worm- or tongue-like invasion,when present, are a typical gross characteristic The tumor margins are more orless smooth, diffuse or clearly infiltrative, depending on the extent of the tumor’sinfiltrative growth

un-Cystic structures are observed in 14 % of cases (115) and can be clearly visualized

in sonography and MRI Larger pseudocysts sometimes lend the tumor a blueishshimmer that can be seen during surgery There are accounts of LG-ESS consist-ing almost entirely of pseudocysts (see below), though such cases are the exception

(B)

(C)

Fig 4.1.1:Low-grade endometrial stromal sarcoma – macroscopic findings; (A) nodulated tumor that

is barely discernible from leiomyoma on gross observation; (B) large smooth formalin-fixated tumor that fills the entire uterine cavity; (C), (D) pedunculated lesion closely resembling leiomyoma that, like the tumor in (B), has prolapsed/is protruding from the cervix and exhibits expansive hemor- rhages in its distal portions; (E) corresponding findings from vaginoscopy.

(Fig 4.1.9 (A), (C)D) (57, 215) Furthermore, tumors can also be very soft and largely composing Different types of necrosis and focal hemorrhages are grossly discernible

de-to varying degrees in all growth patterns, and often have equivalents in imagingdiagnostic procedures (Fig 4.1.10 (A)–(F), 4.1.12 (B)) (115)

LG-ESS can also exhibit a less common growth pattern in which diffuse trial infiltration forces the myometrium apart/separates it In such cases, the wall ofthe uterus appears enlarged and thickened, with a certain degree of nodulation Direct

myome-(A) (B)

(C)

Fig 4.1.2:Low-grade endometrial stromal sarcoma in macroscopy, microscopy and sonography; (A) cut-open LG-ESS specimen with what appears to be a capsule – in the left of the image – that gradually diminishes (or fades) towards the cut base and crosses over into infiltration on the opposite side that is clearly visible on gross observation; (B) corresponding histological aspect with extensive myometrial infiltration; (C) corresponding sonography of (A) with heterogeneous echogenicity and washy tumor margins.

infiltration of the ligaments and the tube are not uncommon in tumors exhibiting thisgrowth pattern VI can also be grossly discernible There are multiple accounts of ex-pansive intravascular tumors in the form of tumor thrombi (Fig 4.1.3 (A), 4.1.15 (B), (C))with growth into the vena cava (30, 193, 223) Such findings appear to be a consequence

of the fact that the intravascular growth of LG-ESS into both lymphatic and blood sels is cohesive, i.e has direct communication to the main tumor (Fig 4.1.3 (A), (B)).The difference to the discohesive intravascular growth exhibited by HG-ESS and UUS

ves-is clearly dves-iscernible (196) (see also Fig 5.1.3 (D)) Thves-is cohesive intravascular growth

is likely also the reason why LG-ESS only develop distant metastases rather late, andwhy distant metastasization is so rare in LG-ESS

LG-ESS with larger sections of myxoid differentiation usually have a gelatinousmacroscopic appearance (168)

LG-ESS occasionally (albeit very rarely) also originate primarily in the cervix,though such tumors account for only 1.2 % of all cervical sarcomas (22, 235) In con-trast, 11.8 % of corporal tumors exhibit cervical involvement (18)

Overall, LG-ESS consist of cells that are reminiscent of endometrial stroma inthe proliferation phase The cells cannot be morphologically discerned from ESN(cf Chapter 3) Microscopically, LG-ESS are characterized by opulent small uniformcells with oval nuclei, small or absent nucleoli, scant cytoplasm, and poorly definedcytoplasm boundaries Significant atypia are absent by definition (154) Accordingly,the microscopic appearance is monotonous and bland (Fig 4.1.4 (A))

Ample hyaline plaques are often visible and can serve as a helpful criterion for ferentiation from smooth muscle tumors (241) LG-ESS can contain entrapped glandsfrom the surrounding normal endometrium, especially at the margins of the tumor.Intra- and extrauterine LG-ESS with endometrial glands distributed either focally oracross the entire tumor have been described in the literature (LG-ESS with extensiveendometrioid glandular differentiation) (148) Such findings can serve to significantlyexacerbate diagnostic differentiation from AS Necroses and hemorrhages also occur

dif-in LG-ESS (231) LG-ESS can contadif-in ample extensive pseudocysts that are usuallylined with mesenchymal tumor cells (Fig 4.1.9 (A), (D))

◂ Fig 4.1.3:(A) worm-like intravascular tumor dissemination (tumor thrombus) of the hormone ceptor positive low-grade component of a high-grade endometrial stromal sarcoma into the vena iliaca interna and communis Corresponding features were also found at other localizations as well, (B) in low-grade endometrial stromal sarcomas, the intravascular invasion – into a lymphatic ves- sel in this instance – usually remains cohesively connected to the primary tumor and provides the foundation for extensive tumor thrombi on the basis of a tongue-like infiltration, as also depicted in Fig 4.1.15 (A), (B) The endothelium of the lymphatic vessel is stained with the endothelial marker CD31 Tongue-like growth into the vessel at the narrow fissure between the infiltration and the ac- tual tumor is recognizable at the center of the image (arrow) The wide connection to the stated tumor is clearly visible in the lower section of the image (arrow head).

re-(A) (B)

Fig 4.1.4:Low-grade endometrial stromal sarcoma – microscopic features (A) the tumor usually consists of relatively monomorphic cells with scant cytoplasm that are usually arranged in an irregu- lar, sometime fascicular fashion, and that can generally not be cytologically discerned from stromal nodules; (B) cytology is usually monotonous/bland, though mitoses (arrows) can sometimes be traced; (C) necroses (arrows) are rather less common; (D) in contrast, enclosures or “enclaves” of foam cells (vacuolized macrophages) constitute a common finding.

MI does not correlate with diagnosis and prognosis, and is usually measured at around

< 5 M/10 HPF, but can also exceed 10 M/10 HPF Atypical mitoses are rare, and true TCNhardly ever occur (Fig 4.1.4 (B), (C)) The vessels most closely resemble uniformlydistributed endometrial spiral arteries (Fig 4.1.4 (A)) LVI and VI are observed in19.1–26.6 % (18, 115) resp 30.8 % of cases (115) The VI that LG-ESS exhibit differsfrom that of HG-ESS and UUS (72, 196) Compared to the aforementioned entities,LG-ESS harbor cohesive intravascular tumor foci with direct communication from themain tumor and attached to the vessel wall The intravascular foci include tumor cellsand small arteriole-type vessels and are surrounded by a thin fibrous band Vascu-lar markers confirmed the LVI and highlighted positively stained endothelial cellsseparating intravascular tumor foci from the blood itself In contrast, intravasculartumor foci in HG-ESS are composed of discohesive cell clusters, lacking the featuresdescribed in LG-ESS (Fig 4.1.3 (A), (B)) (196) This feature can help to explain whyLG-ESS metastasize much less commonly compared to HG-ESS At the same time,

it is also the cause of tumor thrombi in lymphatic and blood vessels that can reachconsiderable sizes (Fig 4.1.3 (A), 4.1.15 (A), (B)) and that correspond to the worm-likeinvasion into the myometrium (72).

There is a strong likelihood that ESN constitutes a precursor for LG-ESS entiating LG-ESS from ESN on the basis of specimens obtained via morcellation orcurettage can be very difficult to nearly impossible if they contain no neighboring tis-sue Often only focal, tongue-like permeative myometrial invasion (Fig 4.1.5 (A)–(C)),LVI and also VI, stronger vascularity and more frequent endometrial involvement arethe key differences between LG-ESS and ESN

(C)

Fig 4.1.5:Low-grade endometrial stromal sarcoma – differentiation from endometrial stromal nodules (A) tongue-like myometrial invasion is the most important criterion for differentiation from stromal nodules Said invasion can often not be verified in curettage or biopsy specimens, which is why final diagnosis can often only be reached on the basis of the hysterectomy speci- men; (B), (C) myometrial invasions can occasionally already be immunohistochemically verified

in specimens obtained from curettage; (B) the CD10 positive tumor cells overgrow CD10 negative leiomyocytes of the myometrium; (C) in this serial section of (B), the leiomyocytes strongly express caldesmon, while the tumor cells are caldesmon negative (C) thus essentially constitutes the re- verse or “negative” image of (B).

LG-ESS typically have a strong expression of ER and PGR (in 71–95 % of cases) (20, 45,

94, 186), though PGR can be predominant (52, 94) It can so occur that only the

PGR-B isoform is expressed (20) ER and PGR are sometimes heterogeneously distributed(154) Absence of ER and PGR expression has been reported, albeit with ER being neg-ative more frequently than PGR (231, 237) AR are also positive in 45 % of LG-ESS (152).LG-ESS can contain aromatases and can thus synthesize estrogens (187) GnRH re-ceptor expression has also been verified in some cases The HR provide the basis fortherapy with progestins, AI and GnRH analogues CD10 expression is strongly char-acteristic of LG-ESS, though not specific to them (Fig 4.1.5 (B), 4.1.7 (B)) Furthermore,

in terms of myogenic markers, LG-ESS express vimentin, often express SMA and casionally express desmin (44); h-caldesmon is not expressed Up to 50 % of LG-ESSalso express cytokeratins (46) While one source states that LG-ESS do not expressEGFR (176), another suggests that EGFR is expressed in up to 70 % of cases (153) Inanother study, EGFR and PDGFR-β expression were immunohistochemically verified(96) VEGFR, PDGFR, c-Kit, p16, p53, and Ki67 are expressed in 26, 72, 82, 46, 10 and

oc-54 % of tumors (176) WT1 positivity is common (48), but Her-2/neu (10) is not pressed in LG-ESS CD10 expression and the absence of h-caldesmon expression arediagnostically relevant features

overex-Like ESN, LG-ESS can also contain larger sections of myxoid and fibrous entiation that can serve to spread the actual tumor cells far apart except for somefocal accumulations However, such tumors can usually nonetheless be classified asLG-ESS on the basis of their typical localization, their growth pattern, the presence

differ-of characteristic arterioles, the typical endometrial stroma and, not least, the lack differ-ofimmunohistochemical verification of another type of differentiation (168) Rarer mor-phologic variants of LG-ESS include such in which oval to polygonal epithelioid cellswith abundant eosinophilic cytoplasm account for 50 to 90 % of the tumor cells (170).Tumors with partial leiomyogenic differentiation constitute a much more impor-tant variant Tumors are referred to as endometrial stromal sarcomas with mixed en-dometrial and smooth muscle differentiation when smooth muscle cells account formore than 30 % of the tumor The smooth muscle component is usually benign andtypically expresses desmin and h-caldesmon This notwithstanding, the tumor as awhole continues to have low malignant potential and its nature (in terms of benignity

vs malignancy) does not differ from that of pure LG-ESS, i.e said nature is likewisedetermined by the exhibited myometrial and vascular infiltration (154) Like ESN, LG-ESS can also contain sex cord-like elements These tumors have been shown to expressPGR B as the only or predominant progesterone isoform (52) In contrast, tumors with

a myxoid endometrial stromal component, or with elements of smooth muscle entiation and ample benign endometrioid-type glands that exhibit the typical features

differ-of IVLM, are extremely rare (147), as are LG-ESS with heterologous elements consisting

of striated musculature, fat or bone (148)

Low-grade endometrial stromal sarcomas are usually intramurally localized, and are often barely discernible from endometrial stromal nodules or regular leiomyoma on gross observation Low- grade endometrial stromal sarcomas are usually considerably softer than leiomyoma, have a yel- lowish color and a smooth cut surface Necroses, cystic areas and hemorrhages can be present The typical tongue-like, partly nodulated invasions can be macroscopically visible.

Infiltration into surrounding tissues and structures constitutes the only microscopic difference between low-grade endometrial stromal sarcoma and endometrial stromal nodules The morpho- logic aspect of the endometrial stroma is still microscopically discernible Significant atypia are absent by definition and the mitotic index is usually lower than 10 M/10 HPF CD10 constitutes the most important albeit non-specific immunohistochemical marker Low-grade endometrial stromal sarcomas generally express estrogen and progesterone receptors.

4.1.3 Clinical presentation, diagnostics, screening

In about 70 % of cases, LG-ESS is an incidental finding during or after HE that is formed on the basis of an LM diagnosis (18, 115, 199, 237) Between 48 and 72 % of allpatients present with AUB-M in the form of intermenstrual bleeding and/or menorrha-gia, or postmenopausal bleeding AUB, while it may be absent in some patients, thusconstitutes the most common symptom (18, 115, 237) Hypermenorrhea are only rarelyobserved (115) The presence of cervical LG-ESS usually becomes apparent relativelyearly on the basis of vaginal bleeding (235) Tumor growth causes diffuse enlargement

per-of the uterus and is linked with lower abdominal pains in around 20 % per-of cases ings of satiation and pressure in the abdomen are also occasionally reported (115, 237).Palpation reveals a noticeably soft, fleshy consistency and/or a lumpy surface on the(usually enlarged) uterus or the palpated “LM” A soft consistency is generally to betaken as suggestive of a malignant or semi-malignant mesenchymal tumor On aver-age, LG-ESS are said to be not larger than ordinary LM (49) LG-ESS have a mediansize of 5.5–5.8 cm (cf Tab 6.1.1) (82, 115) According to a further study, tumors have

Feel-a meFeel-an size of 6.2 cm (0.3–18 cm), Feel-and 41.2–64.5 % Feel-are > 5 cm (18, 115) Where there

is polypoid growth into the cavity of the uterus, the tumor can expand into the vical canal (Fig 4.1.1 (B)–(E)), and distension of the cervix can cause pain So-called

cer-“rapidly growing LM” or a rapidly growing uterus during pubescence are not commonclinical findings in women with LG-ESS, and are observed in only 6.5 % of cases (18)

By contrast, 17 % (115) to 30 % (53) of all ordinary LM occurring during pubescenceare rapidly growing tumors Compared to LMS and UUS, symptoms associated withrapid tumor growth, like lower abdominal pains and uresiesthesis, are rather lesscommon in LG-ESS patients Nonetheless, uterine growth or “myoma growth” are themost consistent findings, and are to be regarded as strongly suggestive of a malignant

or semi-malignant mesenchymal uterine tumor, especially in postmenopausal women(cf Chapter 6)

LG-ESS are occasionally also discovered upon performing (not necessarily cessful) embolization on assumed LM or after new symptoms arise (49, 111) In general,

unsuc-a munsuc-alignunsuc-ant mesenchymunsuc-al tumor should unsuc-alwunsuc-ays be considered whenever medicunsuc-ation-based or interventional LM therapy has been unsuccessful (32, 93).

medication-It is essential that conventional clinico-gynecologic examination be panied by sonographic examination AUB and postmenopausal uterine bleedingmost commonly suggest that the LG-ESS has developed into the cavum of the uterus.Hysteroscopy and fractional curettage are always indicated in such cases The hys-teroscopic appearance bears similarity either to a pedunculated LM or a polypoidtumor (Fig 4.1.6)

accom-Fig 4.1.6:Hysteroscopic finding of low-grade endometrial stromal sarcoma, a specific diag- nosis cannot be reached.

Since LG-ESS are frequently located intramurally, curettage yields unsuspicious ings or a wrong diagnosis in 50 to 59 % of cases (21, 115, 218) It is thus unavoidablethat HSC (Fig 4.1.9 (B)) and/or curettage result in misdiagnoses, a typical diagnosticpitfall It can so happen on rare occasions that an LG-ESS is located within a myoma(Fig 4.1.7 (A)–(D))

find-Further diagnostic steps should be taken (cf Tab 6.5.1, Fig 6.6.1) in order to row down the diagnostic options whenever there are obvious differences between thediagnosis yielded from analysis of the curettage specimen and the anamnestic, clini-cal and sonographic findings

nar-It is usually sufficient to resort only to a sufficiently representative biopsy imen in cases in which tissue is protruding from the cervix When findings are sus-picious or ambiguous, and the patient refuses more extensive surgical intervention,

spec-a trspec-anscervicspec-al punch biopsy or fine needle biopsy cspec-an be performed for cytologictesting analogous to LMS (see also Chapters 2 and 6) (84, 238) Given the differen-tial diagnostic difficulties involved in histologic and cytologic assessment, and takingIHC into consideration, such measures should be performed separately from definitivesurgery Performing intraperitoneal intraoperative biopsies on tumors that appear to

be intact needs to be regarded very critically in light of the potential for causing tumorcell dissemination (see prognosis) More detail is provided in Chapters 2 and 6

to a diagnosis of “stromal sarcoma” This tumor could also be assessed as constituting low-grade sarcoma with mixed endometrioid and smooth muscle differentiation In this case, the nomencla- ture “low-grade stromal sarcoma within a leiomyoma” was opted for This decision was rooted in the fact that, in this case, the two components were, rather unusually, sharply delineated from each other, with the leiomyoma on the outside surrounding the infiltrative stromal sarcoma at the center Usually, the two types of differentiation are more mixed, with smaller sarcomatous foci and more gradual morphologic transitions.

Analogous to the other types of uterine sarcoma, there is no specific or targeted ing for LG-ESS The current state of knowledge requires that ESN be regarded as aprecursor or presarcomatosis of LG-ESS The absence or minimal presence of cellu-lar atypia in ESN and LG-ESS makes it barely possible to discern corresponding cellsfrom normal stromal cells Furthermore, both tumors are usually localized within themyometrium Accordingly, performing a cytologic smear or swab cannot generally beexpected to yield useful results, though cytology is known to have revealed suspiciousfindings on occasion (199) There are no specific tumor markers Furthermore, such tu-

screen-mors are too rare and the specificity of early findings is too low as to make sonography

a viable or helpful tool in such cases

Increased attentiveness is generally required in cases of patients who are currentlytaking tamoxifen, or have taken tamoxifen over longer periods previously Analogous

to tamoxifen-associated EC, symptoms like AUB, postmenopausal bleeding or ine pains as well as LM that are conspicuous in sonography need to be taken veryseriously, and respective patients need to be subjected to more thorough diagnostics.Good clinical symptom-oriented follow-up and aftercare is currently regarded as themost adequate form of targeted screening for “tamoxifen patients”

uter-Symptoms and clinical behavior of endometrial stromal sarcoma largely correspond to those of regular leiomyoma Fewer than 10 % of rapidly growing leiomyoma in premenopausal patients are

in fact endometrial stromal sarcomas Premenopausal tumor or uterine growth is generally highly suspicious Beyond clinical examination and sonography, hysteroscopy and curettage are the cen- tral methods in cases in which there is abnormal uterine bleeding However, the results from these methods usually reveal nothing out of the ordinary since endometrial stromal sarcomas are usually intramurally localized, thus necessitating further imaging-based diagnostic procedures.

There is no screening for endometrial stromal sarcomas Patients with a medical history of moxifen ingestion should undergo regular symptom-oriented follow-up.

to the myometrium (33) Differentiation from an LM can be particularly difficult insuch cases and can culminate in a misdiagnosis as LM and subsequent inadequatesurgery under that diagnosis (Fig 4.1.14 (A), (B)) The literature (101) suggests thatLG-ESS have an echogenicity that is lower than that of the endometrium, thoughthere are also accounts of predominantly hyperechoic LG-ESS with narrow cysticspaces/voids LG-ESS most commonly have a heterogeneous echogenicity compris-ing anechoic spaces/voids as well as strongly hyperechoic sections The bordersbetween the areas of differing echogenicity can be either washy/unclear or sharp andirregular/bizarre (Fig 4.1.2 (C), 4.1.8 (A), (B), 4.1.10 (A), (C), (E)) LG-ESS usually clearly