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SECTION 2 Diagnostic Approach to Tumors

Overview and Resection of Soft Tissue Tumors 20 Clinical Approach Age- and Location-Based Approach to Diagnosis 24 Histologic Approach Pattern-Based Approach to Diagnosis 26 Feature-Based Approach to Diagnosis 34 20

Diagnostic Approach to Soft Tissue Tumors depicted. fragmented andscant,as tissue isoftenheavily used fordiagnosis.However, aspiration (FNA)canalsobe collected fromafine-needle techniques. judicious useofancillary histologic evaluationand often possiblewithcareful tissue sample,adiagnosisis biopsy. Despitethelimited compared withopensurgical morbidity tothepatientas of performanceandminimal popular duetoboththeease needle biopsyhasbecome (Left) General Points Core needle biopsy• Types of Specimens A variety of diagnostic• procedures are currently a FNA• Smaller specimens are • generally more challenging t OVERVIEW May be done in outpatient○ setting for superficial Popular due to minimal○ risk of morbidity to patien Very small sample of○ a tumor/lesion Initial tumor tissue○ sampling may or may not be so surgeons and clinicians to evaluate soft tissue tum Very small sample of○ a tumor/lesion Misclassification is○ possible if several different Underdiagnosis often○ poses greater risk than evaluate due to sampling problems and issues relate or under CT guidance for deep or visceral lesions Tumors that appear likely– benign are often surgica imaging characteristics potential derived from synthesis of clinicaldepending featur on overall impression of tumor biologic Tumors that appear likely– malignant or potentially overdiagnosis share morphologic overlap Collecting tissuebycore Successful diagnosis□ usually leads to local excisi Nondiagnostic results□ may reflex into larger open With increasing frequency,□ soft tissue tumors aremalignant are usually sampled preoperatively excised without sampling, or followed clinically adjuvant &/or radiationwide resection with margins, or preoperative on clinical impression of tumor biologyevaluation or even outright resection, dependingsurgical biopsy with intraoperative frozen section morbidity to the patient aspiration (FNA), or limited biopsy due to minimalsampled initially by core needle biopsy, fine-needl (Right) Cell block Biopsy and Resection of Soft Tissue Tumors oeNel ipyFine-NeedleAspiration Core NeedleBiopsy tumors vailable to ors o lesions e s a n d d to t ught, on, lly e Evaluate histologic growth• pattern and architectur Ensure that lesional tissue• is present Assess mitotic activity• and presence or absence of General Histologic Approach Open surgical biopsy• Local excision• Resection with margins• BIOPSY SPECIMENS Looks for histologic○ clues that suggest specific conjunction with cytologic features of tumor cells Aspiration allows for○ immediate evaluation of samp Tissue may be sent ○ for intraoperative frozen secti Small sample of tumor/lesion,○ but generally contai Popular due to minimal○ risk of morbidity to patien Smaller risk of underdiagnosis○ or misdiagnosis com May be performed following○ chemotherapy &/or Surgical focus is on○ removal of tumor and not achi Entire tumor available○ for histologic evaluation Includes wide resection○ and radical resection Standard approach for○ locally aggressive benign Entire tu tumor available○ for histologic evaluation Standard approach for○ benign, superficial tumors t differentiation (e.g., lipoblasts) more intact tissue than core needle biopsy or FNA immunohistochemical evaluationtissue) with added benefit of cell block foradequacy histol (success or failure of attaining diagnosti consultation or just permanent sectioning morbidity radiation to improve resectability and decrease pot (e.g., ), deep (subfascial) tumors, and to needle biopsy and FNA are not believed to be locally aggressive Radical resection often– contains extensive normal rim of uninvolved soft tissue by tumor retroperitoneal tumors, may contain organs involvedtissue or, in cases of intraabdominal, intrathoraci necrosis e in ogic and on c e v i n g t ns hat m o r s pared c, or ential ling 21 Diagnostic Approach to Soft Tissue Tumors ." king nd ses ation may all y nal nal quacy sion low- nt tent ft tissue ft ssue tumors ssue fibrotic/hyalinized cytomorphologies bizarre including atypical, and contain higher grade areas in resection specimen resection in areas grade higher contain biologic response of tumor to therapy to tumor of response biologic &/or inflamed, necrotic, □extensively be may Tumors pleomorphic markedly □become may cells Tumor molecular analysis) may be utilized as needed as utilized be may analysis) molecular accuracy of histologic grade (if applicable) (if grade histologic of accuracy may biopsy on grade" "low □as diagnosed Tumors grade such as an intramuscular , a myxoma, intramuscular an as such neoplasm grade fibromyxoid low-grade as such be low-grade cannot myxofibrosarcoma low-grade or sarcoma sample." limited this in excluded le the of size large the given neurofibroma, a maligna with unsampled an of possibility the sample clinically, limited this in excluded be cannot component appear pleomorphic following therapy following pleomorphic appear differentiation lipoblastic utilized be not should and chemotherapy/radiation viability biopsy (if available) and confirm diagnosis confirm and available) (if biopsy to due possible be not (may resection on confirmed effect) treatment upon heavily depends –picture histologic Overall histologic sections of tumor to establish diagnosis establish to tumor of sections histologic needed as utilized be –may techniques Ancillary tumors) benign aggressive high-grade malignant should be the goal in these ca these in goal the be should malignant high-grade committing before excluded been have diagnosis tissue soft a to – Ancillary techniques (e.g., immunohistochemistry, –(e.g., techniques Ancillary biopsy (if available) and confirm diagnosis and ade and diagnosis confirm and available) (if biopsy of sampling of assure confirmed, or –established is diagnosis If ○ e.g., "Although these findings are suggestive of a of suggestive are findings ○these "Although e.g., consis are features histologic ○the "Although e.g., tumor treated preoperatively with chemotherapy/radi with preoperatively treated tumor monomorphic cytologically ○usually are that Tumors mimic prominent, be may ○vacuolizations Cytoplasmic following unreliable are ○techniques Ancillary ○ Document approximate percentage of residual tumor residual of percentage ○approximate Document ○status margin Evaluate ○ If tumor has been sampled previously, review origi review previously, ○sampled been has tumor If or established be can ○diagnosis whether Determine ○ If tumor has not been sampled previously, evaluate previously, sampled ○been not has tumor If locall and sarcomas (mainly ○status margin Evaluate defy classification after resection after classification defy a malignant, low-grade benign, ○between Distinction and lymphoma, , ○carcinoma, ensure Always ○ If tumor has been sampled previously, review origi review previously, ○sampled been has tumor If RESECTION SPECIMENS RESECTION • Surgical removal following neoadjuvant therapy neoadjuvant •following removal Surgical • Care is warranted when attempting to classify a so a classify to attempting •when warranted is Care Caveats ti soft of percentage small •a efforts, all Despite • Surgical removal without neoadjuvant therapy neoadjuvant •without removal Surgical General Histologic Approach Histologic General ore asier of y grade er ter on is on ation yositis, try, ive diagnosis sue well ular tumor, ular Biopsy and Resection of Soft Tissue Tumors Tissue Soft of Resection and Biopsy cellular schwannoma cellular , extraskeletal osteosarcoma extraskeletal liposarcoma, diagnosis a is it as biopsy, on made be not should exclusion neural origin neural liposarcoma, myxoid synovial , helpful to guide surgical/clinical planning surgical/clinical guide to helpful classified for pathologists for serves the patient the serves fibroblastic or inflammatory reaction that is that reaction inflammatory or fibroblastic sampled inadvertently tumor lipomatous for mistaken and sampled pleomorphic sarcomas on biopsy often can be more be can often biopsy on sarcomas pleomorphic resection on classified specifically pleomorphic liposarcoma, – dedifferentiated e.g., sarcoma" pleomorphic –"undifferentiated Diagnosis higher grade areas upon resection upon areas grade higher and adipocytic of tumors in – important Particularly suggest malignancy suggest /m proliferative –fasciitis, nodular e.g., benign myxoid sarcoma, –fibromyxoid low-grade e.g., cases to discuss differential diagnosis options diagnosis differential discuss to cases tumor appears benign, low-grade malignant, or high- or malignant, low-grade benign, appears tumor malignant informati this diagnosis, clear ○ of absence in Even diagnosis can help guide surgical/clinical planning surgical/clinical guide help can diagnosis lesion ○fibroblastic benign e.g., benign favor neoplasm, ○myxoid low-grade e.g., further not sarcoma, ○pleomorphic high-grade e.g., diagnosis can be made be can diagnosis ○ Margin status cannot be evaluated be ○cannot status Margin (and histologic grade, if applicable) on biopsy on applicable) if grade, histologic (and e much this making are ○techniques ancillary Modern molecular analysis) as needed as analysis) molecular supported bet biopsy on diagnosis ○conservative a general, In ○ Some tumors may incite prominent peripheral host peripheral prominent ○incite may tumors Some be may tumor to adjacent fat ○subcutaneous Normal mesothelioma before committing to a mesenchymal a to committing before mesothelioma diagnosis ○ Tumors that appear as nonspecific high-grade nonspecific as ○ appear that Tumors ○ Tumors that appear low grade on biopsy may contain may biopsy on grade low ○ appear that Tumors ○ Benign tumors may show histologic features that features histologic ○show may tumors Benign is very important very is pathology theref and bland paradoxically ○appear may Sarcomas • A descriptive comment is highly recommended in man in recommended highly is • comment descriptive A • If clear diagnosis cannot be made, determine wheth determine made, be •cannot diagnosis clear If • If clear diagnosis cannot be established, descript established, be •cannot diagnosis clear If • If constellation of features is classic for partic for classic is •features of constellation If • Be wary of sampling issues related to biopsy evalu biopsy to related •issues sampling of wary Be • Every effort should be taken to establish a clear clear a establish to taken •be should effort Every Reporting • At times, actual tumor does not get sampled get not does •tumor actual times, At Caveats and lymphoma, melanoma, •carcinoma, exclude Always • Utilize ancillary studies (e.g., immunohistochemis (e.g., •studies ancillary Utilize • Only commit to clear diagnosis on biopsy if it is is it if biopsy on •diagnosis clear to commit Only • Awareness of particular idiosyncrasies of soft tis soft of idiosyncrasies •particular of Awareness 22

Diagnostic Approach to Soft Tissue Tumors For tumors treated with• neoadjuvant therapy prior For tumors that cannot• be definitively classified Intraoperative diagnosis• or confirmation of diagno Diagnosis Intraoperative Frozen Section Consultation for May be requested by surgeon• in certain scenarios reports• for soft tissue resecti Reporting In many instances, specific• soft tissue diagnosis SPECIAL TOPICS e.g., epithelioid malignant○ mesenchymal neoplasm, High grade sarcoma ○ with extensive therapy effect ( resection e.g., low-grade myxoid○ sarcoma, not otherwise spec utilized options are exhausted, a descriptive diagnosis can Examples of appropriate○ frozen section interpretat If diagnosis cannot○ be made on frozen section, and Tumor with previous○ benign or low-grade biopsy Additional staging ○ information (e.g., size) can be and margin status (if appropriate)contain tumor diagnosis, histologic grade (if appli Most helpful information○ the pathologist can provi made by frozen section evaluation Tumor was sampled previously○ by biopsy but no spec To confirm previous○ biopsy diagnosis Tumor has not been ○ sampled previously Variability exists ○ between individual surgeons sought to confirm surgical/clinical treatment plan high-grade sarcoma (NOS) Malignant neoplasm, defer– to permanents Tumor present, defer to– permanents Spindle cell sarcoma, favor– low grade High-grade sarcoma– Low-grade spindle cell – proliferation tumor viability) as a checklist sections lesional tissue and defer to evaluation of permanenappropriate to document the presence of satisfactorcomfortably provided by the pathologist, it alternativeis descriptive interpretation cannot be Exercise caution when calling– soft tissue tumor high-grade malignant Whether tumor appears benign, low-grade malignant, higher grade component diagnosis, and there is clinical concern for unsamp diagnosis was attained May continue with resection– plans for benign or lo May halt further – and administer neoadjuvan Some low-grade sarcomas□ can be easily mistaken Use of term "low grade"□ recommended over "benign" on frozen section grade malignancies therapy if high-grade malignancy lead to inappropriately conservative treatmentfor benign tumors on frozen section, which can "benign," unless benignity is absolutely certain Biopsy and Resection of Soft Tissue Tumors cannot be after all ons should cable), be sis can be included to led, de: i o n s 20% t favor ified y w- i f i c or t Molecular analysis• Immunohistochemistry (IHC)• Evaluation by Ancillary Testing Pathologists who are experienced• in evaluation of Expert Consultation Common reasons• Sending 1 or more paraffin• tissue blocks along wit Inclusion of recent clinical• history, imaging repo Common 5-stain screening○ panel: Keratin, S100 prot When needed, limited○ screening panel of It is recommended that○ every attempt be made to Recommendations and○ caveats Representative paraffin○ tissue block can be used f Wide array of antibodies○ available today has made Newer immunohistochemical○ antibodies or molecular Surgeon, primary care○ provider, or patient may req Primary pathologist○ is uncomfortable with &/or has tissue tumors may be consulted to review a case Ideal blocks contain○ well-processed tissue and min for ancillary testing can be helpful surgical notes can also provide useful information Can be modified with additional– stains as necessar Provides reasonably broad– coverage SMA, , CD34 Specific screening panels– vary depending on excluding) diagnoses immunohistochemical stains is helpful for supportin establish the diagnosis or a limited differential b diagnoses on limited tissue sampleseasier for pathologists to make confident soft tiss Diagnosis of very rare – or unusual tumor is rendere Histologic diagnosis is– at odds with clinical impr second opinion Always confirm that external– and internal controls If stain appears positive,– confirm that actual cel Know what constitutes positive– staining for each Examine entire slide and– all tissue fragments Important: On very limited– tissue sample, negative tests are not readily available to primary patholog limited experience in soft tissue pathology variety of sophisticated testing (e.g., FISH, RT-PC Blocks containing areas– of lower grade histology a no necrosis pathologist's comfort level with soft tissue pathol depending upon histologic/clinical context functioning properly expression) antibody (e.g., nuclear, cytoplasmic, membranous e.g., myogenin expression□ in embryonal status of entire tumor staining for a particularly antibody may not reflec interest are staining high-grade pleomorphic morphologyexpression than blocks containing predominantlymore like to show diagnostically useful antigen can be patchy and focal rts, and h slides s o f t y routine R) ls of ist ue e s s i o n or imal to it u e s t t g (or ein, ogy d re are y 23 Diagnostic Approach to Soft Tissue Tumors (Right) Care must (Right) (Right) Care should be taken in If a specific diagnosis is On core needle biopsy, it On core needle biopsy, Classification of low- (Left) (Left) not established prior to neoadjuvant therapy, definitive classification of a soft tissue sarcoma may not be possible due to therapy- related histologic changes, including bizarre nuclear atypia, stromal fibrosis, and . Immunohistochemistry and molecular analysis are also largely unhelpful in this setting. (Left) (Left) may be difficult to distinguish 1 high grade pleomorphic sarcoma from another, particularly if discriminatory immunohistochemical stains or molecular tests are not available to the pathologist. Fortunately, in many cases, designation of "high-grade sarcoma" is often sufficient. (Right) classifying well-differentiated adipocytic on limited biopsy, as atypical lipomatous tumor/well- differentiated liposarcoma can contain large areas resembling conventional . (Left) grade spindle cell neoplasms on limited biopsy can be challenging without ancillary tests, mainly because some low-grade sarcomas can closely resemble benign entities morphologically. This image shows a core biopsy specimen of a low-grade fibromyxoid sarcoma mimicking a benign neural or fibroblastic neoplasm. This image depicts a largely myxoid synovial sarcoma. On a limited biopsy specimen, this tumor could easily be mistaken for a benign or low- grade process. always be taken with IHC performed on limited tissue. One pitfall is focal tumor antigen expression ﬉ (e.g., myogenin, shown) that is not present on biopsy. Biopsy and Resection of Soft Tissue Tumors Tissue Soft of Resection and Biopsy Post-Therapy Changes Immunohistochemistry High-Grade Pleomorphic SarcomaHigh-Grade Adipocytic Neoplasms Well-Differentiated Low-Grade Spindle Cell Neoplasm Deceptively Bland Sarcoma 24

Diagnostic Approach to Soft Tissue Tumors older adults. retroperitoneal tumorsin differential diagnosisfor always beatthetopof retroperitoneum andshould pleomorphic sarcomaofthe is themostcommon Dedifferentiated liposarcoma of infants. frequently arisesinthedigits digital fibromatosis)most fibromatosis (a.k.a.infantile example, inclusionbody anatomic locations.For age groupsandveryspecific predilection forveryspecific neoplasms showastriking (Left) Infancy (< 3 Years Old) How to Use These Guides Myofibroma• Lipofibromatosis• • Infantile • Inclusion body fibromatosis• Fibrous of infancy• Always exclude carcinoma,• melanoma, lymphoma, and Important Caveat For each site and associated• age range listed belo Specific Directions for This Guide Includes entities that• are most commonly or classi The following guides are• neither comprehensive nor Compare this selection• to those created from the o Compile an assortment • of potential diagnoses from Once high-yield diagnoses• have been identified, sp Overlapping diagnoses • derived from these 3 distinc AGE-BASED APPROACH DIRECTIONS associated with particular clinical and histologic diagnosis mesothelioma before committing to a mesenchymal working up a suspected mesenchymal neoplasmperfect and are meant to serve only as a starting p your particular case guide using age of patient and provided tumor site In particular, the ○ Differential Diagnosis sections information and image galleriesentity chapters should be directly consulted for de diagnoses are provided selection of most commonly or characteristically as approach chapters approaches are highest yield and should be your foc of securing the correct diagnosisbe fully utilized to broaden search and increase ch Some mesenchymal (Right) Age- and Location-Based Approach to Diagnosis nlso oyFboaoi Dedifferentiated Liposarcoma Inclusion BodyFibromatosis findings w, a c a l l y should oint for t a i l e d ecific sociated t h e r 2 from t us the ances Pseudomyogenic hemangioendothelioma• Ossifying fibromyxoid • tumor • Myositis ossificans• Localized-type tenosynovial• giant cell tumor • • • of sheath• Epithelioid sarcoma (proximal-type)• Epithelioid hemangioendothelioma• Dermatofibrosarcoma protuberans• • Young to Middle-Aged Adults (~ 20 to 50 Years Synovial Old) sarcoma• Plexiform fibrohistiocytic• tumor Myxoid liposarcoma• Low-grade fibromyxoid • sarcoma Inflammatory myofibroblastic• tumor Epithelioid sarcoma (classic• type) Desmoplastic small round• cell tumor (also children Angiomatoid fibrous • Alveolar soft parts sarcoma• Alveolar rhabdomyosarcoma• Adolescents to Young Adults (~ 10 to 35 Years Kaposiform Old) hemangioendothelioma• (infants and child Giant cell fibroblastoma• Gardner fibroma• Extrarenal rhabdoid tumor• (infants and children) Embryonal rhabdomyosarcoma• Dabska tumor (infants • and children) Calcifying aponeurotic• fibroma Angiomatosis• Infants, Children, or Adolescents (< 20 Years Old) Dedifferentiated liposarcoma• Atypical lipomatous tumor/well-differentiated• lipo Middle-Aged to Older Adults (~ 45 to 60 Years Old) ) sarcoma ren) 25 Diagnostic Approach to Soft Tissue Tumors GASTROINTESTINAL MESENCHYMAL GASTROINTESTINAL LOCATION) BY COMMON (MOST TUMORS LYMPH INVOLVING TUMORS MESENCHYMAL COMMON) (MOST NODES •sarcoma Kaposi •myofibroblastoma palisaded Intranodal •(mural) •tumor cell Granular Stomach tumor •stromal Gastrointestinal •polyp fibroid Inflammatory • Schwannoma Bowel Small tumor •stromal Gastrointestinal •polyp fibroid Inflammatory Colorectum •nonmural) (polyp; Leiomyoma tumor •stromal Gastrointestinal •sarcoma Epithelioid •sarcoma cell Clear • Primary Nodal Retroperitoneum •liposarcoma Dedifferentiated •leiomyoma Deep •fibromatosis Desmoid •tumor rhabdoid Extrarenal • Ganglioneuroma tumor •myofibroblastic Inflammatory • Leiomyosarcoma • PEComa •variant) (cellular Schwannoma •liposarcoma Well-differentiated Back and Shoulders, Trunk, •protuberans Dermatofibrosarcoma •fibromatosis Desmoid • Elastofibroma type) •(proximal sarcoma Epithelioid •fibroblastoma cell Giant lipoma •cell/pleomorphic Spindle •rhabdomyosarcoma Embryonal •hemangioma Epithelioid types) fetal •and (adult neuroma •circumscribed Solitary •rhabdomyosarcoma cell Spindle Esophagus Age- and Location-Based Approach to Diagnosis to Approach Location-Based and Age- LOCATION-BASED APPROACH LOCATION-BASED Distal (Acral) Extremities (Acral) Distal Head and Neck and Head children) and (infants •sarcoma part soft Alveolar •fibromyxoma Atypical •neurothekeoma Cellular •tumor cell Granular •meningioma Ectopic Mesentery/Omentum/Peritoneum •fibromatosis Desmoid tumor cell •round small Desmoplastic tumor •stromal Gastrointestinal tumor •myofibroblastic Inflammatory Genital Region and Groin and Region Genital • Angiomyofibroblastoma •angiofibroma Cellular •angiomyxoma (aggressive) Deep •rhabdomyoma Genital •myofibroblastoma palisaded Intranodal •myofibroblastoma Mammary-type (paratesticular) •rhabdomyosarcoma cell Spindle •fibromyxoma Acral •myxoma sheath nerve Dermal •hemangioma Epithelioid •sheath tendon of Fibroma •tumor Glomus •fibromatosis body Inclusion tumor cell giant •tenosynovial Localized-type sarcoma •fibroblastic Myxoinflammatory •chondroma tissue Soft Fingers and Toes and Fingers • Calcifying aponeurotic fibroma •aponeurotic Calcifying •sarcoma cell Clear •hemangioendothelioma Composite type) •(classic sarcoma Epithelioid tumor •fibrolipomatous Hemosiderotic • Lipofibromatosis •fibromatosis Palmar/plantar tumor angiectatic •hyalinizing Pleomorphic Older and Elderly Adults (> 50 Years Old) Years 50 (> Adults Elderly and Older •fibroxanthoma Atypical • Elastofibroma •fasciitis Ischemic • Myxofibrosarcoma •liposarcoma Pleomorphic •rhabdomyosarcoma Pleomorphic sarcoma •pleomorphic Undifferentiated •fibroblastoma Desmoplastic •chondrosarcoma myxoid Extraskeletal •osteosarcoma Extraskeletal tumor •fibrolipomatous Hemosiderotic •myxoma Intramuscular •fasciitis/myositis Proliferative fibrosarcoma •epithelioid Sclerosing lipoma •cell/pleomorphic Spindle 26

Diagnostic Approach to Soft Tissue Tumors Compare this selection• to those created from the o histiocytoma. angiomatoid fibrous This appearanceiscommonin to sharethesamecytoplasm. independent cellnucleiappear inconspicuous and which cytoplasmicbordersare a syncytialappearancein of spindledcellscanalsohave fibrous tumor. sarcoma (shown)andsolitary pattern iscommoninsynovial are notuncommon.This bundled orfasciculargrowth orientation; however,areasof without obviousdirectional growth ofspindlecells tends tofeaturediffuse (Left) How to Use These Guides Always exclude gastrointestinal• stromal tumor (GIS Always exclude carcinoma,• melanoma, lymphoma, and Important Caveats The following list of • histologic patterns has been Specific Directions for This Guide They include entities • that are most commonly or cl The following guides are• neither comprehensive nor Compile an assortment • of potential diagnoses from Once high-yield diagnoses• have been identified, sp Overlapping diagnoses • derived from these 3 distinc For each histologic pattern• listed below, a select DIRECTIONS Can demonstrate almost○ any morphologic patterntumor arises within abdominal cavity or pelvis case guide using main histologic pattern(s) from your pa In particular, the ○ Differential Diagnosis sections information and image galleriesentity chapters should be directly consulted for de diagnosis mesothelioma before committing to a mesenchymal working up a suspected mesenchymal neoplasmperfect and are meant to serve only as a starting p provided commonly or characteristically associated diagnoses Approach chapters vasculature) various stromal characteristics (e.g., myxoid,cytologic prom features (monomorphism vs. pleomorphism),using a combination of cell types (spindle or epith associated with particular histologic patterns in s approaches are highest yield and should be your foc chances of securing the correct diagnosisbe fully utilized to broaden the search and increas A sheet-likepattern (Right) Sheets Pattern-Based Approach to Diagnosis Monomorphic SpindleCells:Sheets ion of more oft tissue generated elioid), should inent oint for t a i l e d assically ecific T) when rticular t h e r 2 t us are each e t h e and Solitary circumscribed• neuroma Schwannoma• Plexiform fibrohistiocytic• tumor Mammary-type myofibroblastoma• Low-grade myofibroblastic• sarcoma Lipofibromatosis• Leiomyosarcoma• Kaposi sarcoma• Inclusion body fibromatosis• Fibrous hamartoma of infancy• Fibromatosis• Deep leiomyoma• • Fascicles Monomorphic Spindle Cells Arranged in Bundles Synovial or sarcoma• • Schwannoma• Malignant peripheral nerve• sheath tumor Low-grade fibromyxoid • sarcoma Hypocellular Areas Monomorphic Spindle Cells Featuring Hyper- and Synovial sarcoma• Solitary fibrous tumor• Pseudomyogenic hemangioendothelioma• Angiomatoid fibrous histiocytoma• Synovial sarcoma• Spindle cell rhabdomyosarcoma• Malignant peripheral nerve• sheath tumor Infantile fibrosarcoma• Fibrosarcomatous dermatofibrosarcoma• protuberans Adult-type fibrosarcoma• "Herringbone" Fascicles Monomorphic Spindle Cells Arranged in Cellular Monomorphic Spindle Cells Arranged in Sheets MONOMORPHIC SPINDLE CELL PATTERNS Monomorphic SpindleCells:Sheets (Syncytia) 27 Diagnostic Approach to Soft Tissue Tumors PLEOMORPHIC SPINDLE CELL PATTERNS CELL SPINDLE PLEOMORPHIC • •fibromyxoma Atypical •liposarcoma Dedifferentiated •osteosarcoma Extraskeletal •PEComa Malignant •liposarcoma Pleomorphic •rhabdomyosarcoma Pleomorphic sarcoma •pleomorphic Undifferentiated Fascicles in Arranged Cells Spindle Pleomorphic •liposarcoma Dedifferentiated • Leiomyosarcoma tumor sheath •nerve peripheral Malignant •rhabdomyosarcoma Pleomorphic sarcoma •pleomorphic Undifferentiated Stroma Myxoid Within Cells Spindle Pleomorphic •schwannoma Ancient •neurofibroma Atypical (anaplastic) •rhabdomyosarcoma Embryonal •fibroblastoma cell Giant tumor sheath •nerve peripheral Malignant • Myxofibrosarcoma sarcoma •fibroblastic Myxoinflammatory (variant) •liposarcoma Well-differentiated Monomorphic Spindle Cells Amidst Prominent Amidst Cells Spindle Monomorphic Vasculature Stromal •tissue soft of Angiofibroma • Angioleiomyoma •angiomyxoma "aggressive" Deep type) (myxoid •protuberans Dermatofibrosarcoma sarcoma • fibromyxoid Low-grade • Myopericytoma •liposarcoma Myxoid • Schwannoma •tumor fibrous Solitary Mature With Associated Cells Spindle Monomorphic Tissue Adipose • Angiomyofibroblastoma •angiofibroma Cellular • Elastofibroma •infancy of hamartoma Fibrous tumor •fibrolipomatous Hemosiderotic • Lipoblastoma • Lipofibromatosis •myofibroblastoma Mammary-type • Myolipoma (variant) •tumor fibrous Solitary •lipoma cell Spindle • Neurofibroma •fasciitis Nodular • Perineurioma •rhabdomyosarcoma Sclerosing •tumor fibrous Solitary Pleomorphic Spindle Cells Arranged in Sheets in Arranged Cells Spindle Pleomorphic Pattern-Based Approach to Diagnosis to Approach Pattern-Based Monomorphic Spindle Cells Within Collagenous, Within Cells Spindle Monomorphic Stroma Sclerotic or Hyalinized, •fibromyxoma Acral •tumor fibrous Calcifying •angiofibroma Cellular •fibroblastoma Desmoplastic • Elastofibroma •sheath tendon of Fibroma • Fibromatosis tumor •myofibroblastic Inflammatory sarcoma • fibromyxoid Low-grade sarcoma •myofibroblastic Low-grade Monomorphic Spindle Cells Within Myxoid Stroma Myxoid Within Cells Spindle Monomorphic •fibromyxoma Acral •angiomyxoma ("aggressive") Deep •myxoma sheath nerve Dermal type) (myxoid •protuberans Dermatofibrosarcoma •fibromatosis Desmoid •rhabdomyosarcoma Embryonal •tumor sheath nerve Hybrid tumor •myofibroblastic Inflammatory •myxoma Intramuscular •(variant) Leiomyosarcoma sarcoma • fibromyxoid Low-grade •liposarcoma Myxoid • Neurofibroma •fasciitis Nodular • Perineurioma •fasciitis/myositis Proliferative •sarcoma Synovial •lipoma cell Spindle •chondrosarcoma myxoid Extraskeletal • Myoepithelioma •(variant) Perineurioma •(variant) Schwannoma Monomorphic Spindle Cells Arranged in Reticular or Reticular in Arranged Cells Spindle Monomorphic Pattern Microcystic •tumor cell Granular tumor •fibrohistiocytic Plexiform •neurofibroma Plexiform •schwannoma Plexiform neuroma •circumscribed Solitary Monomorphic Spindle Cells Arranged in Multinodular in Arranged Cells Spindle Monomorphic Architecture Plexiform or •histiocytoma fibrous benign Deep histiocytoma) •(fibrous •protuberans Dermatofibrosarcoma sarcoma •cell dendritic Follicular •tumor sheath nerve Hybrid •fibromatosis body Inclusion sarcoma • fibromyxoid Low-grade sarcoma •myofibroblastic Low-grade •fasciitis Nodular • Perineurioma Monomorphic Spindle Cells Arranged in Storiform or Storiform in Arranged Cells Spindle Monomorphic Architecture Whorled 28

Diagnostic Approach to Soft Tissue Tumors Perivascular epithelioid• cell tumor (PEComa) Paraganglioma• Myoepithelioma of soft• tissue Granular cell tumor• Glomus tumor• Epithelioid sarcoma (classic• type) Epithelioid Cells Arranged in Nests or Lobules Synovial sarcoma (poorly• differentiated) Neuroblastoma• Infantile fibrosarcoma• Extraskeletal mesenchymal• chondrosarcoma Extrarenal rhabdoid tumor• Ewing sarcoma• Alveolar rhabdomyosarcoma• Cytoplasm) Epithelioid Cells Arranged in Sheets (Minimal/Scant Tenosynovial giant cell• tumor, diffuse-type Extrarenal rhabdoid tumor• Epithelioid sarcoma (proximal• type) Epithelioid angiosarcoma• Alveolar soft part sarcoma• Adult rhabdomyoma• Cytoplasm) Epithelioid Cells Arranged in Sheets (Abundant Sclerosing epithelioid• fibrosarcoma Myoepithelioma of soft• tissue Mammary-type myofibroblastoma• (epithelioid variant Ossifying fibromyxoid • tumor Epithelioid Cells Arranged in Cords or Trabeculae Epithelioid malignant • peripheral nerve sheath tumo Desmoplastic small round• cell tumor Clear cell sarcoma• Cellular neurothekeoma• Alveolar soft part sarcoma• Alveolar rhabdomyosarcoma• Undifferentiated pleomorphic• sarcoma Pleomorphic hyalinizing• angiectatic tumor Myxofibrosarcoma• Vasculature Pleomorphic Spindle Cell Amidst Prominent Stromal Undifferentiated pleomorphic• sarcoma Pleomorphic liposarcoma• Myxofibrosarcoma (high• grade) Dedifferentiated liposarcoma• Architecture Pleomorphic Spindle Cells Arranged in Storiform Undifferentiated pleomorphic• sarcoma Myxoinflammatory fibroblastic• sarcoma Giant cell fibroblastoma• Atypical lipomatous tumor/well-differentiated• lipo Hyalinized, or Sclerotic StromaPleomorphic Spindle Cells Within Collagenous, EPITHELIOID CELL PATTERNS (MPNST) Pattern-Based Approach to Diagnosis sarcoma r ) Cellular solitary fibrous• tumor (formerly PEComa• Paraganglioma• Glomus tumor• Angiomyofibroblastoma• Alveolar soft part sarcoma• Vasculature Epithelioid Cells Associated With Prominent Stromal Tenosynovial giant cell• tumor, localized-type Sclerosing epithelioid• fibrosarcoma Perineurioma (variant)• Myoepithelioma of soft• tissue Epithelioid sarcoma• Desmoplastic small round• cell tumor Sclerotic Stroma Epithelioid Cells Within Collagenous, Hyalinized, Soft tissueo chondroma• Myxofibrosarcoma (variant)• Myoepithelioma of soft• tissue Glomus tumor• Extraskeletal myxoid chondrosarcoma• Epithelioid MPNST• Epithelioid hemangioendothelioma• Epithelioid Cells Within Myxoid Stroma Synovial sarcoma• Schwannoma• Malignant peripheral nerve• sheath tumor Leiomyosarcoma• Leiomyoma• Dermatofibroma (fibrous• histiocytoma) Nuclear Palisading Proliferative myositis• Low-grade myofibroblastic• sarcoma Intramuscular myxoma• Intramuscular lipoma• Intramuscular hemangioma• "Checkerboard" Pattern Synovial sarcoma (biphasic)• Schwannoma• Plexiform fibrohistiocytic• tumor PEComa• Myoepithelioma of soft• tissue Malignant mesothelioma• (biphasic) Leiomyoma• Epithelioid sarcoma• Angiomyofibroblastoma• Hibernoma• • Angiomyofibroblastoma• Epithelioid Cells Associated With Mixed Epithelioid and Spindle Cells OTHER PATTERNS hemangiopericytoma) r 29 Diagnostic Approach to Soft Tissue Tumors ﬉ (Right) A (Right) (Right) Classic bundled or Plexiform growth is A mixed light and dark A herringbone pattern is (Left) (Left) characterized by discrete globular &/or serpiginous nodules of tumor cells. It tends to be most common in neural tumors, including plexiform neurofibroma and plexiform schwannoma (shown). A reticular pattern is created by thin spindled or stellate cells arranged such that cytoplasmic extensions appear to interconnect in a net-like or sieve-like fashion. Acellular microcystic ﬈ spaces in between cells are also seen. (Left) (Left) pattern due to alternating areas of low ﬊ and high cellularity is often best appreciated at low is magnification. This pattern commonly seen in schwannoma and MPNST. (Right) fascicular growth features cells oriented in parallel more groups. Directionality is conspicuous than is usually seen in the sheet-like pattern, and bundles/fascicles may intersect or be organized in different directions. This image shows fibrous hamartoma of infancy. (Left) created when spindle cells within adjacent fascicles are oriented in roughly the same direction yet appear to slope away from each other. This orientation results in a wide V- shaped or chevron morphology. storiform pattern is manifested by spindled cells that appear to radiate outward from a central point, often with a vague swirling or whorling, similar to a pinwheel. This pattern is most closely associated with DFSP but may be seen in a variety of other tumors. Fascicles Microcystic Pattern Whorled Architecture Monomorphic Spindle Cells: Bundles or Spindle Cells: Bundles Monomorphic Monomorphic Spindle Cells: Reticular or Monomorphic Spindle Cells: Storiform or Monomorphic Spindle Cells: Storiform Pattern-Based Approach to Diagnosis to Approach Pattern-Based Herringbone Fascicles and Hypercellular Areas and Hypercellular or Plexiform Architecture Monomorphic Spindle Cells: Cellular Monomorphic Spindle Cells: Hypocellular Monomorphic Monomorphic Spindle Cells: Multinodular 30

Diagnostic Approach to Soft Tissue Tumors myofibroblastoma. lipoma andmammary-type Examples includespindlecell component ofthetumor. feature fatasatrue of infiltration,somelesions present inatumorasresult mature adiposetissuemaybe liposarcoma. perhaps mostnotablymyxoid conspicuous insomelesions, vascular channels﬈are (Left) pleomorphism isabsent. significant nuclear increased cellularity.However, may featureareasof grade fibromyxoidsarcoma, liposarcoma (shown)orlow- tumors, suchasmyxoid lipoma, DFSP). tumors (e.g.,spindlecell often seeninvariantsofother intramuscular myxoma)butis inherent tosometumors(e.g., monomorphic. Thispatternis that arecytologically particularly spindledlesions common insofttissuetumors, (Left) tumor) arenotableexceptions. (particularly solitaryfibrous prominent, sometumors vessels arenotusually tumors. Althoughthese focal findinginsofttissue ﬈ arerelativelycommonasa dilated orectaticbloodvessels arrangements. storiform, orhaphazard may showfascicular, or densesclerosis.Tumorcells show prominenthyalinization stroma thatmayornot conspicuous collagenous characteristically featurea spindle celltumors (Left) Smaller capillary Myxoid stromaisvery Some monomorphic (Right) (Right) (Right) Although Some Large, Monomorphic SpindleCells:Collagenous, Monomorphic SpindleCells:Prominent Pattern-Based Approach to Diagnosis Monomorphic Spindle Cells: Myxoid Monomorphic SpindleCells: Hyalinized, ScleroticStroma Stromal Vasculature(Small) Stroma Monomorphic SpindleCells:Prominent Monomorphic SpindleCells:Adipose Monomorphic SpindleCells:Myxoid Stromal Vasculature(Large) Tissue Component Stroma (Cellular) 31 Diagnostic Approach to Soft Tissue Tumors A (Right) (Right) (Right) (Right) The pattern of Diffuse, cellular sheets Significant prominent nonneoplastic stromal vasculature ﬊ is a feature of some pleomorphic spindle cell neoplasms, including both low-grade (e.g., pleomorphic hyalinizing angiectatic tumor, shown) and higher grade (e.g., myxofibrosarcoma) tumors. (Left) (Left) pleomorphic spindle cells arranged in whorls or storiform arrays is rather nonspecific and can be seen in a variety of often morphologically similar high- grade sarcomas. (Left) (Left) are of highly pleomorphic cells typical of many high-grade sarcomas, including undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, and high-grade myxofibrosarcoma. growth Fascicular and bundled in patterns can also be present pleomorphic spindle cell neoplasms, particularly leiomyosarcoma and MPNST. a Pleomorphic cells within herringbone growth pattern is often MPNST. (Left) pleomorphism within a prominent myxoid stroma is most frequently associated with myxofibrosarcoma; however, it can also be seen in dedifferentiated and pleomorphic types of liposarcoma. Pleomorphism within a prominent collagenous matrix is often associated with various high-grade sarcomas; however, it can also be the pattern of sclerosing well- differentiated liposarcoma (shown). Fascicles Stromal Vessels Hyalinized, or Sclerotic Matrix Pleomorphic Spindle Cells: Prominent Pleomorphic Spindle Cells: Bundles and Spindle Cells: Bundles Pleomorphic Pleomorphic Spindle Cells: Collagenous, Pattern-Based Approach to Diagnosis to Approach Pattern-Based Whorled Architecture Pleomorphic Spindle Cells: Sheets Pleomorphic Pleomorphic Spindle Cells: Storiform or Pleomorphic Spindle Cells: Myxoid Stroma 32

Diagnostic Approach to Soft Tissue Tumors necessary fordiagnosis. Immunohistochemistry isoften tumors. to assmall,round,bluecell neoplasms areoftenreferred increased celldensity.These very blueorbasophilicdueto minimal cytoplasmappear smaller epithelioidcellswith (Right) carcinoma ormelanoma. morphology cancloselymimic mitotic activity.This marked cytologicatypiaand high gradeandfeature of epithelioidcellsareoften diffuse sheet-likearrangement (Left) cellular cohesion also showacentrallossof part sarcoma(shown),may tumors, suchasalveolarsoft epithelioid neoplasms.Some patterns arecommonin (Left) are examples. fibromyxoid tumor(shown) Myoepithelioma andossifying fibrous stroma. myxoid, fibromyxoid,or cells maybeseenwithina arrangements ofepithelioid (Right) a pseudoalveolarappearance. others. epithelioid sarcoma,and be seeninmyoepithelioma, however, thispatterncanalso fibrosarcoma (shown); of sclerosingepithelioid always leadtoconsideration collagenous stromashould Epithelioid cellswithina epithelioid MPNST. myxoid chondrosarcoma,and myoepithelioma, extraskeletal Examples oftumorsinclude but notgenerallycommon. myxoid stromaisdistinctive epithelioid cellswithina (Left) Tumors thatshowa Nested orlobular The patternof Tumors withsheetsof Distinct, linear ﬉ (Right) imparting Pattern-Based Approach to Diagnosis Epithelioid Cells:Sheets(Abundant pteii el:Nsso oue EpithelioidCells:CordsorTrabeculae Epithelioid Cells:NestsorLobules Epithelioid Cells:MyxoidStroma Cytoplasm) Epithelioid Cells:Collagenous,Hyalinized, Epithelioid Cells:Sheets(Minimal/Scant or ScleroticStroma Cytoplasm) 33 Diagnostic Approach to Soft Tissue Tumors typify a ﬈ Linear rows Adipose tissue (either small or ﬈ (Right) (Right) (Right) (Right) Plexiform Although any Sheets or nests of Some soft tissue tumors and epithelioid ﬊ tumor cells, either as discrete components or closely admixed. Examples include synovial sarcoma and epithelioid sarcoma (shown). (Right) fibrohistiocytic tumor is a neoplasm that may feature predominantly spindled cells in bundles/fascicles, predominantly epithelioid cells in nests, or a mixture of the 2 patterns (shown). larger vessels) is classically tumor associated with glomus cellular but can also be seen in solitary fibrous tumor (previously hemangiopericytoma) and others. of can be an integral part some epithelioid soft tissue tumors but is generally uncommon. Examples include angiomyofibroblastoma (shown) and chondroid lipoma. palisading pattern, as shown. Although classically associated with neural tumors, this pattern can also be seen in nonneural tumors including leiomyoma, GIST, and synovial sarcoma. (Left) (Left) intramuscular neoplasm can show infiltration of normal skeletal muscle, some tumors characteristically feature cells growing in between fibers ﬈, imparting a checkerboard pattern. Examples include proliferative myositis and low- grade myofibroblastic sarcoma. of nuclei (or cells) (Left) (Left) epithelioid cells arranged around a prominent vasculature (Left) feature a mixture of spindled ﬉ Component Epithelioid Cells: Adipose Tissue Epithelioid Pattern-Based Approach to Diagnosis to Approach Pattern-Based Vasculature Mixed Spindle and Epithelioid Cells Spindle and Epithelioid Cells Epithelioid Cells: Prominent Stromal Epithelioid Checkerboard Skeletal Muscle Pattern Nuclear Palisading 34

Diagnostic Approach to Soft Tissue Tumors and adultrhabdomyoma. (shown), PEComa,hibernoma, congenital granularcellepulis tumor butcanalsobeseenin associated withgranularcell cytoplasm aremostcommonly granular, eosinophilic (Right) patchy andrarelydiffuse. tumors isusuallyfocalor change inmesenchymal epithelial neoplasms,clearcell (shown), amongothers.Unlike alveolar softpartsarcoma myoepithelioma, PEComa,and cytoplasm include featuring cellswithclear (Left) How to Use These Guides Always exclude carcinoma,• melanoma, lymphoma, and Important Caveat The following list contains• a variety of distincti Specific Directions for This Guide They include entities • that are most commonly or cl The following guides are• neither comprehensive nor For each histologic feature• listed below, a select Once high-yield diagnoses• have been identified, ch Compile an assortment • of potential diagnoses from DIRECTIONS diagnosis mesothelioma before committing to mesenchymal working up a suspected mesenchymal neoplasmperfect and are meant to serve only as starting poi Overlapping diagnoses○ derived from these 3 distinc In particular, the○ Differential Diagnosis section information and image gallerieson specific entities should be directly consulted f Each listed feature○ is more commonly or morphologies to specific stromal componentsfeatures ranging from unique nuclear and cellular associated with particular clinical and histologic Compare this selection○ to those created from other case guide using the particular feature(s) from your par provided commonly or characteristically associated diagnoses Approach chapters tumors and not others characteristically associated with some soft tissue focus approaches are highest yield and should be your pri of securing the correct diagnosisbe fully utilized to broaden search and increase ch Soft tissuetumors Cells withprominent Feature-Based Approach to Diagnosis la el GranularCells Clear Cells ve histologic findings ion of most or detailed s should ticular nt for assically apters are the ances mary t 2 Retiform hemangioendothelioma• Papillary intralymphatic• angioendothelioma (Dabska Hobnail hemangioma• Epithelioid hemangioma• Hobnail Cells PEComa• Leiomyoma• Hibernoma• Granular cell tumor• Extranodal Rosai-Dorfman• Congenital granular cell• Chondroid lipoma• Alveolar soft part sarcoma• Adult rhabdomyoma• Granular Cells Sclerosing epithelioid• fibrosarcoma PEComa• Myoepithelial carcinoma• Myoepithelioma• Ewing sarcoma• Desmoplastic small round• cell tumor Clear cell sarcoma• Alveolar soft part sarcoma• Synovial sarcoma (poorly• differentiated) Pseudomyogenic hemangioendothelioma• Myoepithelial carcinoma• Extraskeletal myxoid chondrosarcoma• Extrarenal rhabdoid tumor• Epithelioid sarcoma• Epithelioid MPNST• Desmoplastic small round• cell tumor Angiomatoid fibrous histiocytoma• Rhabdoid Cells Clear Cells CYTOLOGIC FEATURES )