1. Acta Cytologica 2012;56:15–24
Matthew T. Olson a Syed Z. Ali a, b Departments of a Pathology and b Radiology, The Johns Hopkins Hospital, Baltimore, Md. , USA

2. Fine Needle Aspiration
Myxofibrosarcoma:
Cytomorphologic Findings and
Differential Diagnosis on
Fine Needle Aspiration

3. Objective:
To analyze the cytomorphologic findings of
myxofibrosarcoma (MFS) on fine needle aspiration (FNA)
and examine the differential diagnoses.

4. Myxofibrosarcoma:
is a soft tissue sarcoma that typically presents on the extremities of adults
6th–8th decades.
It has previously been called myxoidmalignant fibrous histiocytoma (MFH)
MFS also portends a better prognosis than the variants
of MFH

5. Locasion: classically presents superficially in :
the lower extremities
trunk
upper extremities
neck, and head

6. but it has also been: reported superficially in the breast perineum
orbit
esophagus
hypopharynx
vocal fold
parotid
heart
aorta
pulmonary
artery
lung and brain

7. Why is it important to diagnosis by FNA?
While different schemes have been developed for
grading MFS , there is agreement that the histologic
grade is a predictor of metastatic potential and
worse survival . Regardless of grade, resection is currently
the mainstay of treatment for MFS. Adjuvant radiation
plays a role at some institutions because of evidence
that it reduces the risk of local recurrence
Reducing local recurrence is a clinically desired outcome both due to the morbidity reduction and the evidence that local recurrences may have a higher grade than the initial neoplasm

8. This work is a cytohistological correlation of 22 MFS patients seen at The Johns Hopkins Hospital, giving emphasis on cytologic features.

9. METHOD: Specimen Identification and Cytopathology:
All surgical resections over the last 30 years that were diagnosed MFS or myxoid MFH were queried to find those cases for which an FNA was obtained prior to surgery.

10. Surgical Pathology
The resection specimens were sectioned and sampled in the standard fashion. They were diagnosed by a different group of pathologists than the cytopathologists who interpreted the FNA biopsies. Immunohistochemistry was not routinely performed on the resection specimens. Grading was assigned prospectively according to the National Cancer Institutes (NCI) grading scheme for soft tissue sarcomas.

11. Retrospective Review
The cases were reviewedlooking for: the classical features: spindle cells, multinucleate cells, myxoid background, nuclear pleomorphism, and curvilinear vascular structures. Each feature was scored for each case as either present or absent. The histopathology of the resection specimens was also reviewed.

12. Radiographically, MFS is best visualized with MRI and typically has a nodular T 2 -enhancing appearance. This view demonstrates MFS in the thigh.

13. Results: In our series, we identified 22 patients who had a final
resection diagnosis of MFS and had undergone FNA prior to resection.

14. The tumors were seen in both men (n =13) and women (n = 9) with a male/female ratio of 1.4: 1.
The usual clinical manifestation was a painless incidentally
discovered mass beneath the skin, although these
tumors did present with pain in a subset (n = 3) of patients
when the mass involved a joint or came into contact with
clothing or sites of grooming. The age at first presentation
ranged from 38 to 92 years (median 65 years). The demographics, cytologic diagnoses, and ultimate MFS grade the resection are listed in table 1 .

16. The majority of MFS cases in this series were grades 2and 3 on resection.
Five (23%) of these cases were local recurrences;
These cases were the only ones in which the specific diagnosis of MFS was made.
Seven cases (32%) were diagnosed as ‘high-grade sarcoma’
although ‘spindle cell neoplasm’ (18%), ‘sarcoma’ without
a grade (14%), and ‘low-grade sarcoma’ (9%) were also
used.

17. FNA from MFS: In general was cellular on low power
The most prominent features included:
myxoid matrix
spindle cells,
nuclear pleomorphism
multinucleated cells
curvilinear vascular structures

18. Smears prepared from FNA of MFS typically show high cellularity at low power (Papanicolaou stain).

24. Given the high percentage of cases that contained more than one feature, the number of coexistent features well as specific features that occurred together was examined:
Interestingly, only 1 case demonstrated spindle cells alone, and this had been called ‘spindle cell neoplasm’ at the time of sign-out. The case that demonstrated only 2 features was erroneously diagnosed as‘pleomorphic adenoma’ due to its placement in the upper neck. The majority of cases demonstrated three or more of the classic but nonspecific features.

26. the typical image emerged of a smear with:
myxoid matrix,nuclear pleomorphism, and spindle cells. Spindle cells had a high level of coobservation with both nuclear pleomorphism and multinucleated cells. Interestingly,the two least frequent observations – multinucleated cells and curvilinear vessels – had a very high rate of coobservation.

27. Upon resection, g ross appearances of these tumors:
heterogeneous and nodular with variable and scattered pockets of grossly apparent matrix.

28. Gross cross-section of the resection specimen
Gross cross-section of the resection specimen. The tumor invading the vastus lateralis muscle.

29. Histologically,
MFS resections demonstrated all of the features that were apparent on cytopathology – including curvilinear vessels,spindle cells, nuclear pleomorphism, and myxoid matrix

30. Histopathology from a low-grade MFS resection specimen with myxoid matrix and predominantly spindle-shaped cells with some epithelioid cells. Curvilinear vascular structures can also be seen in this field.

31. Differential Diagnosis:
myxoid variant of nodular fasciitis (MNF)
myxoid liposarcoma(MLS)
low-grade fibromyxoid sarcoma (LGFMS)
extraskeletal myxoid chondrosarcoma(EMCS)
Intramuscular myxoma (IM)
Myxoid neurofibroma
Myoepithelialtumors of soft tissue
Vascular tumors with myxoid features, such as pleomorphic hyalinizing angiectatic tumor, and angiomyxoma
spindle cell melanoma
pleomorphic sarcoma

32. myxoid variant of nodular fasciitis
MFS
smaller size.
Greater size
Faster growing lesion, pain
Slower growing, painless
the nuclei of MNF usually have
prominent nucleoli, -
IHC for smooth muscle actin and histiocyte markers,
NEGATIVE

33. Nodular fasciitis : Subcutaneous pseudosarcomatous fibro sarcoma
History of rapid growth
Small size
Microscopic : cellular spindle cell growth set in a loosely texture myxoid matrix . Vascular prolifration , lymphocytic infiltration , and exteravasated red blood cells are also present
Band of collagen like keloid scar

34. Nodurar fasciitis… Metaplasic bone formation
Red blood cell extravasation
Markedly atypical cell(hyperchromatic nuclei)
Hypercullar
Mitotycaly active

35. MLS less and vacuolization in the tissue fragments
MLS less and vacuolization in the tissue fragments. more cellular uniformity. t(12; 16)(q13;p11) translocation and less commonly the t(12; 22)(q13;q12) translocation
MFS: prominent vascular network not associated with clonal translocations

36. Liposarcoma: Most frequent soft tissue sarcoma in adult Gross:
circumscribed but not encapsulated
mucoied , bright yellow appearence mimicking lipoma

37. Myxoid Liposarcoma: most common type of Liposarcoma Lower extrimities
Microscopicaly:
Few or no mitotic figures
Prolifrating lipoblast in different stage of diffrentiation
Prominent anastomosing capillary network(presence of delicate network of thin-walled vessels is an important feature in the differential diagnosis with myxoma and other myxoid tumors)
Myxoid matrix

38. low-grade fibromyxoid sarcoma (LGFMS)
MFS
typically presents 10–20 years earlier than MFS,
classically presents in the 6th–8th decades.
Poorly vascularized,and vacuolizationin the tissue fragments.
curvilinear vessels.
the nuclei are not as pleomorphic
pleomorphism
t(7; 16)(q34;p11)
negative

39. low-grade fibromyxoid sarcoma (LGFMS)
Evans tumor:
Usually deep
But sometimes superficial especialy in children
Alternating fibrous and myxoied erea
Focally whorled pattern of growth
Low cellularity and a bland appearance of fibroblastic spindle cell

40. low-grade fibromyxoid sarcoma (LGFMS)

41. low-grade fibromyxoid sarcoma (LGFMS)

42. EMCS:(MOLECULAR)
Another translocation-associated sarcoma, extraskeletal myxoid chondrosarcoma (EMCS), is often separated from MFS with light microscopy alone because of the arrangement of EMCS cells into cohesive cords and the characteristic lacunar appearance.EMCS has stereotyped cytogenetic translocations; classically EMCS harbors t(9; 22)(q22,q12) [64, 65] , although t(9; 17)(q22;q11) and t(9; 15)(q22;q21) have also been reported.

43. extraskeletal myxoid chondrosarcoma(EMCS)

44. Chordoma:
Although very rare, chordoma periphericum can be placed in the differential diagnosis as it contains myxoid matrix .
The physaliferous cells arranged in chords and immunoreactivity for cytokeratin stains are helpful features in making this diagnosis and distinguishing it from MFS.

47. Intramuscular myxoma (IM)
The two entities can be difficult to separate with FNA based on morphology alone As MFS can invade muscle, and myxoma can spread superficially, location is not always helpful in separating these two entitie

48. IM……….. The distinction is important :
IM has a benign natural history with a low risk for recurrence and metastasis

49. IM:
Histologically, IM is a poorly vascularized tumor as opposed to MFS, in which the curvilinear vasculature is often prominent.

50. Intramuscular myxoma (IM)
Histologically poorly vascularized tumor
Low risk f metastasis
Low risk of recurrence
GNAS1 mutation(but not MFS )

51. IM;;

54. neurofibroma
MFS
Collagene fibrilary -
Less nuclear pleomorphism
nuclear pleomorphism
IHC:S100 positive
S100 negative

57. Neurofibroma Microscopically:
Combined by prolifration of all elements of a peripheral nerve:
Axons
Schwann cells
Fibroblast
Perineural cell

58. Neurofibroma…
Mucinous changes in stroma may be prominent and result in mistaken diagnosis of myxoma or myxoid liposarcoma
may exhibit scattered large hyper chromatic nucleie

63. Myoepithelial tumors of soft tissue
MFS
Metaplastic feature: duct,clear cell,cartilage -
IHC:S100,CK,calponin

64. Myoepithelial tumors of soft tissue
Malignant Mixed Tumor :Histopathology findings: 
Histologically the tumors are mixed. The tumors have a lobulated appearance, with cords up epithelioid and spindle cells. Tumors Have a plasmacytoid appearance. The stroma may be chondromyxoid, or hyalinized. The tumors may contain cartilage, bone, or both. Mycoses are frequent, ranging from a few to many dozens per high-power field. The tumors ranged from low-grade to high grade, depending on the degree of cytological atypia and abnormal cytomorphology. Low-grade tumors are considered to be myoepithelioma, whereas high-grade tumors are classified as myoepithelial carcinoma (when the epithelioid or spindle cells predominate), or malignant mixed tumor (when cytologically malignant cartilage or bone is present). Immunohistochemistry shows universal reactivity for epithelial markers such as keratins or epithelial membrane antigen.

65. Myoepithelial tumors of soft tissue
The criteria for malignancy are cytological, that is at least moderate cytological atypia
At low power there is often a lobular architecture
Cellularity is often greater at the periphery of lobules with cells forming trabecular, nests or solid sheets.
The cells are variably epithelioid, clear, spindled or plasmacytoid; almost always more than one cell type is present
The mitotic rate is very variable
The stroma is myxoid or hyalinised, sometimes with cartilaginous differentiation. Rarely there is metastatic ossification

66. Myoepithelial tumors of soft tissue

67. Vascular tumors with myxoid features, such as pleomorphic hyalinizing angiectatic tumor, and angiomyxoma
Vascular tumors
MFS
More vascular telangectasia
Less vascular telangectasia
less morphological heterogenity
More morphological heterogenity
IHC:CD34 piositive -

68. spindle cell melanoma High grade MFS can overlap morphologically
but IHC for any of the melanoma provide resolution

69. spindle cell melanoma IHC:
HMB45
Melan-A
Tyrosinase
microphtalmia transcription factor

70. pleomorphic sarcoma
A pleomorphic sarcoma is a type of malignant tumor that usually arises in fat or muscle tissue. Most tumors grow very slowly and do not cause physical symptoms until cancer starts to spread to other body parts. A pleomorphic sarcoma is most likely to appear in one of the extremities, though it is possible for a tumor to develop in the torso or neck as well. When a pleomorphic sarcoma is detected in its early stages, a combination of surgery and radiation treatments are usually effective at eradicating cancer from the body.

71. There are several different types of pleomorphic sarcoma, classified by the types of tissue they affect and the nature of their onset. The two main groupings are liposarcomas, which are tumors arising in deep fat tissue, and malignant fibrous histiocytomas (MFH), masses that typically develop in skeletal muscle. Both types are most commonly seen in patients over the age of 50, and it is suspected that genetics is the most prominent risk factor for their development.

72. Discussion
The diagnostic sensitivity of prominent myxoid material for making the classification of a myxoid neoplasm on FNA material is dubious based on these data given the observation that only 88% of our cases demonstrated prominent myxoid material. In several cases, the myxoid stroma was very thin and difficult to appreciate.

73. Conclusion
In conclusion, FNA interpretation of myxofibrosarcoma can be challenging since the cytopathologic findings overlap those of numerous other entities.

74. Conclusion………………
However, the placement of the tumor into the spectrum of myxoid neoplasm is realistic with the morphologic findings. Advances in the molecular characterization of myxoid neoplasms appear to provide the necessary specificity to distinguish between the entities within the differential diagnosis. If the combination between morphology and molecular methods accomplishes this task, FNA could provide the ideal diagnostic procedure for the initial workup of soft tissue neoplasms.