Nodular Fasciitis (Analysis of 100 Cases and Review of the Literature)

Path. Res. Pract. 162, 133-165 (1978)

Nodular Fasciitis (Analysis of 100 Cases and Review of the Literature) P. MEISTER" F.-W. BDCKMANN", and E. KONRADl

Summary According to the literature and to our own study NF is not a common disease. In the classical case the male or female patient is about +5 years of age with a tumor node at the right or left forearm. Inmost cases the history is less than 3 months, occasionally tenderness or pain are noticed. Macroscopically and microscopically there is an ill-defined nodular lesion, measuring between 1. 5 and 2 em, related to a fascia, with infiltration of fat and/or muscle tissue. Microscopically a moderately cellular and fibrillar growth with focal variations, myxoid areas, prominent vascularity, hemorrhages, inflammatory cells and occ.isional giant cells or fOCI of necrosis is found. There may be transitional lesions to proliferative myositis and mtramuscular myxoma. Both diseases can be interpreted as var iant-, of NF. Rarely bone formation is present. In NF with "heterotopic ossificauon" the typical zonal phenomenon of "myositis ossificans" is not seen. - The varYll1g lustological pattern and proposed histological subclassifications of NF appear to have no bearing on It; biological behavior. NF is a benign disease, with apparently reactrvc cell proliferation. treated by simple or wide excision. Rarely recurrences may occur.

According to the International Classification of Tumours (Enzinger et al., WHO, 1969), nodular fasciitis, synonymously termed pseudosarcomatous fibromatosis, is considered to be "a benign and probably reactive fibroblastic growth extending as a solitary nodule from the superficial fascia into the subcutaneous fat or, less frequently, into the subjacent muscle". In this definition the relationship to other fibroblastic tumorous lesions, as proliferative myositis, is mentioned. The diagnostic distinction from sarcomas is emphasized, as these lesions may show clinically suspicious symptoms, such as rapid growth, as well as disturbing histological findings, such as high cellularity, numerous mitoses and cellular atypism. Because of the great variety of microscopical findings, the diagnostic evaluation of nodular fasciitis (NF) is associated with apparently never 1 Pathologisches Institut der Universitat, Miinchcn (Direktor Professor M. Eder) und 2

Pathologisches Institut, Allgemeines Krankenhaus, Hagen

10 Path Res

Pract Vol 162

134 . P . M eister, F.-W. Buckrna nn, and E. Konrad

ending surprises. The number of differential diagnostic considerations IS vast. The purpose of thi s revision of 1 0 0 patients with NF is: I. to compare our own findings with such already published, concerning the overall incidence, sex, age distribution, locali sation, size and clinical data if available. II. to test the above defin ition of NF, with regard to the changes being recognizabl y nodula r, topographicall y related to fascia with histological signs of inflam m atory response, and involvement of subcutaneous fat OJ musculature. III. to demonstrate th e vari ety of histological patterns of NF in different cases, or regionally, within one and the same lesion, and to probe the mentioned relationship betw een NF, proliferative myositis, intramuscular myxoma and "myositis ossificans", In this context the differential diagnosis of NF will be discussed. IV. to study possible correlations between various pathologic anatomical and clinical features.

Material and Methods 100 patients with NF we re studied with re spec t to age , sex, lo calisation and size of the tumor (Biickmann, F ., P arhologisch es In stirur, Allgemein es Krankenhaus Hagen, and USAREUR, Me dica l Lab or ator ies, 1')6'+-1 97(,; M eister , P ., P athologisches Inst it ur del' Universirat Mii nch en , 196 0- 1969). C lin ica l information Incl udi ng data on th e course o f the di sease bef or e and a ft er surge ry was avai la ble o nly in a certain n umbe r of patients. H istologica lly .i -cm iqu a nurative d eterm ination was ca r ried out (0 to + -:- + ) of charac te ris tic rmcroscop ical Fe.itures such as topograph ical relation of N F to fa scia , fat or mu scle ti ssue, ove ra ll nod ular configura n on, cell ula r a nd fibrill a r d ensit ies, myxoid chan ges, vascularit y, e vide nce of rece nt or o ld hemorrhage \ w ith ext rav asa ted ery t hrocytes or hemosi de ri n laden m acr ophagcs), signs of cellul ar in fl.unm ar or y respo nse, (multi nucleat ed) gia nr cells , mitot rc act iv it y, cel lular a typism and evid ence of nec rosis. The semiquantit at iv e ev aluat ion was carried ou t by tw o observers. Severa l parameters such .1S age, localisation and size of the tumor and various m icroscopical Features were t ested a, to possible statistically sign if icant interrelations.

Results I. Sex : An equal distribution between the two sexes was found, 51 of the patients 'being female and 49 male. Age (Table 1): The mean age, including both sexes, was 44 years. The mean age for female patients was 46 years , with the highest incidence in

Nodular Fasciitis . 135 Table

Nodular fasciitis. age, known for 9, patients

1.

13 12

U>

11

~

female

n~48

(total :51)

10

0

male

n~47

(lolal.49)

8

C

;

(;j

6

!!!

a.

:::1 111

:::~

'0

.+.i<

1HE

~

Q)

.0

E

::I

mij

3

++++

Z

++++

dekade

Table

Nodular [asciiriv: localisation; known for 97 patients

2.

~Ol

28l 26j

ill

22

" C

'!!

0

16

lJ

5

16 -

1

14

I:lI female

12

..0

E ,., 2

ill

f'lffii... head/r!eck

o

-

--~

g

G;

z

31 4

~o

(;j 10

a.

1

~

:!~

III lrunk

upperextremIty

lowerextremlly

male

13 6 . P . Meister, F.- \'i: . Biickman n, and E. Konr ad Tabl e 3.

No dula r Iasciiris : vize of lesions;

10 0

pat ients

30 28 26 24

22

20 18 16 14


C

.!!! 12

a

10

'0

...

III

$J

E 4 ~

2

Z

0,5 1

Table 4.

10

ems

Nodula r Iasciitis : d ura tio n ; known fo r 36 pat ient s

mean duration: 5 months 18 16
C

-s l\l C.

'0

...

III

.D

14 12 10 8

6

E

4

Z

2

~

< 1

2

4

6

12

36

60

months

Nodular Fasciitis . Table 5.

137

Nodular fasciitis: chnical impressions, 82 cases

"tumor"

myositis

lymphadenitis

nevus

fibroma

pleomorphic adenoma (parotid gland)

fibrolipoma

Fascial sarcoma

lipoma

myosarcoma

myoma


ganglion

malignant tumor

atheroma

recurrent carcinoma

I

3

the 7th decade. In male patients, however, the mean age was 42 years, with the highest incidence in the yth decade. The youngest patient was 2 weeks, the oldest 74 years of age. Localisation (Table 2): Most frequently the upper extremity was involved, followed by the lower extremity and the trunk. Least common was NF in the head or neck area. In the upper extremity NF was frequently located on the forearm, in the lower extremity on the thigh. There were no significant side or sex differences. Size (Table 3): The maximum diameter of NF averaged 2 em (range from 0.3 to 10 em). Most of the lesions were between 0.5 and 2.0 em, the highest incidence was found for the group with a maximum diameter between 1. 5 and 2.0 em. Clinical data: In 35 patients a history of tumor development was available with a duration from less than one month to 60 months, more than half of the patients giving a history of less than I month (Table 4). Pain was present in 26 patients and denied in 5 cases. A history of trauma was confirmed in 5 cases, negated in one case. One of the patients revealed histological proven multiple lesions of NF. 4 patients showed recurring NF. The control period was up to 15 years. No information was available as to the initial mode of surgery such as wide, simple or incomplete excision. In 82 cases preoperative clinical impressions were stated (Table 5). 38 of the cases had been designated as "tumor", without further commitment as to its dignity, 37 were considered to be benign and 7 to be malignant.

II. Histological features consistent with the term cc Nodular Fasciitis" 6 I cases showed a histologicall y obvious nodular pattern of cell proliferation, in 39 cases the lesion was rather diffuse; 96 cases revealed histologicall v a topographical relationship between proliferative areas and fascial structures (Fig. I, 2);

13 8 . P. Meister, F.- W. Biickmann, and E. Konrad

Fig. 1. NF showing typical ongm from fascia and nodular configuration. It appears rather well defined with largely intrafascial proliferation and varying cellularity with denser central area. HE; .' IO.

Fig. 2. Fascial origin of NF: note central fascial remnant, showing inflammatory changes and hemorrhages. Large number of capillaries and inflammatory cells are seen along fascial surface and within adjacent fat. HE; >: 100.

Nodular Fasciiti s . 139 Table 6. Nodular [ascutis: location

In

depth ;

1 00

patie nts

30

25

m female o male

20 III

-o C ~

15

co

C-

10

II>

.c

E

"

5

Z

Int ra fascial prohferanon

inh lt ratio n of derm is

Fig. 3. Subcutaneous NF : cellular prolife ra tion radiating into adjacent fat tissue along 40. both sides of the fascia, H E;

97 cases presented "mobile" inflamma to ry cells, chiefl y lymphocytes or neutrophils, mostl y in a mild to moderat e degree (com pare Table 7). Location in depth and to pogra phica l relations to fascia, subcutaneous fa t or mu scle revealed 4 va ria nts (T able 6) :

140

P. Meister, F.- W. Biickmann, and E. Konrad

Fig. 4. Deeper subcutaneous and muscular fascia: fat tissue as in subcutaneous NF and skeletal muscle as in "proliferative myositis" are involved. HE; X 40.

Table 7. Nodular Fasciitis: semiq uantita ti ve evaluation of microscopical features (from o to + + +); 100 patients

+

++ +++

cellularity

24

64

12

100

fibrillar density

J4

62

24

100

35

34 54 27

7 2

76 100

20

30 8

5 6

9

°

myxoid changes

2+

vascularity

44

extra vasatcd erythrocyte,

II

57

hemosiderin-macrophage,

62

inflammatory cell, (multinucleated) giant cells

3 66

33 62

mitoses

47

H

cellular atypism

3°

55

I.

J4

total number of posi ti ves

89 38 97 34

53 70

Intrafascial growth on both sides well delineated without "infiltration" of surrounding fat tissue.

Nodular Fasciitis

141

Fig. 5. Typical NF; ++ -cellular and fibrillar densities, with S-shaped pattern, distinct vascularity and sprinkling of inflammatory cells. HE; -, roo.

Fig. 6. NF with an area showing plump, hyalinized collagen fibers, similar to keloid. HE; >< roo.

14 2

.

P. Meister, F.- W. Biickmann, and E. Konrad

Association with superficial fascial structures and infiltration of subcutaneous fat tissue on one or both sides - the classical and most common situation (Fig. 3). 3. Association with a deep fascia with involvement of adjacent fat tissue and/or skeletal muscle (Fig. 4). 4. Intradermal growth with relation to superficial fascia - rare. In one case of group 1. and one of group 2. periosteum was involved.

2.

III. Semiquantitative evaluation of microscopical features (7able 7) A majority of cases showed a medium degree of cellular and fibrillar density (Fig. 5). However, there were cases in which either slender fibrils or even plump collagen fibers prevailed (Fig. 6). The latter cases also showed low cellularity. Maximum cellularity (+ + +) was accompined by low fibrillar density (+) in 18% , by moderate density (+ +) in the majority, i.e. 820/0, but never by maximum (.i- + +) fibrillar density. Maximum fibrillar density was associated with low cellularity (+) in 350/0, in the majority (650/0) with (+ +) cellularity, but never with high (+ + -+) cellularity. Thus maximum cellular and fibrillar densities excluded each other. On the other hand, low cellular as well as low fibrillar density were also found in cases with abundant mucoid intercellular material and myxoid changes. Certain myxoid changes were found in 76% of the cases. Within individual lesions, as a rule, regional differences of cellular and fibrillar densities, or myxoid changes could be seen (Fig. 7). There was only one exception: possibly burned out cases of NF were rich in collagen fibres throughout (Fig. 8). All cases showed marked vascularity, sometimes with a typical focal fascicular pattern with parallel arrangement of capillaries (Fig. 9). In 89 cases extravasated erythrocytes were seen, in 38 cases hemosiderin-laden macrophages were present. 97 of the cases showed mobile inflammatory cells. In only 3 cases no obvious inflammatory cells could be recognized. Collections of neutrophils, lymphocytes, together with macrophages, fibroblastic and capillary proliferation may at least focally resemble granulation-tissue. Rather typical is a cellular inflammatory response with capillary proliferation at the site of fat infiltration. 70 cases showed cellular atypia which, however, was only mild to moderate with one exception. Together with mitotic activity, which was only mild to moderate, 53 cases exhibited focal changes which resembled an undifferentiated sarcoma and qualified as "pseudosarcomatous" in a strict sense (Fig. 10).

Nodular Fasciiti s . 143

Fig. 7. NF with ty pical vary mg cellularity, fiber formation, myxoid changes and va s cularity. H E; Y 40.

Fig. 8. N F with high fibrillar density and maturity resembles fibrom atosis; note, however, pro minent vascul ar ity. Left upper corne r : fascial remnant. HE; X 40.

144 . P. Meister, F.- W. Biickmann, and E. Konrad

Multinucleated giant cells were present in 44 cases, chiefly similar to those found in giant-cell reparative granulomas ("giant cell epulis"). They were often in clusters and associated with capillaries and hemorrhages (Fig. I I). 15 cases showed "ganglion cell-like" giant cells, 13 with (Fig. 12) and 2 without muscular involvement (Fig. 13). Relation to proliferative myositis In 6 cases, cellular proliferation apparently originating from a fascia with infiltration of subcutaneous fat tissue and skeletal muscle and "ganglion cell-like" giant cells was seen. Thus, features common to NF and proliferative myositis were found in one and the same lesion. 13 cases qualified as proliferative myositis. "Ganglion cell-like" giant cells, however, were not obligatory to NF with involvement of musculature; in 10 additional cases with an otherwise typical pattern of proliferative myositis they were absent (Fig. 14). Relation to intramuscular myxoma 2 cases with typical features of NF also showed marked myxoid changes within the musculature which were compatible with "intramuscular myxoma" (Fig. 15). Of 4 cases qualified as intramuscular myxoma, 2 showed additional features of proliferative myositis. Relation to "myositis ossificans" (or ectopic ossification) Only I case of NF showed bone formation with trabecular pattern in a few small intramuscular foci (Fig. 16). Necrosis Jn 10 cases foci of necrosis varying in number, size and age were found, sometimes with cyst-formation (Fig. 17, 18). IV. Correlations between various pathologic-anatomical and clinical parameters In the extremities, trunk or head/neck and in different locations as intrafascial, superficial or deep fascia, with fat or muscle infiltration, the majority of cases showed sizes between I. 5 and 2 em, corresponding to the overall average size. Statistically no relations could be detected between size, age, localisation, superficial or deep situation with or without fat infiltration, nor between localisation and cellular or fibrillar density, or between age and sex of the patient". n Credit for the statistical evaluations is given to Doktor Kraus, ISB (Dir. Professor K. Obeda, Univcrvit y of Munich).

Nodular Fasciitis . 145

Fig. 9. Proliferated cap illanes showing tendency to band-like parallel arrangement ; ad diti onal inflammatory cells Impart sirnilarity to granulation tissue. HE ; X 1 0 0 .

Fig. t o. Hi ghly cellular area, with at ypisms, mitoses, focal parallel alignment; "p seudosarcornatou s" appearance , with simi la r ity to frbrosarcoma. HE; X 160 .

14 6 . P. Meister. F.- W. Biickmann, an d E. Konrad

Fig. I I . Area with man y wide ca pillaries and occasional intimatel y related osteoclastt yp e multinucl eated gian t cells. HE ; " 16 0 .

Fig. 12 . Pr oliferation of dark (amphophilic) occasionall y multinucle ar , plump cells, with lar ge vesicular nuclei an d pr omin ent nucl eoli; "ganglion cell-like" cells are found in NF and " proliferative myositi s". HE ; )< 1 6 0.

Nodular Fasciitis . 147

Fig. 13. Proliferation of "ganglion cell-like" cells in subcutaneous fat with myxoid changes in NF, without muscular involvement. HE; >: 160.

Fig. 14. Musculature with fibrous septa showing checkerboard pattern typical for "proliferative myositis", but without prominent ganglion cell-like cells, in case of NF with muscular involvement. HE; 40.

14 8 . P. Meister, F.-W. Biickmann, and E. Konrad

Pig. 15. FaSCIa with -keletal muscle pushed aside by a hypocellular, extremely myxoid tissue, compatible With intramuscular myxoma. HE; ,< 40.

Fig. 16. NF or "proliferative myositis" respectively: between muscle cells partly mineralized osteoid IS seen with rows of osteoblasts; ossifying variant of NF (= heterotopic ossrhcation). HE; 100.

N odular Fasciiti s . 149

Fig. 17. Recent necro sis (upper third ) wit h nuclea r shadows, marg inal hemorrhage and infla mma to ry reaction . H E ; -. 40 .

Fig. 18. Older cystic degeneration. without inflammatory response : cysti c or bu rsa- like variant of N F. HE ; :-: 40. 11 Pat h Res Prac! Vo l 162

l 50 . P. Meiste r, F.-W . Biickrnann , a nd E. Konrad

Discussion and Review of the Literature A revision of 20 5,836 surgical specimens (Pathological Institute, University of Munich, running numbers from 1960 to 1969) yielded 2.86% soft tissue tumors (Meister and En gelhardt). 0.28% of the ent ire material were classified as fibrom ato sis. A micro scopic al revision of cases with fibromatosis and lesions or iginall y designated as fibroma, myxofibroma, myxoma, neurofibr oma , fibrosa rcoma, neurogenic sarcoma, myxosarcoma, synovial sarcoma or spindle-cell sarcoma, fina lly yielded 22 cases wh ich qualified as NF (= O.O l 5010 of th e enti re mat erial). The incidence was about double in the series of Biickmann with 17,000 surgical specimens including 6 cases with NF (0.0 35%). It is reasonable to assume that the overall incidence of NF in an un selected material of biopsies may be about 0.025%. Thus NF is not a very common disease. However, being easily accessible to surgical removal, NF should not be confused w ith other lesions. Its wide ran ge of different microscop ical featu res constitutes a major problem in surgical pathology. D ifferenti al d iagnostic considera tions ran ge from common inflammatory rea ctio ns to sarcomatous prolifer ations. Therefore , pooling of a lar ger material and comparison of the results with alread y published series appears to be worthwhile to shed light on th e real nature of N F. Sex: Larger series always show onl y a slight preponderance of either sex (Ta ble 8), in th e compiled sta tistics there is onl y little predominance of men. Age: NF may occur at all ages (Ta ble 9). Our series revealed on the average, higher va lues fo r the mean age; especially disti nctive is the peak incidence for male in the 5th decade. Compiled statistics show a grand mean age of 4°.5 years an d a general peak for the 4th decade. As to the low peak age and male predominance in Allen's series, it has to be considered that the AFIP material may show a certain selection, includ ing a substantial number of military patients. Localisation: In a number of series, like in ours , similar figures are given for NF located on the tr unk or th e lower extremity (Table 10). The compil ed sta tistics, ho wever, clearl y show the following sequence: I. upper extr emity, 2. trunk , 3. lower extremity, being always as fr equently involved as 4. head and neck. Size: As in other series (Table I I ), most lesions measured up to 3 em, the vast majority of cases was found in the range from I to 2 em. Du ration: Literature dat a concern ing the duration of NF are given with

Nodular Fasciitis . Table 8.

15 1

Nodular fasciitis: comparison of sex distribution; 548 patients ------

Author

female

male

unknown

total ---------------

55 10

41

Dahl et al.

15

3°

Hutter et al.

29

38

7° 8

Allen

Konwaler et al. Price et al.

4

4

45

96

Soule

27

19 28

Stout

65

57

own results

49

51

65 56 123 100 ---------

284

253

548

I I

-------

Table 9.

Nodular fasciitis: comparison of age distribution

---

Author

-------

Years trom

to

mean age 111 years

peak decade

------

Allen

r st

Dahl et al.

1 9ft2

dec.

8th dec

jrd

-

85

-

75

4° 38

6th

29

-

40

4°

3

-

67

3rd

-

7° 8th dec

4th 3rd

-

74

Hutter et al. Konwaler et al. Price et al. Soule

-t.. st dec.

Stout

I

own results

'/24

-

44

4th 4th

5th

varying accuracy (Table 12). However, the duration very rarely exceeds 3 months. In many patients the only symptom was tumor growth, which often was alarmingly rapid, over days or few weeks and usually less than one month. Pain: If stated, pain or tenderness was more frequently present than absent (Table 13). These results, however, are biased, as reference to pain can be expected to be more frequent in the presence of pain. Patients with pain, in some cases showed histologically recognizable involvement of nerves by NF (Dahl et al.).

25

82 9 66

-

other location

35

-

l OS

lower extremity

7

4 13

6

384

upper extremity

I I

Hutter er al.

I4

170

trunk

2

Dahl et aI.

5

161

Allen

N od ula r Fasciiris: comparison of localisat ion

head /neck

T able 10.

65

-

-

8

8

3I

4 22

Price et aI.

2

6

-

-

Konw aler et aI.

56

I

10

35

8

2

Soule

123

6

25

56

24

12

Stout

97

1,269

I3

194

22

-

60 3

26S

19 1

Total

49

20

6

own result s

c,

~

::I

..,

0

;:>::

tTl

~

::I 0-

.?

::I

3~

c: ~

tl:l

~

~ 7'1

g.

~

~

'"

'"

I

r,

3

I

total number of cases with exact measurements

39

25

94

49

3.5 em : 87 pat.

36

15

<

Stout

own results

to

from 0.5

Soule

to

21

2-2·9

from 2.5

7

13

25

l-I.9

from 0.4

[

from [

[0

<

Nodular fasciitis: comparison of sizes

Price et al.

Konwaler et a.

Hutter et al.

Dahl et al.

Allen

size (em)

Table

9

3

3.5 em

3.5 em to

to

6

3-3·9

5

1

CIJ.1

>

5-5·9

5 em

1

6-6·9

9

4

from 4

2

2 I

(subcutaneous NF) 4 em (deep-seated NF)

5

4-4·9

2

I

to

I

7-7·9

-

9-9·9

-

I

I

10·5 em : 7 pat.

8-8·9

7

-

100

-

12 3 -

56

70

30

96

total

29

5+

70

7

3+

not stated

.,

Z

0

\,;.>

""

...

§:

'11 ~

....

~

c,

12.

I

=

8

26

I74 22

m, years

total

months

y

I

18

own results

I

2

4

4

37

Stout

I

4

+-

-

I

8

9

-

5

9 6

3 m m

2

33

Soule

7

34

I I

24

=

I

mm

10

<

2

-->-

-

-

I

5 m

4

-

4

3

> 3 months:

3

16

-

I

4 m

6 m

-

5 pat.

-

7 m

I

-

+-

-

I

8 m

Nodular Fasciitis: comparison of duration

Price et al.

Konwaler et al.

Hutter et al.

Dahl et al.

Allen

Table

I

-

4

-

I

m

9

I

-

-

-

I

m

10

-

-

---+

m

II

2

-

-

I

3

-

m

12

I

-

-

-

2

I

y

2

4 y

I

-

I

2

-

-

-

more thorn

3 y

I

I

-

-

-

year

5 y

-

-

6 y

-

-

-

7 y

-

-

-

-

8 y

-

-

-

-

9 y

-

-

-

I

y

10

-

-

-

I

y

I I

-

-

-

y

12

-

13

65

- 37

-

- 12

I}

II

-

57 I

100

12 3

56

57

8

7°

3°

96

total 38 not stated

'" 0..-

::s....

0

~

r'1

0..-

::s

to>

?

::s

to>

3

~

c:

to

~

~

.~

g.

~

:-0

.j>.

V'>

Nodula r Fasciitis . 155 Table 13.

Nodular Fasciius : pain or tenderness not stated

negat ive

positive "a few"

Allen Dahl et al. Hutter et al.

7

23

43

(pain -;- ten der ness: 2 pat .} 29 (pai n: 17 pat .) (tenderness: 24 par .)

6

Konwaler et al. Price et al.

22

28

Soule

20

15

15 21

Stout

29 26

13

81

own result s

T able 14. --

-

total

123 100

69

Nodular fa sciin s: multiplicit y of lesions; history of trauma?

--

single

Allen Dahl et al. Hutter et al.

not stated

96 30

Konwaler et al.

63 8

Price ct al.

57

Soule

55

99

total

trauma

96 30 69 8

6

123

Stout own results

mult iple lesions

57 56 123 100

7

?3 ?

Trau ma: A po ssibl e relat ionship between N F and t rauma is mentioned only in 16 cases of the compared series, including our ow n 5 cases (Table 14)·

Multiplicity: Most authors considered possible multiplicity of NF. With

the exception for the series of Hutter et al., multiple NF seems to be extremel y rare (Table 14). Hutter et al. describe one patient with up to 10 nodules in di fferent regions of the bo d y, which appeared simultaneously; bu t only on e lesion was biopsied. T he remainin g 5 patients showed histologically verified mul-

15 6 . P. Meister, F.- W. Biiekmann , and E. Konrad

t iple lesions of NF, which occurred at different times, either at different sites or as satellites near the pre viously excised NF. In our own material onl y one "mult iple" case was histologically proven, another one was clinicall y suspected. Terminolo gy and relation of NF to v arious structures The name "fasciiti s" allegedl y was coined by Fred M. Stewart, Memorial Hospital, Ne w York, either in 1941 (Mackenzie) or 1944 (Hutter et al.). NF was a known ent ity at Memorial Hospital before its publication by Konwaler et al. 1955 . Being a benign fibroblastic proliferation with some features suggesting a cellular reaction and characteristically showing an anatomical relation to fascial tissue, the disease was appropiately named: "fasciitis", The series of Price et al., Allen, Dahl et al., as well as our own findings point to th e key position of fascial tissue changes in the pathogenesis of NF. The following adjectives had been used to further characterize fasciitis: "infiltrat ive", "pseudosarcomatous", "proliferative", "subcutaneous" - which seem to be a ppropiate, with restrictions for "subcutaneous", as quite a number of NF show deeper local isat ion. Most commonl y used at th is tim e and also applied in the WHO-Classification (Enzin ger et al.) is the term "nodular fasciitis", whereby "nodular " ma y apply to the clinical and gross impression of a circumscript swelling or tumor as well as to a nodular histolo gical appearance. In th e original description (Konwaler et al .) N F was term ed "subcutaneous pseudosarcomatous fibromato sis" is not yet closed (Ma ckenzie; Prechtel and Meister; Price et al., should be included in th e group of fibroblastic disorders kno wn as "fibromato sis" is not yet closed (Mackenzie; Prechtel and Meister; Price et al., Stout). An ultrastructural and histochemical study of NF (W irman) revealed that the main population of cells seems to be related to "myofibroblasts" . "M yofibroblasts" are thought to be characteristic of inflammatory and t rauma-related conditions (granulation-tissue), rather than of fibromatosis or even sarcomas (Rem berger et al.), After the classical description of subcutaneous NF (Konwaler et al.), deeper seated cases of NF wer e reported in a lesser, but substantial number (Table 15 ). The se cases often showed relation to muscular fa scia with in vol vement of skeletal muscle and transitional changes to typical proliferat ive myositi s. In only a few cases the periosteum was involved. - In our series there was a number of cases with well delineat ed intrafascial cell proliferation without infiltrat ive pattern: this is in contrast to Soule's opinion that fa scial ti ssue is only superficially invol ved.

4

9

83

--------

56/70

3

25/3 0

TO

39

.. (?)

Hutter et al.

3

T9

3

Dahl er al.

8/8

65/ 65

-

13

-

-

52

Price et al.

2

Konwaler et al.

3 8/5 6

-

3 8 ",)

Soule

"') 38 cases with anatomical relationship to fascia, no data as to involvement of superficial or deep fascia

--

number of cases with known location/ 96/96 total number of cases

extension into periosteum

deep fascia / with extension into skeletal muscle

superficial fascia / with extension into subcutaneous fat

Allen

IJ h 2 3

-

3

10

Stout

t

7 4 0 1/44 8

ool ioo

36

266

33

total

2 (?)

2T

5I

26

own results

Nodular fasciitis: location in depth and relationship to fascia, subcutaneous fat tissue, skeletal muscle or bone

intrafascial I without extension into adjacent tissues

Table 15.

.,...

z

..." .....,.

....

§:

~

'Tl

PC

o

15 8 . P. Meister, F.- W. Biickmann, and E. Konrad

At the peripheral zone of NF, a gradual transition from normal regular fascial connective tissue to the fully developed changes of NF is seen. There is edema with scattered inflammatory cells, capillaries and increasing cellular proliferation as seen in some of our cases. Rarely this zone also enclosed tiny foci of necrosis. The infiltrative pattern may be observed along one or both sides of recognizable fascial remnants; in NF of deep muscular fascia, there may be involvement only of the overlying fat tissue or the subjacent muscle tissue, or both tissues may show infiltration. Two cases of our material located in the dermis presented findings compatible with NF, including origin from bundles of denser connective tissue, probably representing very superficial fascia.

Histological features Cell and fibrils: As in the WHO-Classification, a proliferation of fibroblasts, with either plump or spindle-cells, is listed as first and main histological feature of NF in the series discussed (Allen; Dahl et aI.; Hutter et aI.; Konwaler et al.; Soule; Stout). A characteristic meshwork of cellular processes and fibrils is described resembling a tissue culture (Soule). Cells and fibrils, if at all, do not show a straight arrangement with formation of long bundles, but an S-shaped, sometimes even storiform pattern similar to fibrous histiocytomas (Allen). Thought to be characteristic for NF are argyrophilic fibrils, or collagen fibers, which take only little stain with the trichrome-method for collagen and lack bi-refringency (Price et al.). But several authors also mentioned cases of NF with hypocellularity and more compact and occasionally hyaline collagen fibers (Allen; Hutter et al.; Soule, Stout). These features were thought to express maturity of NF (Soule). Hutter et aI. rejected the idea of NF rich in collagen necessarily being older, as they were not able to find a relationship to longer duration in these patients. Stout found in 9 of 123 cases a denser appearance, resembling "common fibromatosis". Dahl et aI. described compact bundles in 12 out of 30 cases, Soule in 4 of 54 cases. Allen classified 5 of 96 cases as a "hyalinized" variant. 24 of our 100 cases exhibited a high fibrillar density, sometimes with plump or hyalinized fibers and occassionally with longer bundles. The majority of our cases, however, revealed mean values as to cellular or fibrillar densities (64 or 62 cases respectively), characteristically with whorling and S-pattern. Our semiquantitative evaluation tried to give overall values, concerning the entire lesion. The focally changing patterns within a given lesion,

Nodular Fasciitis . 159

which is distinct and characteristic for most cases of NF, is not expressed by this evaluation. Regional differences were mentioned in the original description of NF (Konwaler et al.) and were later emphasized especially by Allen, Soule and Stout. These regional differences also concern cellular and fibrillar density. Even cellular shapes vary as loose areas may show rather plump cells, while dense areas may contain more slender spindle cells (Price et al.). A regular, repeating pattern in analogy to the zonal phenomenon in myositis ossificans became not evident in our study. However, such zonal orientation was postulated also for NF by Hutter et al. Ground substance: The focally changing pattern is intimately related to the ground substance, which is labelled as edematous, serous, mucoid or myxoid. Myxoid appearance, the second main feature of NF, is mentioned by all authors. It may already be suggested at gross inspection. Price et al. proposed a subclassification of NF into 3 types according to predominance of myxoid areas or fiber formation. Their material of 65 cases of NF included 23 myxomatous cases (type I), 29 intermediate cases (their type 2, comparable to our majority of NF with + +-cellular and fibrillar density) and I I fibromatous cases (type 3, corresponding to our 24 cases with + + + fiber formation). Myxoid changes dominated in 9% of Dahl's et al. series and in 7 of our 100 cases. We found distinct myxoid changes in another 34 patients, slight myxoid changes in 35, and absence of myxoid features in 24 patients . Vascularity: A third histological main feature of NF is an endothelial proliferation with pseudovascular spaces, mature capillaries and occasionally even small arteries or veins (Allen; Dahl et al.; Hutter et al.; Konwaler et al.; Price et al.; Soule; Stout). The following descriptions can be found as to the typical vascularity in NF: festooned, radial, parallel or band-like arrangement and "probing rays". "Myxoid foci", "around myxoid areas" and "the periphery" are mentioned as regions with especially distinct vascularity . In our material, all cases showed well recognizable vascularity, which was moderate in the majority. Peripheral capillaries, sometimes with "probing rays" in the area with fat infiltration and bands of capillaries with parallel arrangement at the border of myxomatous foci appeared to be characteristic. In contrast to a statement of Soule, vascularity was also prominent in some of our cases with marked fiber and collagen formation . Pseudovascular clefts were not common features of NF in our material. Allen coined the term "repair type" of NF for cases resembling granulation tissue due to prominent vascularity together with hemorrhages and inflammatory cells.

r60 . P. Meister, F.-W. Biickmann, and E. Konrad

Extravasated erythrocytes in varying, often high number are mentioned as almost constant findings in NF. They could not be detected in I I of our cases. Hemosiderin-laden macrophages were thought to speak against NF and for fibrous histiocytoma by Konwaler et al. However, I case of Soule, 7 of Dahl et al. and 38 of our cases showed hemosiderin-laden macrophages. Inflammatory cells: A fourth important and almost obligatory feature of NF are inflammatory cells. "Round cells" are emphasized, chiefly lymphocytes, occasional plasma cells, rarely mast cells (Dahl et al.; Soule) and foamy histiocytes, especially close to fat infiltration (Stout). Allen denotes the inflammatory cells as inconspicuous, Hutter et al. as scant, Price et al. as sparse. In Dahl's et al. cases they were always present but to a varying degree. They were missing in 18 and prominent in 2 of 56 cases reported by Soule. In our material, only 3 cases did not reveal any mobile inflammatory cells, in 62 they were graded as + (= "inconspicuous"), in 30 cases as + (= "moderate"), in 5 cases as (= "marked"). With increasing degree, especially in proximity of necrosis, histiocytes and polymorphnuclear leukocytes were seen in addition to lymphocytes. Mitosis: A fifth and significant histological feature of NF is the mitotic activity which is mentioned in all series. Mitoses are either specified as: always present, usual, common; they were not infrequent, never in large number or quite numerous and usually regular, with the exception of one observed tripolar mitosis (Allen). Soule recorded up to 4 mitoses per HPF, Dahl et al. in 3 cases up to 3/HPF. In 47 of our cases no mitoses could be detected, in 44 a few, in 9 a moderate, but never a large number. Atypism: Especially within loose areas of NF, fibroblasts with plump nuclei, varying in shape and size (= pleomorphism), occasional prominent nucleoli and nuclear hyperchromasia are described by Allen, Konwaler et al., Hutter et al., Price et al., and Soule. Cellular atypism, chiefly expressed by nuclear pleomorphism and hyperchromasia, was found in 70 of our cases. The great majority showed only slight atypism (+), in only one case it was marked. - The adjective "pseudosarcomatous" had been applied to NF by Allen, who stressed large atypical cells and mentioned even occasional bizarre cells in his two original descriptions of NF. Reviewing the literature, it seems likely that the sarcomatous impressions are rather based on the undifferentiated, immature myxoid fibroblastic proliferation in NF with obvious mitotic activity than on cellular, respectively nuclear atypism. Another factor may be the frequent but not obligatory rapid tumor growth (Dahl et al.).

+

+++

Nodular Fasciitis .

161

Giant cells: Giant cells as optional feature in NF are mentioned by Allen, Dahl et al., Konwaler et al., Price et al., and Soule. Allen and Dahl et al. distinguish two different kinds of giant cells: 1. ganglion cell- or myoblast-like giant cells, which may show transitions from the plump variety of the fibroblastic main population of NF, with prominent vesicular nuclei, nucleoli, amphophilic cytoplasm and a single nucleus or 2-3 nuclei. These cells may be ver y similar to ganglion cells or to degenerating or even more to regenerating skeletal muscle cells. They were originally described in proliferative myositis (Kern; Enzinger and Dulcey), but also may occur in subcutaneous location as variant of proliferative myositis or NF (Stiller and Katenkarnp) pointing to a relationship between the two lesions. These ganglion cell-like cells were present in 9 of 30 cases of NF (Dahl et al.). 44 of our cases showed giant cells, 15 cases the ganglion-cell type. Of these 15 cases a vast majority also revealed muscular involvement indicating proliferative myositis. Only two cases showed NF with ganglionlike cells, without muscular changes. Electron microscopical studies (Gokel et al.) show these ganglion celllike cells to be active immature mesenchymal cells, similar to fibroblasts. The second kind of giant cells show a higher number of often centrally located smaller nuclei. Their derivation from fibroblasts or macrophages is discussed (Price et al. ). Phagocytosis, however, has not been reported. These multinucleated giant cells resemble multinucleated osteoclast but not foreign-body giant cells (Soule). Called osteclastic-type giant cells by Allen, they can sometimes be observed especially in loose myxoid areas, in small groups, associated with capillaries, possibly with vascular budding and also with small hemorrhages (Allen; Dahl et al.; Soule). These findings were present in 8 of 3 0 cases (Dahl et al.), 25 of 56 cases (Soule) and in 3 I of our 100 cases. Occasionally we found giant cells containing hemosiderin. NF with features resembling giant cell reparative granuloma (or "giant cell tumor") was termed "osteoclastic" variant of NF by Allen. Bone or cartilage are rare additional features of NF (Allen; Hutter et al.) and were not seen in Dahl's et al. series of 30 cases. Only I of Allen's and I of our cases showed bone formation, partly with rows of osteoblasts along slender trabeculae. This variant, called "fasciitis ossificans" by Allen, points to relations with myositis ossificans, even if the typical zonal phenomenon could not be seen in the few cases reported (Ackerman). One case of Stout showed only osteoid, like one of the series of Dahl et al., another one only calcifications which were visible on X-ray. Relationship to other tumorous lesions of connective tissue Our study showed simultaneous involvement of fascia, fat and muscle, frequently with typical ganglion cell-like cells, or focally marked myxo-

r62 . P. Meister, F.-W. Biickmann, and E. Konrad

matous changes also within the musculature. Few cases showed also bone formation. These findings support the concept that NF, proliferative myositis, intra-muscular myxoma and myositis ossificans are related tumorous myxoid-fibroblastic disorders. As expected, transitional forms may exist (Dahl et al.; Biickmann; Mackenzie). Necrosis or cystic changes were present in 10 of our cases. These lesions focally may resemble a necrotizing and granulomatous inflammation. This lead to the conjecture that necrosis of fascial tissue may possibly be the initial lesion of NF. The foci of necrosis may contain finely granular eosinophilic material, but no fibrinoid changes, and no unequivocal fibrin is seen (Dahl et al.), Some of our cases showed larger spaces, without conspicuous inflammatory reaction, similar to 5 of Allen's 96 cases, and 5 of Dahl's et al. JO cases, subclassified as bursa-like or "cystic variant" of NF.

V. Correlations between various pathologic-anatomical and clinical features In our material none such relationships were found which showed statistical significance. The proposed 12 subtypes of Allen and 3 subtypes of Price et al. also appear not to be of clinical significance. Moreover, NF characteristically shows focally changing histological patterns within one given lesion. Therefore no further subclassification of NF appears to be useful. Differential diagnosis. A comprehensive differential diagnostic checklist is essential for an accurate histological demarkation of NF. Of utmost importance is the distinction of NF from sarcomas. The original diagnosis of a sarcoma had been made in 5 of 22 cases revised by us (Meister and Engelhardt), in 17 of Allen's 96 cases, but 56-times in Stout's series of 123 and even 38-times (!) in Soule's series of 56 patients. Most frequently fibrosarcoma was suspected because of the fibroblastic aspect and fiber formation of cellular proliferation. Because of myxoid changes myxosarcoma, embryonal rhabdomyosarcoma, synovial sarcoma and neurogenic sarcoma were mentioned. Intramuscular location and myoblast-like cells also can be made responsible for the diagnosis of rhabdomyosarcoma. Infiltrated and incorporated fat tissue with myxoid changes leads to the diagnosis liposarcoma (especially of myxoid type), the high vascularity with hemorrhages to the assumption of angiosarcoma or hemorrhagic sarcoma Kaposi. Variable fiber formation, scattered giant cells and myxoid changes or occasionally even a storiform pattern may simulate fibrous histiocytomas, malignant or benign. Because of changing fiber formation and myxoid changes NF may be

Nodular Fasciitis . 163

mistaken for a fibroma (or "myxofibroma"), myxoma (or "fibromyxorna") and neurofibroma or neurinoma (Allen; Meister and Engelhardt; Price et al.). Price et al. emphasize the inclusion of inflammatory processes in the differential diagnosis of NF, f.i. such ubiquitous lesions as rheumatic or rheumatoid nodules, erythema nodosum or induratum, nodular subcutaneous vasculitis, non-supurative panniculitis (Weber-Christian) or sclerosing lipogranulomas and finally abundant post-operative granulation tissue (Soule). Multiple sections from different areas of the lesion are frequently necessary in order to arrive at a correct diagnosis. Besides fibrosarcoma, the differential diagnosis especially includes all tumors of the fibrous histiocytoma group (pleomorphic or not, benign or malignant), spindle cell lipomas, and liposarcomas (myxoid or well differentiated and fibrosing) (Meister). - Deep seated NF may be larger than subcutaneous NF, when first recognized and less well defined, with muscular infiltration (Price et al.). If these cases of NF also exhibit marked fiber formation or even hyalinization, the differention from aggressive fibromatosis (desrnoidfibroma) may be difficult (Allen; Meister et al.). As mentioned by Soule, obviously post-traumatic reactions, f.i. postoperative cellular proliferations, may assume NF-like aspects. In subcutaneous location we found NF-like changes especially after breast or thyroid surgery. These cases were included in Dahl's et al. series, but not in ours. Course and therapy. There is no good knowledge about the course or prognosis of untreated NF. However, it is postulated that with "typical clinical constellation ", no surgery might be necessary at all and medical attendance may reserve to observation; Allen also states that, if objected by the patient, no further surgery will be necessary if the biopsy reveals NF with incomplete removal. On the contrary, Stout advised initial wide excision, because that way also most of the various other lesions included in the differential diagnosis will be treated adequately. If the tumor is very large, first a diagnostic biopsy of the tumor should be done. Problematic are deep-seated, frequently larger lesions of NF which are ill-defined and involve vital structures such as blood vessels, nerves and tendons. Price et al. also advise simple excision for subcutaneous and wide local excision for deep-seated NF. Soule reported optional X-ray therapy. On the other hand, also partial excision is considered adequate treatment, as residues may show consequent involution, and patients with multiple lesions, apparently being NF, are also reported to have shown spontaneous regression of tumor nodules (Hutter et al.). Soule followed 46 patients, with known incomplete excision. Over an

16 4 . P. Meister, F.-W. Biickmann, and E. Konrad

average period of 3.3 years, all were free of recurrences. Hutter et al. reported 26 patients observed over 5 to 20 years without recurrences or metastases. Recurrences were found in 8 of I I 5 reported cases reviewed by Kleinstiver and Rodriguez (= 7%), in 5 of 21 (Dahl et al.), 2 of 15 (Makkenzie), 4 of 100 (our series) and in 9 (= 10f0) of 865 patients of the AFIP (Allen), which however were not completely followed. In all these reports about recurrences, it seems uncertain if the excision of NF was complete or incomplete. These results confirm that NF is a benign lesion (Kleinstiver and Rodriguez), sometimes self-limited and spontaneously regressing (Hutter et al.). Depending on the circumstances of an individual case, simple or wide excision should be done. The excision also serves for histological verification of the diagnosis. Recurrences may occur. However, they are rare.

Zusammenfassung Unsere Reihenuntersuchung und der Vergleich mit den bereits publizierten Serien zeigt,

daf die nodulare Fasziitis keine haufige Krankheit ist. Irn klassischen Fall handelt es sich urn einen weiblichen oder mannlichen Patienten, ungefahr 45 Jahre alt mit einem Tumorknoten am rechtcn oder linken Unterarm, In den meisten Fallen ist die Vorgeschichte kiirzer .11; 3 Monate, gelegentlich werden Schmerzen angegeben. Makroskopisch und mikroskopisch handelt es sich urn cine unseharf abgegrenzte knotige Veranderung, meist zwischen 1,5 und 2 em grof], mit Beziehungen zur Faszie und Infiltration des Fett- und/oder Muskelgewebes. Mikroskopiseh besteht meistens eine ma~ige Zell- und Faserdichte mit regionalen Unterschieden, myxoiden Bereichen, ausgcpragter Gefa~versorgung, Blutungen, Entziindungszellen und gelegentlich mehrkernigen Riesenzellen oder herdfOrmigen Nekrosen. Manche Patienten zeigen Befunde, die sowohl einer klassischen subkutanen nodularen Fasz iit is w ie auch et ner "proliferativen Myositis" oder einem intramuskularen Myxom entspreehen. Es gibt also Ubergangsformen zu beiden erwahnten Krankheiten, die als Varianten der nodularen Fasziitis aufgefalir werden konnen. Nur selten findet sich bei der nodularen Fasz iitis auch Knoehenbildung. Bei dieser "heterotopen Ossifizierung" konnte jedoeh d.l' fiir die Myositis ossifieans als typiseh besehriebene Zonenphanomen mit untcrschiedlicher Ausreifung nichr gesehen werden. - Unterschiedliches biologisches Verhalten entsprechend unterschiedliehem histologischem Bau oder den in der Literatur vorgeschlagenen histologischen Subklassifrzierungen der nodularen Fasziitis konnte nicht erkannt werden. Die nodulare Faszirtis ist eine gutartige Krankheit, gekennzeichnet durch eine offensichtlich reaktive Zellproliferation, die durch einfache oder weite Exzision im Gesunden behandelt wird. Rezidive sind selten.

References Ackerman, L. V.: Extra-osseous localized non-neoplastic bone and cartilage formation (so called myositis ossifieans). J. Bone, Jt Surg. 40 A, 279-298 (1958)

Nodular Fasciitis . 165 Allen, P. W.: Nodular [asciins. Pathology 4,9-26 (1972) Biickmann, F.: Tumorahnlichc bmdcgewebige Proliferation in Subcutis und Muskulatur (nodulare Fasciitis). Zbl. allg. Path. [09,451 (1966) Dahl, 1., Angervall, L., Magnusson, S., and Stener, B.: Classical and cystic nodular fasciitis, Path. Europ. 7, 211-221 (1972) Enzinger, F. M., Lattes, R., and Torloru, H.: Histological typing of soft tissue tumours. WHO, Gcneve (1969) Enzinger, F. M., and Dulcey, F : Proliferative myosins. Report of thirty-three cases. Cancer 20, 2213-2223 (1967) Gokel, ]. M., Meister, P., and Hubner, G.: Proliferarive myositis, A case report with fine structural analysis. Virchow-, Arch. A Path. Anat. Histol. 367, 345-352 (1975) Hutter, R. V. P., Stewart. F. W., and Foote, F. W.: Fasciitis. A report of 70 cases with follow-up proving the benignity of the lesion. Cancer 15,992-10°3 (1962) Kern, W.: Proliferati ve rnyovit is ; " pvcudosarcomatous reaction to injury. Arch. Path. 69,2°9-216 (1960) Kleinstiver, B. J, and Rodriguez, H. A.: Nodular fascinis, A study of forty-five cases and review of the literature. .J. Bone ]t Surg. 50 A, 120-1-1212 (1968) Konwaler, B. E., Keasbey, L., and Kaplan, L.: Subcutaneous pseudosarcomatous fibromatosis (fasciitis) . .J. Clm. Path. 25, 2-1 1-252 (1955) Mackenzie, D.: The diffcrenn.il diagnosis of fibroblastic disorders. Blackwell Scientific Publ., Oxford-Edmburgh (1970) Meister, P.: Spindle cell lipoma Bcur. Path. 161,376-38-1 (1977) Meister, P., and Engelhardt, A.: to be published Meister, P., Walcher, K., and Cr abmger, A.: Dcsmoidfibrom (= aggressive Fibromatose). Munch. med. Wschr. 1I5. 2025-2032 (1973) Prechtel, K., and Meister, P.: Pathologische Anatomic. Fibromatosen (Geschwulstahnliche Wucherungen de; Bmdegew cbes). Munch. med. Wschr. JI2, 1972-1976 (1970) Price, E., Silliphant, W. M., and Shurn.m, R.: Nodular [asciitis. A clinicopathologic analysis of 65 cases. Amer..J. elm. Path. 35. 122-136 (1961) Remberger, K., Gokel, J M., Mcrvter , P., and Gay, S.: Myofibroblasten und Kollagentypen bei Fibromatosen. Verh. Dtsch, Gcs. Path. 61, 388 (1977) Soule, E.: Proliferative (nodular) [ascritis. Arch. Path. 73, 437-444 (1962) Stiller, D., and Katcnk arnp. D : The subcutaneou, fascial analogue of myositis proliferans, Electron microscopic e xarmnatton of two case; and comparison with myositis ossificans Iocahsata. Virchows Arch. A Path, Anat, Histol. J68, 361-371 (1975) Stout, A.: Pseudosarcom.uous [.iscutis in children. Cancer 14, 1216-1225 (196 I) Wirman, J. A.: Nodular fascllm, a lesion of rnyofibroblasts. An ultrastructural study. Cancer J8, 2378-23S9 (r976)

Received September 15, [977 . Accepted m revised form December 15, 1977

Key words: Nodular [asciitis - Anatomical-pathological variants - Literature

Professor Dr. med. H. Peter Meister, Pathologisches Institut der Universitat, Thalkirchner Str. 36, D-8000 Miinchcn 2 12 Path. Res

Pract Vol 162