A Comparative Study of Canine and Human Dermatology

A COMPARATIVE STUDY OF CANINE AND HUMAN DERMATOLOGY II. CUTANEOUS TUMORS—THE MAST CELL AND CANINE MASTOCYTOMA*

MILTON ORKIN, M.D.f AND ROBERT M. SCHWARTZMAN, V.M.D., M.P.ll.t

In a previous report (1) we discussed the im- adult is maintained by homoplastic and heteroportance of comparative studies; reviewed basic plastic regeneration; the former accomplished by comparative (dog to man) anatomy, physiology mitotic division of pre-existing mast cells and the and reaction patterns; and delineated several latter by elaboration of mast granules in various tissue cells (lymphocytes, plasma cells, interesting dermatologic entities of canines, connective clasmatoeytes, adventitial cells, endothelial cells

including mastocytoma (in this paper mastocytoma will be represented by the initials MCT). The increasing awareness of the mast cell in health and disease and the ready availability of canines with mast cell tumors has prompted the authors to study intensively 13 cases of canine MCT and investigate the comparative aspects. Nickel (2) has recently presented a comprehensive study of urticaria pigmentosa (mastocytosis, human mast cell disease). Because of the extensive bibliography included in the latter report,

and possibly reticuloendothelial cells).

Michels further states that tissue mast cells

occur in all areas of the mammalian body, though

there may be quantitative differences between species. Their numbers are proportional to the amount of connective tissue present. Parenchymatous organs such as the kidneys, adrenal and liver

have little connective tissue and therefore few mast cells are present. The canine liver is an exception. Nielsen and Cole (4) emphasize their frequency around small blood vessels in canine skin

and liver. The amount of connective tissue, and

only salient references will be listed in the present therefore the number of mast cells, is greater in study. the testis, ovary, salivary glands, heart, pancreas, Many case presentations and discussions of lymph nodes and spleen. In the tonsils, spleen and various facets of urticaria pigmentosa emphasize lymph nodes many mast cells are present in the the systemic ramifications. Since MCT of dogs capsule, adventitia of the large vessels, trabeculae has systemic potential from its onset we may well and medullary strands. Not infrequently mast cells lie free in the lymph sinuses but apparently ask:

never in the efferent lymphatics. Mast cells are numerous in the serous membranes, pars nervosa of the hypophysis, various layers of the digestive and respiratory tracts and organs which have a large amount of connective tissue (tongue, lung, omentum, subcutaneous and intermuscular connective tissue, etc.). Mast cells are fairly abundant in the normal bone marrow of mammals.

1. Is mast cell disease in dog and man related (aside from the obvious fact of mast ccli involvement in both)? 2. If they are related, then what information can be obtained from their comparative study? MAST CELL

Michels (3) devotes 119 pages in Downey's

Cartilage and bone (except for the periosteum and

Handbook of Hematology to discussion of the mast

perichondrium) are the only tissues devoid of

cell. Only those segments which are germaine to the present topic will he presented. Mast cells are of histogenous origin. Their supply in a normal

mast cells.

Received for publication July 9, 1958.

Supported in part by grant, Minnesota Divi* From the Division of Dermatology and the College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota. Trainee, National Cancer Institute; Fellow, Division of Dermatology, University of Minnesota, St. Paul, Minnesota. (Dr. F. W. Lynch, sion, American Cancer Society, Inc.

Lever (5) states that in man the relatively few mast cells in the normal skin are spindle-shaped and grouped around blood vessels and hair folli-

cles, and in the papillary layer of the dermis. Johnson (6), however, writes that "the normal human skin has somewhere between 2000 and 7500

mast cells per cubic millimeter depending on the area from which it is taken." In the normal skin of thy dog mast cells are abundant, patticularly around small blood vessels. Their cell outline is Director.) Instructor in Veterinary Medicine, University pleomorphic (fusiform, spherical, and stellate), t of Minnesota, St. Paul, Minnesota; Research the nucleus round or ovoid (never lobulated) and Fellow; Mark L. Morris Memorial Animal Founthe cytoplasm abundant and filled with coarse dation. 451

452

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

granules denoting maturity. The same cell mor- the number of mast cells closely parallels the inphology pertains in those conditions in the canine tensity of metachromatic staining. Michels states in which there is benign proliferation of mast cells that mast cells are decreased during acute inflammation, absent in scar tissue and markedly in(dermatitis, etc.). There is evidence in both species that the mast creased in chronic inflammation and lymph cell cytoplasm contains histamine, heparin and stagnation. The authors have observed an hyaluronic acid in its metachromatic granules. increased number of mast cells in acute and Despite the heparin content macroscopic hemor- chronic canine dermatitis (Fig. 1). rhage concomitant with MCT is rare, although Larson (7) reports severe post-excision hemorCANINE MASTOCvTOMA rhage in a significant number of cases (though only Mast cell tumors are frequent in dogs and rare a slight increase in the coagulation time). in other species. Of 1000 canine neoplasms colWest and Parratt (8) state that there is no parallelism between the concentration of mast lated by Mulligan (9), 201 were sarcomas, 87 of cells and 5-hydroxytryptamine (serotonin) in the which were of mast cell origin. The MCT constiskin of the guinea pig, rabbit, man, cat, mouse, tutes 10 to 13.2% of all canine tumors. Bloom hamster and dog, despite previous reports to the (10) was the first to give a detailed pathologic contrary. They further uphold that even in condi- description of this condition (Table I). Nielsen tions of mast cell proliferation (MCT of dogs, and and Cole (4) present 100 cases (including 8 autopurticaria pigmentosa of man) there is no appre- sies) collected over an 8-year period. ciable increase in skin 5-hydroxytryptamine. This condition shows a predilection for Boston The tendency for mast cells to occur in densely Terriers (over 40% of all neoplasms in this breed), packed clusters is augmented under pathologic conditions. Lever states that an increased number Boxers (over 30% of neoplasms) and Fox Terof mast cells accompanies granulation tissue, most riers (9% of all neoplasms) . The incidence of itching dermatoses (atopic eczema, contact der- MCT increases uniformly with age, the majority matitis and lichen planus, etc.), neurofibromas, of the subjects being six years or older. There is the stroma of cutaneous carcinoma, urticaria pig- no sex predilection. mentosa and lupus erythematosus. In the latter, The hindquarters (particularly the thigh)

S

Fin. 1. Typical mast cell as seen in normal canine skin; increased numbers in dermatitis. Toluidine blue; X 720.

* MC.

cutaneousinvolvement,hepato splenomegaly, caehexia. Oral involvement.

mac.-pap.-nod.

Disseminated

standsfor MastCell.

yr. male.

Al"

Homan—71

thal et

Human—iyr. Numerous undochild 1st au- lar lesionsskin topsy report & oral mucoss, —urticaria hepatomegaly, pigmentosa. wasting, CIT. symptoms,

tumors, penpenile lymphadenopathy.

generalized skin

Recurrence postexcision, intense pruritus,

Canine—lst Report—

MCT.

Clinical

Species

Loewen-

Ellis'5

Bloom'0

Author

(sometimes elnngated or bibbed).

witb abundant cytoplasmpacked with fine granoles; nuclei pale, round or oval

Polygonal or round

deep metachrumatie granules (closely packed), 2) immature fewer more widely spaced granules, take up less dye.

2 types: 1) mature

mitotic figures.

many multinucl. giant cells, occas.

Atypical MCT,

Mast Cell

TABLE

I

Great acenmolation of M.C. in red polp (discrete masses),

Dense Some M.C. in siM.C. noses & around under blood vessels, epidermis.

52nd in no. of M.C.

poip, capsule or trebeeolae.

capsule trebecolae. *2nd in no. of M.G.

red puip. No M.C. in white

Malpig. Corps.

tered throughout

opsy.

by hi-

Livec

(single or

grouped).

myeloid-

erythroid ratio.

Large nus. M.C. in portal tracts, sinosoidsdistended, disorganized liver cords with destruction parenchymal cells.

During life op to 30% of all W.B. C. were MC.

Other Organs

blood vessels (except veins).

neetive tissue M.C. are in relation to

alveolar septom, in eon-

considerable infiltrate MC. intra-

Some sreas

pros-

tate, adrenal.

ereas,

kidney, palate, aorta pan-

capsule,

Pituitary

Kidney, pan cress, pituitary capsule.

Throughout in- Omentumter-alveolar mesentery tissue numerous MC.

Lung

are neoplas tie M.C. reversal of

2.2% of marrow cells

Bone Maccow

Extreme widening Large no. M. Marked intraof portal aress by C. & eosinn- alveolar hemconnective tissue, phils adorrhage. many M.C. in fijaeent to brotie areas. endusteom. M.C. most nomemos of any organ.

Pattern undis- Generalized nuderturhed, through- ate parenchymal out pulp nudegeneration merous MC. periportal eollecin nodules, tions of MC, MC. solitary diffuse, freqoently invade

Spleen

Large no. eusinophils & many M.C. in

tity.

trebeeulae, sinuses & interlollieular tissue; pattern obscured, sinuseslust iden-

Peripenile—numerous MC. capsule,

Lymph Node

Mesenteric—lymphoid cells in reticoIon replaced by eosinophils & M.C.-M.C. seat-

Proven

cell.

mast

See

Skin

Comparison of salient tissue involvement—autopsies

454

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

scrotum and vulva are frequent sites of occur- stained granules in their cytoplasm. Rapidly rence. Mulligan states that 40% of the tumors growing tumors contain immature cells with tiny occur on the scrotum, abdomen, axilla and eyelid; dust-like cytoplasmic granules, a few large 30% on the posterior extremities; 20% on the granules or no granules. Paff and co-authors (12) in studying the bevulva, perineum, anterior extremities, thorax and

neck; and the remainder on the ear, mammary

havior of neoplastic mast cells in tissue culture,

gland, lip, penile sheath and mesenteric and note spontaneous ameboid movements, amitotic mediastinal connective tissues. The present cell division and multinueleated cells. Oliver and authors could find no other report of the occur- co-authors (13) show that the heparin content of rence of a primary MCT in an extracutaneous the MCT varies with the degree of anaplasia; the mature tumor containing 50 times and the location. Clinically a lesion may be noted for one to two immature 1.7 times the concentration of the years prior to examination; then grow rapidly in normal dog liver. There are multiple opinions as to the causal a few months to significant size. The growth originates as a small dermal mass which gradually nature of the MCT. Hangartner (14) considers infiltrates the epidermis and the loose connective them to be infectious granulomata while Bloom tissue of the subcutis, but has little tendency to (10) states that single tumors are benign and involve the deeper fascia and muscles (11). multiple tumors generally malignant. Nielsen (11) In Bloom's initial report (10), he presents 3 believes that all tumors (single or multiple) may cases of solitary (benign?) and 2 of multiple be sareomatous. Involvement in the regional lymph nodes (26% (apparently malignant?) MCT. He assumes that the neoplastic cells result from a proliferation of in Nielsen and Cole's (4) series), spleen and liver tissue mast cells (homoplastic regeneration). In is common in MCT. The general health of the the process the cells become more uniform (oval dog usually is not affected except in the terminal or spherical) and acquire a large vesicular nucleus. stages where anemia, cachexia and other signs He describes intracytoplasmic bodies which have may be manifest. Nielsen and Cole (4) point that it is difficult not been mentioned in subsequent literature or to differentiate between hyperplasia and neoobserved in our own material. Mulligan divides the MCT into mature and plasia since transitional forms are well known. anaplastic varieties. In the mature type mast cells They state that the cardinal criterion for maligare discrete and polyhedral and their cytoplasm nancy is a growth which will kill the host by pale, aeidophilie and sometimes vacuolated. The invasion and/or metastasis. This criterion cannot nuclei are round or slightly oval, centrally placed, and have a fine chromatin network bordered by a heavy perinuclear membrane. Mitotic figures are infrequent. The cells of the anaplastic type have

be satisfied frequently in the canine, because dogs

indistinct borders and unevenly enlarged nuclei with irregular mitotic figures. Occasional multinucleated forms are observed. Nielsen and Cole (4) state that eosinophils are

1. rapid infiltrating growth of immature cells; 2. recurrence after surgical removal often asso-

common in MCT. In addition they note hi-

3. metastases to regional lymph nodes or

nucleated and trinueleated giant cells, somewhat

similar to Reed-Sternberg cells in 3% of their

are commonly euthanized before reaching a terminal state. They believe that many eases of MCT possess the following features of a sarcoma:

ciated with rapid invasion of the surrounding tissues;

internal organs.

The therapy of choice for the small MCT is

cases. At times the latter together with immature surgical excision. Adrenaleortieal hormones procells, many eosinophils, necrosis and fibrosis sug- duce a marked reduction in the number of normal gest human Hodgkin's disease. Only the meta- mast cells. Bloom (15), utilizing this knowledge,

chromatic stain could definitely separate these conditions. These authors further point out that there are areas of MCT which contain no stainable granules. In general mast cell hyperplasia (in dermatitis etc.) and slow growing MCT have

treated a ease of recurrent multiple MCT with cortisone (900 mg. over a 9-day period). After 3 days of therapy there was a sudden reduction in the size of the lesions. Microscopic examination

revealed an ample number of mast cells with

an abundance of mature cells with coarse, deeply- cytoplasmic vacuolation and clumping of gran-

CUTANEOUS TUMORS—THE MAST CELL AND CANINE MASTOCYTOMA

455

with Wright's stain. Purple-red granules in cells disappeared; histopathologie examination re- 8—18 in diameter were considered diagnostic of vealed almost complete absence of mast cells, mast cells. ules. By the ninth day the nodules had completely

with those present undergoing degeneration. Six weeks later, however, a new nodule appeared at a

distant site and inguinal nodes were enlarged.

The authors obtained clinical data and tissue

in 7 cases of urticaria pigmentosa from the

of Dermatology for comparison with The pathologic changes in the mast cell in Division the biopsy findings and clinical data of MCT. Bloom's study were the same as those observed

by Asboe-Hanson (16) in independent study. The benefits of cortisone therapy in MCT were not verified by Larson (7). Urbach and co-authors (17) used desoxycorticosterone (DOCA) in the treatment of 7 patients with urticaria pigmentosa. In one, a 54-year old white woman, a decrease in whealing was noted in 2—3 months and a flattening of the lesions in 6 months. Some degree of relapse was noted three months after discontinuing therapy. METHODS AND MATERIALS

One hundred dogs with cutaneous tumors were

studied over a one-year period (May 1957 to May 1958). Seventy-six canines were examined at

the University of Minnesota Veterinary Clinic. In an additional 24 cases tumor tissue, together with clinical data, were submitted by veterinarians

in the surrounding area. A majority of the cases of the Veterinary Clinic were presented because of cutaneous tumor(s); the remaining cases were discovered during examination for some other condition. Thirteen per cent of these tumors were of mast cell origin. The other tumors will be the subject of a subsequent communication. Complete physical examination was done on all the clinic animals. A punch or excision biopsy was performed on one or more tumors in each of the dogs. Touch smears and bleeding and clotting time were determined in those cases in which MCT was suspected. Punch Biopsy—Hair was removed with a scissors and the site anesthesized with Frigadcrm.®

A punch biopsy was performed in the usual manner and the tissue fixed in 10% buffered For-

malin for at least 24 hours. Hcmatoxylin-eosin and toluidine blue stains were performed in the usual manner on all tumors. Excision Biopsy—This was performed under general anesthesia (pcntobarbital sodium) and the tissue fixed and stained as above. Touch Smears—A dry, clean slide was pressed gently against the fresh cut surface of the excised tumor. The slide was allowed to dry and stained ®BrachvogelHovey, Los Angeles, California.

RESULTS

A. Clinical Study of MCT (See Table II) 1. Age—14 weeks to 14 years; average 7.9 years. 2. Breed: Boston Terriers—4 (30%); Terriers—3 (23%); Dachshund—2 (15%);

Boxer, Black Laborador, Chesapeake, and English Setter, 1 each. 3. Sex—S female (62%) and 5 male (38%).

4. Duration before seen by veterinarian: 1—19 months; Average: 6.3 months.

5. Location of primary lesion—posterior extremities—4 (30%); scapular region—3

(23%); groin and scrotum—2 (15%); trunk—2 (15%); lower lip—i (7.7%) and forearm—i (7.7%).

6. Clinical features (Fig. 2, 3)—the last 3 cases in Table II were submitted without complete description and, therefore, will not be included in some of the statistics. a. Surface—yellow or white; ulcerated— 3 (30%); alopecia—4 (40%). b. Size (diameter)—0.5 to 15 cm.; average 4.7 cm.

c. Form—firm, raised, papular-nodular—

4 (40%), cystic—2 (20%); fixed to skin and free below.

7. Clinical diagnosis—correct in 4 (30%); incorrect in 9 (70%); misdiagnosed as reticulum cell sarcoma, lipoma, fibrosarcoma, etc.

8. Number of tumors—3 cases (23%) with multiple tumors. 9. Physical examination—lymphadenopathy (Fig. 4)—3 (23%). 10. ilematologic data (4 cases)—no abnormal bleeding or clotting time found. 11. Bone survey (2 cases—Case 10 showed a discrete cystic area of rarefaction of the ischium (Fig. 5).

12. Touch smears (4 cases)—positive in all cases performed (Fig. 6).

13. Pathology—typical in S (62%); atypical inS (38%).

a

i4

2

Terrier

5 yre.

Cheea-

peake

13

8

(cross

breed)

yra.

11

9

hund

Dache-

Terrier

Terrier

Boston

Dachahnnd

Terrier

Boston

Terrier

Boaton

Breed

Black yre. Labrador

yre.

336

yra.

14

yra.

8

wks.

14

7

6

5

4

3

3½ yrs.

5

yrs.

Age

No.

I mo.

F

F

M

F

F

F

I

anteriorly

White, raised, ½ em. diameter, firm, fixed to skin, free below, alopeeia, surface smooth Yellow, i3.l cm., firm, fixed to skin, free below, alopecia, ulcer

Clinical Description

Right groin

Lower lip

Knee

Forearm

Yellow-white, 5 cm. soft, fixed to skin, free below, akin smooth

pathy 1

Neg.

lympha-

Popliteal

low, alopecia, emooth

1

Neg.

pathy

Submaxillary lymphadeno-

pathy

deno-

Inguinal lympha-

Neg.

Neg.

Neg.

Neg.

Physical

deno-

6

1

7

1

1

i

5

,g0

Erythematoue.Main lesion 25 cm., firm, nodular, free below, alopeeia, ulcerated, eubeut.; satellite 4 em., lesions, abdomen Yellow-white, 15 cm., peduneuletedeyetic, fixed to ekin, free be-

Erythematoue,134 cm., firm, fixed to skin, free below, no alopecia, ulcerated

no alopecia

skin with ulceration,

alopecia White, 5 cm. cystic nodular, fixed to skin, free below, no alopecia White, largestlesion5 cm., satellites 13.6 cm., all firm, fixed to

Inter. Soap- White, lit cm. flat papular ule, firm, fixed to skin, free below, no

5th digit left leg

Left Soapula

Loc.

yr. Sud- Popliteal den enregion largement 1 mu. 4 moe. Scapula

1

2 moe.

2 moe.

18 mos.

F 6 wke.

F

yr.

M

1

Duration

Sex

ting

bleeding time normal

Clotting &

bleeding

&

C.B.C. normal, clot-

—

mal

bleeding time nor-

Clotting &

Hrmat

TABLE [I 13 cases of maslocytoma

Normal

Skel. Snr.

Poeitive

plc excision

oma)

reticulum cell lymph-

pearanee of

Atypical (ap-

Typical

Atypical (both larger lesions diagnosed reticulum cell lymphoma)

reticulum cell lymphoma)

pearance of

Atypical (ap-

oma)

primary) Simple cxcision

&

elon (gland

Simple exei-

cutaneous mass

Excieion sub-

sion

Simple cxci-

main lesion

Previous elmreticulum cell lymph-

pearance of

Simple excision

sion

Simple cxci-

digit

Excision of

eion

Simple cxci-

Treat.

Positive Atypical (ap-

Typical

appendages left) Typical

Positive Typical (sweat glands only

Typical

Path

ap-

No recurrence

permissionautopey denied) 3 moe. later 2 new leeione at different eitee

zematization,

Euthanized (reeietant wound infection & cc-

No recurrence

peared

eatellitee

primary lesion after to moe., S moe. later

Recurrence of

No recurrence

No recurrence

No recurrence

No recurrence

Course

—1

13

12

8

11

yrs.

6

yrs.

10

yrs.

7 yrs.

10

Boxer

English Setter

M

Terrier

mos

1 mo.

2—8

F

—

M 0 moe.

M

Boston Terrier

Flank

1(nee

Scrotum

&

right left thigh

(largest)

Thorax

i

White-yellow, 4 cm., firm

2½ cm., firm

2l cm., spherical,firm

firm; 13t cm. firm; cm. firm

3 cm.

1

1

1

3

Neg.

Neg.

Neg.

Neg.

—

—

—

Clotting & bleeding time norma!

—

— —

—

Typical

Typical

* DiePositive Atypical (mu!tinuel. giant crete, cystic, cells) Rarefact. Isehium — — Typical Simple cxcision Simple cxcision

SiOfl

Simple cxci-

Simple excision

No recurrence

No recurrence

No recurrence

No recurrence

458

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

14. Treatment—excision. 15. Course (complication)—recurrence in 1

(7.7%); new lesion—2 (15%); 1 case euthanized (autopsy permission denied). B. Histopathologic Findings

outline distinct cells look like fragments of a mosaic; in some area cells separated by clear spaces. Cytoplasm —eosinophilic (at times red-purple), some areas vacuolated; granules not

seen without special stain. Nucleus —5 to 10 /2 diameter, large, vesicu-

1. Typical (Fig. 7,8)

diameter; outline variable (usually polygonal), when

a. Cytology—8-18

lar, basophilic, centrally located; outline variable (usually round or oval, C-shaped, reniform); occasionally hinucleate; nucleoli—(none, 1 or 2); occasional mitotic figures. b. Architecture—Epidermis—One-third of cases ulcerated with subjacent necrosis,

polymorphonuclear and fibrotic response; if intact regular acanthosis. Corium—Tumor usually fills corium; no grenz zone; tumor cells push aside

connective tissue (some remaining strands surround linear arrangement of tumor cells); some areas simulate hepatic parenchyma; tumor sharply outlines appendages and blood vessels (Fig.

9) but in no instance invades these structures; numerous eosinophils (fig.

10) were scattered among the tumor cells; occasional hemorrhage observed. c. Toluidine blue stain—red-purple gran-

ules vary in size and intensity of staining; usually fill cytoplasm, if Fm. 2. Single lesion lower lip (MCT).

diffuse obscure cell detail. 2. Atypical—(frequently diagnosed as retic-

Mt

Fin. 3. Multiple lesions knee (MCT).

459

CUTANEOUS TUMORS—THE MAST CELL AND CANINE MASTOCYTOMA

4. —

*

ii

FIG. 4. Popliteal lymph node (case 8). Numerous mast cells disrupt architecture. Toluidine blue;

X 75.

figures, multinueleated giant cells. (One ease suggests Hodgkin's disease.)

b. Architecture—no marked difference from the typical variety; eosinophils present.

c. Toluidine blue stain—less positive, smaller granules; some areas have no granules (fig. 12).

). Comparative Study—7 eases of urticaria pigmentosa in humans. 1. Age—S months to 24 years; average 4.5 years. 2. Sex—female 5 (71%); male—2 (29%).

3. Clinical—maeule dominant lesion in 4 (57%), nodule dominant in 3 (43%) eases.

There was no evidence of systemic involvement (skeletal survey done in 2 patients). All lesions urtieated on stroking (Darier's sign). None of the dogs with FIG. 5. Cystic area of rarefaction of ischium (case 10).

MCT had a positive Darier's sign. 4. Histopathology

a. The findings in the maeular type ulum cell lymphoma until special stains done). a. Gytology—anisoeytosis (fig. 11). Cyto -

amount, foamy appearance. Nucleus—more frequent mitotie plasm—lesser

corresponded to Lever's description (majority of cells spindle-shaped resembling fibroblasts); these cells were indistinguishable from normal canine mast cells as described by Bloom (10)

460

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

S

—

Fm. 6. Touch smear of MCT nodule. Wright's stain; X 720

at a

4

IS

Fin. 7. Typical MCT. llematoxylin-eosin; X 720

CUTANEOUS TUMORS—THE MAST CELL AND CANINE MASTOCYTOMA

FIG.

461

8. Typical MCT. Toluidine blue; X 720

FIG. 9. Typical MCT; tumor cells outline appendages but do not invade them. Toluidine blue; X 330

462

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

s

S • 1w

4 4k

p

:t ir

FIG. 10. Typical MCT; numerous eosinophils scattered among tumor cells. Hematoxylin-eosin; X 330

4

p •ø't, S a,

p

4'1:

'C4 I,. :

Fin. 11. Atypical MCT. Malignant appearance together with polymorphism suggests a lymphoma (Hodgkin's disease, etc.). Hematoxylin-eosin; X 720.

463

I"

CUTANEOUS TUMORS—THE MAST CELL AND CANINE MASTOCYTOMA

FIG. 12. Atypical MCT. Some areas have paucity of granules. Toluidine blue; X 720

FIG. 13. Human nodular urticaria pigmentosa. Note similarity of cells to those of typical MCT. Hematoxylin-eosin; X 720.

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

464

and seen by the authors; also indis- tumors and in those suspected of having a tinguishable from normal mast cells lymphoma, particularly Hodgkin's disease, and associated with benign proliferation the reticulum cell type. Nickel suggests that a routine stain for mast cells in the most difficult (dermatitis etc.). b. The findings in the nodular type (fig. ease may give more information than routine 13) corresponded to Lever's descrip- connective tissue stains especially in so-called tion (tumor-like aggregates extending non-specific lymphoblastoma. throughout entire dermis and subcutis, The authors were unable to distinguish becuboidal with angular cytoplasm); cells tween the mast cell of the maeular type of were strikingly similar to those of urticaria pigmentosa and the normal (or benign hyperplastie) canine mast cell and had difficulty typical MCT. c. Eosinophils were present in quantity in distinguishing between the cell of the nodular form of urtiearia pigmentosa and the typical one case (nodular type). d. Most of the mast cells of the nodular canine MCT. This is of interest but does not and macular types stained heavily necessarily imply prognostic import; since the with metachromatic stains. macule may appear in the systemic variety of urticaria pigmentosa (20) and the nodule in the COMMENT "benign" form. Of similar interest is the striking The statistics in our series of cases of MCT similarity between the 3 autopsy findings (10, agree with those of the literature with the fol- 19, 21) presented in Table I. In the autopsy of lowing exceptions: lesions were examined earlier the one-year old child the two types of mast cells described could correspond to the typical and were smaller, there was slight female preand atypical histopathologie forms of MCT. ponderance and relatively frequent scapular involvement. The series is too small for these Ellis points out the close parallelism between the autopsies of the one-year old girl and Bloom's differences to be significant. The eases with atypical pathology (38% of the dog, emphasizing the similar cutaneous, lung, series) comprise 2 out of the 3 dogs with lymphad- bone marrow, liver and periadrenal involvement. The cystic rarefaction of the isehium (ease 10) enopathy and all of the eases (3) with surface is of great interest. Sagher and associates (22) ulceration and multiple lesions. They also include

the only case with an abnormal skeletal finding and 2 of the 3 dogs in which recurrent or new lesions developed after excision. Thus the atypical variety appears to be more malignant. The atypical case is more difficult to diagnose on histologic examination. In most instances a reticulum cell lymphoma was simulated and in one, Hodgkin's disease. The diagnosis could be established only by using metaehromatic stains. Nielsen and Cole (4) report that the histologic appearances in some cases of MCT is similar to that of Hodgkin's disease. Reports of the pathology of Hodgkin's disease, however, are rare in the

describe two types of bone lesions associated with urtiearia pigmentosa: (1) general widespread osteoporosis and osteoselerosis; and (2) similar changes confined to local sites (skull, femur, etc.). The bone changes in our ease of MCT might be local There was no other reason for bone involvement.

The production of a wheal after physical stimulation of a MCT (Darier's sign) has not been recorded. It is well accepted that release of histamine produces the wheal in eases of urticaria pigmentosa. Histamine is thought to be present in MCT. Yercauteren (23) points out that horse

dog (18). Tn the autopsy of a ease of urticaria eosinophils contain a natural antihistamine which can be extracted from preparations of pigmentosa (Table I) Ellis (19) considered eosinophilic granules. He believes that eosinoHodgkin's disease as a possible underlying process where there were numerous eosinophils and phils may detoxify histamine. The presence of Hodgkin's disease.

It would not be amiss in canine or human medicine to examine metaehromatie stains in

eosinophils at the site of certain allergic reactions in both species is of interest in this regard. Riley (24) describes an influx of eosinophils in a MCT excised from a dog previously treated with compound 48/80, a histamine liberator. Drennan (25)

eases of suspected sarcomas, unusual mesodermal

describes a rapid influx of eosinophils, into a•

fibrosis (but no Reed-Sternberg cells). EHowever,

he found few mast cells in 10 cases of verified

CUTANEOUS TUMORS—THE MAST CELL AND CANINE MASTOCYTOMA

465

lesion of urticaria pigmentosa stimulated by experimentation in relation to human urticaria trauma, cytoplasmic vacuolization and disrup- pigmentosa. tion with loss of metachromasia. All eases of We wish to express our gratitude to Dr. Francis human urtiearia pigmentosa included in this study urticated, despite the fact that one nodular W. Lynch for his guidance and advice, and to Dr. lesion had a large number of eosinophils. Further Robert W. Goltz for considerable assistance in study is necessary to test the thesis that eosino- interpreting the histopathologie sections. phils inhibit Darier's sign. ADDENDUM

It is not clear whether human "malignant"

Since the submission of this manuscript, Head urticaria pigmentosa or the canine MCT represent a sarcoma, systemic hyperplasia, rcticulo- (Cutaneous Mast-Cell Tumours in the Dog, endotheliosis, or systemic inflammatory process. Cat and Ox. Brit. J. Derm., 70: 389, 1958) has The finding of the mast cell in lymph nodes, published a review of mastocytoma in the dog, spleen, liver, bone marrow, etc. does not neces- cat and ox based on the study of 166 animals. sarily imply metatascs in either species; since, He reported 8 cases of canine mastocytoma in as Michel has pointed out, mast cells are nor- which only internal organs were affected, and mally present in these areas; therefore, autoch- offered a tentative classification of animal mastocytoma. Gorlin, Clark, and Chaudhry (The thonous development cannot be ruled out. Oral Pathology of Domesticated Animals. Oral Surg., Oral Med. and Oral Path., 11: 500, 1958) SUMMARY have reported one case of canine mastocytoma A review of some facets of the mast cell and originating on the hard palate and cited Riser the canine MCT is based on 13 cases studied. (Treatment of Tumors in the Dog: Comparison Atypical histopathology in a MCT (canine of Surgery and Physiology, Proc. 91st Annual mastocytoma) implies a more malignant poten- Meeting, A.V.M.A., p. 279, 1954) as having obtial than the variety with typical histopathology. served 3 eases in the nose and mouth. Touch smears are useful in making a rapid REFERENCES diagnosis of canine MCT. This procedure would 1. SCHWARTZMAN, R. M. AND OmaN, M.: A likely be a valuable adjunct in the diagnosis of comparative study of canine and human human urticaria pigmentosa (particularly the dermatology. I. (General Introduction). Arch. Dermat. & Syph., (to be published). nodular or tumor types). W. R.: IJrticaria pigmentosa. Arch. The cystic rarefaction of the ischium observed 2. NICKEL, Dermat. & Syph., 76: 476, 1957. in one of our canine cases coincides closely to 3. MICFIELs, N. A.: The Mast Cell, Handbook of Hematology, edited by H. Downey. New some reported oases of bone involvement in York, Paul B. Hoeber, Inc., 1938. urticaria pigmentosa. 4. NIELSEN, S. W. AND COLE, C. R.: Ganine mastocytoma. Am. J. Vet. Research, 19: 417, The inability of canine MCT to whcal on 1958. physical trauma may be a function of the large 5. LEVER, W. F.: Histopathology of the Skin. number of cosinophils present (antihistaminic Philadelphia, J. B. Lippincott Co., 1954. 6. JoHNsoN, H. H., JR.: Histamine levels in content). human skin. Arch. Dermat. & Syph., 76: It is suggested that metachromatic stains be 726, 1957. (In discussion of his own paper). performed in canine and human sarcomas, un- 7. LARSON, B.: Studies of Canine Mastocytoma, in Collected Papers from the Royal Vet. usual mesodermal tumors and lesions suspected College of Sweden, Stockholm, 1957. S. WEST, G. B. AND PEERATT, J. R.: Hydroxyof being a lymphoma (particularly Hodgkin's tryptamine and the skin. Arch. Dcrmat. & disease and the reticulum cell type). Syph., 76: 336, 1957. The cause of canine MCT and systemic urti- 9. Mulligan, R. M.: Neoplasms of the Dog. Baltimore, The Williams and Wilkins Co., caria pigmentosa is not known. The presence of 1949. mast cells in the viscera may not be evidence of 10. BLOOM, F.: Spontaneous solitary and multiple mast cell tumors ("Mastocytoma") in dogs. metastasis but may reflect an overgrowth of mass Arch. Path., 33: 661, 1042. cells present normally. 11. NIELsEN, F. W.: Clinical aspects of Mastocytoma in dogs. Procs. Book An. Vet. Med. Since there is a striking similarity between the Assoc., page 213, 1952. canine mastocytoma and some cases of urticaria 12. PAn, G. H., BLOOM, F. AND REILLY, C.: The morphology and behavior of neoplastic mast pigmentosa, the canine MCT is suitable for

466

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

cells cultivated in vitro. J. Expter. Med., 19. ELLIs, J. M.: IJrticaria pigmentosa: report of a case with autopsy. Arch. Path., 48: 426,

86: 117, 1947. 13. OLIVER, J., BLOOM, F. AND MANGIERI, C.: On

the origin of heparin. J. Expter. Med., 86: 117,

1947.

14. HANGARTNER, 1949.

F.:

P.: Inaug.-Diss.

REILLy, E. B., SHINTANI, J. AND GOODMAN, J.:

mast-cell disease with urticaria pigmentosa. Arch. Dermat. & Syph., 71: Systemic

(Thesis, Dein

561, 1955. LOEWENTIIAL, M., SCNER, R. J., BERLIN, C.

cortisone on mast cell tumors of the dog. Proc. Soc. Exper. Biol.

21.

action on connective tissue. Proc. Soc.

22. SAGHEE, F., LIBAN, E., UNGAR, H. AND SCROEB,

pigmentosa treated with desoxycorticosterone. Arch. Dermat. & Syph., 70:

isolated granules from blood eosinophils.

15. BLOOM,

Effect of

& Med., 79: 651, 1952. 16. A5BOE-HANSEN, G.: The mast cell: cortisone

Exper. Biol. & Med., 80: 677, 1952. 17. IJEBACH, F., JACoBsON, C. AND BELL, W.: TJrticaria

18.

1949. 20.

675, 1954. MOULTON, J. P., AND BosTIcsc, W. F.: Canine malignant lymphoma,

simulating Hodgkin's disease in man. J. Am. Vet. M. A., 132: 204, 1958.

AND WECH5LER, L.: Urticaria pigmentosa

with systemic mast-cell disease. Arch. Dermat. & Syph., 75: 512, 1957.

S.: Urticaria pigmentosa with hone involvement. J. Invest. Dermat., 26: 431, 1956. 23. VERCAUTEREN, R.: The properties of the Enzymologia, 16: 1,

1953—54.

24. RILEy, J. F.: Pharmacology and function of the mast cells. Pharmacol. Rev., 7:267, 1955.

25. DEENNAN,

J.

M.: The mast

pigmentosa. J. Path.

cell in urticaria

& Bact., 63: 519, 1951.

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

94

linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.

24. Wynn, C. H. and Iqbal, M.: Isolation of rat

skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.

human epidermis, p. 511, The Epidermis

Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-

No warranty is given about the accuracy of the copy.

Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.

Cell Biol., 27: 603, 1965.

27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-

C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.

30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.

31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-

lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.

32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.

33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.

34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:

Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.

43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.

44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.

45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.

46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,

Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by

Res., 33: 176, 1964.