VII EUROPEAN CONGRESS OF PATHOLOGY

FRIDAY, SEPTH1BER 21, 1979

SLIDE SEMINAR - OR. JUAN ROSA!

PROBLEHS IN DIAGNOSTIC SURGICAL PATHOLOGY

DIAGNOSES

1. R76- 747 - Thymus-Malignant thymoma (lymphoepithelioma- like)

2. R78-1128 - Spleen-Systemic mastocytosis

3. UH78-5867 - Lymph node, cervical - "Post-transplant malignant lymphoma"

4. 270767 - (SHI•1L #115 ) Skin-Sinus hi stiocytosis with massive lymphadenopathy

5. R75-1187 - Stomach-Multiple carcinoid tumors (in a patient with multipl e endo-crine adenomatosis)

6. R78-1336 - Appendix-Goblet cell carcinoid

7. R78-1206 - (S78-1038), - Testis-Seminoma with trophoblastic giant cells

B. $56-235 & - Skin-Masson ' s hemangioma $58-2101

9. R78-805 & - Soft tissue - Myospherulosis R78-808

10. R79-156 - Spleen - Histiocytoid lymphangioendothelioma

CASE 1 -

VII EUROPEAN CONGRESS OF PATHOLOGY

FRIDAY, SEPTEMBER 21, 1979

SLIDE SHUNAR - DR . JUAN ROSAI

PROBLEMS IN DIAGNOSTIC SURGICAL PATHOLOGY

CASE HISTORI ES

This 27 year old Portugese cleaner presented to his doctor in August, 1g75 with the gradual onset of hoarseness. He was given medicati on for this and it cl eared up. He had some difficulty sleeping as well but there ~1as no speci fi c history of chest pain, s hortness of breath or dyspnea . A ches t x-ray was taken at that time. This showed a densi t y i.n the anterior superior medi astinum extend­ing to t he left of midli'ne at the l evel of the aortic arch . Cl inically, an il l ­defined left subcl a vi cular mass could be pa 1 pated. On Apri 1 12, 1976 he unden~ent a mediastinoscopy and mediastinotomy and the mass was biopsied . This showed frag­ments of thymus with cysts , as well as fragments of tumour co~osed of nests of malignant cells in l~hoid tissue. Left tracheobronchial and subcarinal lymph nodes removed at the same procedure were negative. On April 26; 1976 , the entire mediastinal mass was removed in two pieces - - a large 9 x 6 x 5 em. mass representing the main tumour and a smal ler lobulated 5 .5 x 5 x 4 em. mass felt by the surgeon to be residua 1 t hymus . His t ol ogi ca ll y, botti specimens show thymic t issue with cys t formation and some epithel ial proliferation. The ye ll ow l obul ated poorly defined area i n the l arger tumour and foci in the smal l er also show a neopl asm similar to that seen at mediastinoscopy. A urological consultation was obtained and it was felt that he did not have a testicular tumour at this time. The Seminar section is from the second operation. (Courtesy of Or. M. E. Platts, Toronto, Canada).

CASE 2 -

This 73 year o 1 d man ~1as hospita 1 i zed because of pancytopenia, monocytosis and splenomegaly with wei ght l oss . Towards the s ummer of 1g77 he lost his appeti te and has been l osing weight (about 45 lbs) ever si nce. He was hospi ta l ized i n the fall of 1977 and was found t o have splenomegaly . In t~arch of 1g 73 he was found to have t he hemoglobin in the range of g~, white count approximately 2,000 to 2,500 with up to 30% monocytes. He did have a bone marrow examination at tha t time, which showed some neutropenia and monocytosis. One of the sections of the aspiration material showed an epi the 1 i oi d granuloma without necrosis.

During this hospitalization, the patient also had a liver biopsy ~thich showed minimal round celled portal infiltrates . The patient had a T4 of 4.3 and had somewhat e l evated al kaline phosphatase a t 365. His platelet count ranged from 80,000 to 136,000 and sed r ate was 115. His proti me was s l ightly pro l onged and he received vitamin K for that . He was then discharged but has cont inued t o feel week and continued to loose l·le i ght.

The patient gives no particular history of fever or night s1·1eats. He has no definite history of any skin rash or arthralgias. No particular urinary sympto­matology. There is no history of exposure to TB.

Physical examination reveals somewhat pale looking man who is oriented and in no acute distress . BP is 130/70. Neck i s supple with no cervical lymphadenopathy . Abdomina l exam reveal s the spleen to be f i rm and about 2~ to 3 fingerbreadths bel ow the costal margi n. Liver is not pal pated. A spl enectomy was carried out. The weight was 1,650 gm. I t measured 20 x 16 x g em. Cross secti ons sh01~ed ill -defined

.. - 2 -

fibrosis, but no definite nodules . The Seminar section is from the spleen (Courtesy of Or. L.V. Crowley , Minneapolis, U.S.A.) .

CASE 3 -

A 67 year old male had a renal transplantation on September 1970. He was . i11111unosuppressed with prednisone and Irmiuran. In Apri 1 1978 developed an exophyt1 c lesion at the base of the tongue , which gradually resolved in the fol l o1~ing 3 months. In July 1978, serum titers of 32 for CI~V (CF) and 160 for EBV were recorded .

In Septefl'ber 1978, enlargement of submandibular lymph nodes 1~as noted. The virus titers at this time were CHV (CF) 32 , (IF) 1280, EBV from 2560 to 5120. A lyq:~h node biopsy ~1as taken in October 1978. At this time, titers were CMV (CF) 8, {IF) 1280, EBV 1280. No therapy was instituted.

In January 1978, back pain developed. A filling defect was detected on l iver scan; a 1 i ver biopsy was performed and combination chemotherapy was begun. In March 1979, the liver defect has markedly increased in size, j udging from the scan . The specimen for the Seminar is a cervical lymph node biopsy .

CASE 4 -

A 48 year old male with asymptomatic dermal nodule in skin of shoulder, present for several months. The clinical diagnosis was lipoma. There are no peripheral lyrephadenopathies , hepatomegaly, splenomegaly, other skin lesions or fever. Labora­tory studies revealed a marked polyclonal hypergammaglobulinemia. The Seminar section is from t he skin nodule (Courtesy of Dr. Juan J. Segura F., San Jose,

. Costa Rica).

Note:

CASE 5 -

In some of the Seminar sets, this section corresponds to a skin biopsy from another patient with the same disease.

This 45 year old white male had come t o medical attention on several occasions over a four-year period because of several episodes of rena l lithiasis and a perfora­ted duodenal ulcer, At hi s most recent presentation, the patient complained of the sudden onset of i nt ermittent severe abdominal and costovertebral-angl e pain which radia ted into t he scrotal and s houlder areas. Roentgenographic examinations revealed mul tiple bi lateral renal calculi, marked thickening of the gastric ruga l fo lds, and deformation of the duodenal bulb with a 1 em. ulcer crater . Clinical laboratory exa­minations revealed increased levels of serum calcium (10.9 to 11.9 mg/dl), decreased levels of serum phosphorus (2.2 to 2. 6 mg/dl), and elevated levels of serum para­thyroid hormone (2.0 ng/ml; normal range= 0.0 to 1.5 ng/ml with normal serum calcium levels). Renal tubular reabsorption of phosphorus was 74~ . while the blood level of ionized cal cium was 2.9 mg/dl. The serum gastrin level was elevated to 2,554 pg/ml (adult normal up to·300 pg/ml), and correlated with large volumes of highly acidic gas tric secreti on. Blood and urine leve l s of histamine and of other biol ogically active amines were not determined. Se lective celiac and superior mesenteric arteria­grams 1~ere norma 1 , as 1~ere roentgenogr ams of the hands. Esophagogas troduodenoscopy disclosed markedl y enlarged rugae 11ith active ul ceration i n a pattern highl y sugges­tive of l~netrier's disease. The constellation of clinical findings described was felt to be highly suggestive of the Zollinger-Ellison variety of mulitple endocrine adenomatosis , Type I.

Surgical exploration of the neck revealed a parathyroid adenoma in the left superior position and three apparentl y normal parathyroid glands. The adenoma weighed 2.2 grams, n1easured 3.8 x 1.5 x 1.1 em., and was composed of dense sheets of chief and oxyphil cell s compressing a narrow r im of more normal cell ularity. Neverthel ess, t he subjects serum ca 1 ci um 1 eve 1 s remained abnormally high in the post-operative period.

- 3 -

Subsequentl y, t ota 1 gastrectOIJlY 1~as carried out. The stomach 1~as massi vely wlarged, measuring 64 em. along the greater cur vature and 21 em. along the l esser curvature. Its wall ranged in thi ckness from 0 .6 to 4.5 em. and was rigi d to pal pa­tion. The mucosal surface bore numerous superficial ulcers whi ch were most promin­ent over the 1 arges t ar eas of submucosa 1 tumefaction .

It i s noteworthy that t he subjects sist er di ed approximately 15 years prior to his presentat i on from a condition remarkably s i milar t o his. The Seminar secti ons are from t he gastrect omy specimen . (Courtesy of Dr. J. Kyllo , Minneapoli s , U.S .A.).

CASE 6 -

A 56 year old ma l e 1~i th symptoms of acute appendicitis. An exploratory 1 aparo­tomy was carri ed out. A mass was found in the appendix, and a right hemi co I ectomy was carried out. Grossly, the appendix had a mar kedly t hickened \•tall. The cross section showed a di ffuse t hickeni ng, of a somel'lhat gelatinous appearance. The l umen 1~as not dilated. The secti ons are from t he appendiceal mass (Courtesy of Dr . H. Sumner, Minneapoli s , U.S.A. ) .

CASE 7 -

A 36 year ol d male wi th uni l ate r al tes t icul ar swell i ng of 8 months duration . Laboratory studies shoNed marked el evat i ons of serum HCG {beta subunit) , as determi ned by radioi mnunoassay. A radical orchiectomy ~tas performed. The tumor meas ured 7 em in greates t diameter and rep}aced most of the testis. It \'las solid, gray-white and homogeneous, wi t h seve ral small foci of ne crosi s . The sections are from the t esticular t umor .

CASE 8 -

Adult mal e 1~ith life-history of angi omatous lesi on involving most of t he l eft upper extremi t y. Thi s has been accompanied by t he appearance of dermal and subcu­taneous nodules over the years, overlying t he angiomatous areas. Some of these have been bi opsied (Courtesy of Dr . Bruce Webber , Bethesda , ~10 ., U.S. A. ) .

CASE 9 -

A 43 year old male f rom Costa Rica consul ted for a cystic mass in the soft t i ssues of the gluteal region. The clinical diagnosis was "sebaceous cyst" . A local excisi on was carri ed out . Grossly, there was a s ubcutaneous cystic mass measuring 2 em indi a­meter. composed of a thick 1~al l and a center occupied by a semisolid yell owi s h material. Smaller cavi t ies of simi l ar appearance were seen surroundi ng the l arger one (Courtesy of Dr. Juan J. Segura F., San Jose, Costa Rica}. ·

CASE 10 -

A 13 year ol d gi rl was found to have a left upper-quadr ant abdomi nal mass on routine preathleti c physical exami nat i on . In retrospect, she had been aware of a mass in this region for at l eas t six months . It was symptomatic only i n that it occasional ly "fell" from the left upper- quadrant to the midabdomen . At these times, she experienced a "tugging" sensation and was aware of a mass . She then would manipulate the mass into its normal position beneath the rib cage and would become asymptomatic .

There was no hi story of feve r , in fection, wei ght loss, or ot her systemic symptoms . Careful history showed absolutely no gastrointesti nal, genitourinary, or hematol ogic symptoms. On admission, her ~Ieight was 54. 5 kg (120 lb}, and she appeared to be healthy.

Results of phys ical examination were normal, except for a mass in the l eft upper­quadrant of he r abdomen . The mass was pal pabl e 6 em. below the l eft-costal margin and

) ~ ·. - 4 -"

extended across the mi dline . It was fi rm, irregular, and freely movable . The mass moved with respiration and did not t ransilluminate.

' Results of laboratory studies on admission including platelet count , 1~ere within normal l imits. Chest x-ray films v1ere normal. Results of an upper- gas t rointestinal tract series showed medial displacement of t he stomach by an extrinsic mass. Examina­tion by barium enema showed inferior and l ateral displacement of the colon; an intra­venous pyelogram demonstrated pronounced do1~m~ard displacement of the left kidney.

After the preliminary evaluation, the patient undel"'~ent abdominal exploration and sp 1 enectomy.

Grossly, the spleen was enlarged and irregular in size and in shape . Its weight ( 850 gm) 1~as nine t i mes the norma 1 v1ei ght (93 gm). The outer surface showed four irregular nodules, each with a s,mooth surface. The cut surf ace showed t hat these four nodules . were situated superf icially immediately under t he splenic capsule. A fifth nodule was found deep within the spleni c tissue . The nodules v1ere brownish- red, with a gl is t ening surface and umbilications in the center . They were well circumscribed, but lacked gross capsules (Courtesy of Dr. Ala B. Hamoudi, Columbus, Ohio , U.S.A.).

VII EUROPEAN CONGRESS OF PATHOLOGY

FRIDAY , SEPTEMBER 21, 1979

SLIDE SENINAR - Dr. Juan Rosai

PROBLEt-IS IN DIAGNOSTJ C SURGl CAL PATHOLOGY

DISCUSS ION AND REFERE NCES

tASE 1 - THYI~US - Thymic ca rei noma ( lymphoepithelioma variant)

This is a good example of a type of thymoma that can be identified as malignant

oo microscopic grounds . Both the architecture and cytologi c features are highly remi ­

niscent of the so-c a 11 ed lymphoepithel i oma of the upper res pi ra tory tract. One of the

rost characteristic features of these tumor cells is their l arge vesicular nucleus of

round or ova l shape, smooth contour s and a singl e , large , eosir~ophil ic or amphophi l ic

nucleolus.

lie propose the fo 11 011i n9 class ifi cation for ma 1 i gnant t hymomas, a term t hat refers

both to invasive thymomas that spread locally in the mediastinum and thorax to involve

nerves, vessels , pleura, lungs, and myocardium and to the rare examples of typical

thj'lroma that ITI?tastasize hematogenously or via lymphatics (Table). The designation

thymic carcinoma is best reserved for cytol ogi cally malignant thymomas (rega rdl ess of gross pattern ) .

In category I 1·1e incl ude thymomas t hat show at most only modest degrees of

epitheli al atypia . ~1itotic counts are of littl e value, as these are in any event

usually high in lym;:>hocyte rich benign thymomas. Paucity of lymphocytes is said to be

associated with aggressive behavior, but once again, in any one case, this is of little

prognostic value. In the final analysi s it is the finding at surgery of an encapsulated

versus t ruly invasive les ion that determi nes the des i gnat ion benign versus malignant

tliymoma. Encapsula ted t hymoma i s adequate 1 y treated by s urgery a 1 one and r ecurrence is

rare (2 per cent). fnvasive thymoma is an indi cation for postoperative radiotherapy.

Thymomas are rare i n children and usually carry a poor prognosis in this age group.

A review of the literature reveal s that lymphatic or hematogenous spread from a

category I rna 1 i gnan t thymoma is extremely rare. Care must be taken to exc 1 ude the

many cases of lymphoma, carcinoid, and germ cell tumor that have been erroneously

Case 1 Page 2

reported as rretastatic thymoma . In 1978 , 1~hen we reviewed the literature on the

subject , 11e satisfi ed ourselves as to the va 1 i dity of only some 15 cases of meta­

sta tic typical thymoma.

Category I I is consti tuted by t hymic t umors that are obvi ously malignant

cytological ly . These may be squamous carcinoma, emul ate l ymphoepithel ioma of the

nasopharynx, or have an undifferentiated or sarcomatoi d appearance (even with

rhabd0f11Yosarcomatous areas). We have also encountered a glycogen rich, clear cell

lliymic carcinoma that closely simulated renal carcinoma and a case of primary t hymic

~coepi dermoid carcinoma . The true i ncidence of poorl y different i a ted thymic carci­

noma is unclear, si nce most series of t hymomas de l i berately exclude such cases. The

series of Thomson and Thack ray is a not \lb 1 e excepti on , for they reported 54 t hymomas

of which 20 1~ere "undifferentiated". These tumors can easily be confused with

histiocytic lymphoma. Without ultrastructural examination, irrmunoperoxidase or cell

surface studies, it is often difficult to reach a diagnosis other than "malignant

tu100r, unclassified" . If fresh tissue is available , the tumor cells should be examined

for possibl e lymphoid characteristics such as surface immunoglobulin, complement recep­

tors, and E resett i ng capacity.

Thymic carci noma may be encapsulated and appare nt cure can be achieved by s i mpl e

resec tion . Hov1ever , thymic carcinoma i s more likely to be invasive and to me tastas i ze .

Cure may be achi eved even in cases that demonstrate local lymph node rretastasis.

Although the diagnosis of thymic carcinoma can be made with certainty only after

retastasis to the anterior mediastinum , especially from the l un g, is excluded, there

a~ enough well documented cases that verify the exi stence of a true thymic carci noma.

The treatment of choi ce for malignant thymoma (inc l uding t hymi c carcinoma) i s surgi cal

excision supplemented by radiation therapy.

CLASSIFICATION OF MALIGNANT THYMOMAS

I. With no or mini mal cytologic atypia a. Local ly invasive (usual form) b. With true lymphati c or hematogenous spread (rare)

II. Cytol ogically mal ignant (=thymic carcinoma) ; morphol ogic variants : a. Squamous cell carcinoma b. Lymphoepithel ioma-like c. Clear cell carcinoma d. Mucoepidermoid carcinoma e. Sarcomatoid (electron microscopy often needed to distinguish from epithelial

tumors) f . Undifferentiated (electron microscopy often needed to distinguish from histio­

cytic lymphoma and germ cel l tumors)

Case 1 Page 3

REFERENCES

l. Bernatz, P.E ., Khonsari, S., Harri son, E.G., Jr., and Taylor , W.F.: Thymoma: factors i nfluencing prognos is. Surg. Clin . N. Amer ., 53 :885, 1973.

2. Chapek, M.W., Rosai, J., and Levine, G. D.: Mal ignant thymomas with rhabdomyo­sarcomatous ("111Yoid-cell" ) differentiati on: report of a case and review of t he literature. Lab . Invest., 36 :5, 1977 (abstract).

3. Dehner, L. P. , et a l. : Thymus related tumors and tumor- 1 ike 1 es ions in chfldhood with rapid clinical progression and death. Hum. Pathol. , 8:53, 1977 .

4. Gray, G. F., and Guto~o1ski, W. T. II I: Thymoma. A clinicopathologic study of 54 cases. Am. J . Surg. Pathol., 3:235 , 1979.

5. levine, G. D., and Rosai, J. : Thy!lli c hyperplasia and neopl asia: a review of current concept s . Hum. Pathol., 9 :495, 1978.

6. levine, G. D., Rosai, J., Bearman , R.N. , and Polliack, A. : The fine structure of thymoma , with emphasis on its differential diagnosis. A study of ten cases. Am. J. Pathol., 81:49, 1975.

7. f1arks, R.D., Wallace, K.M., and Pettit , H.S.: Rad iation therapy control of nine pati ents with malignant thymoma. Cancer, 41: 117 , 1978 .

8. Rosai , J., and Levine , G.D.: Tumors of the thymus . Atl as of Tumor Pathol ogy. Second Series. Washington, D.C., Armed Forces Institute of Pathology, 1976.

9. Shimosato, Y. , Kameya, T. , Nagai , K., and Suemasu, K.: Squamous cel l carcinoma of the thymus. An analysis of 8 cases . Am. J. Surg. Pathol ., 1:109, 1977 .

10. Thomson, A.D. , and Thackray, A. C.: The histology of tumours of the thymus . Br. J. Cancer, 11:348, 1957.

Case 2 - SPLEEN - Systemic mastocytosi s

The spl een shows widespread involvement by ill-defined nodules of granulomatoid

appearance accompanied by fibrosis. The infiltrate is composed of a vari ety of ce 11

types, among which cells of somewhat irregular nucleus, clear cytopl asm and \~ell ­

defined cell border are prevalent. These are mast cel ls, as demonstrated by meta­

chromatic stains and the von Leder's reaction .

Diseases of mast cells can be divided in three types : (1) urticaria pi~wentosa

arising in infancy or early childhood without significant systemic lesions ; (2)

urticaria pigment osa arising in adol escence or adult life without s ignificant systemic

lesions; and (3) systemic mast cel l di sease . The Semi nar case i s an example of the

third type. In this condition, there ' is progressive involvement of many organs, inclu­

di ng the liver, spleen, intestinal tract, meni nges, bones and bone marro1~. J.last cells

r.:ay be released into the blood , occasionally reaching the proportions of mast cell

leukemia. Of a total of 29 cases of systemic mast cell disease reviewed by Mutter e t al.

in 1963, 11 had died at the time of reporting. In 5 of the 29 patients cutaneous l esions

were absent. Although mos t cases of fatal systemic mast cell disease have been reported

in ad ults, a fata l outcome may occur in children.

Mi croscopically, extensive aggregates of mast cel ls are present, Iii th diffuse

infiltration especial l y of lymph nodes, spleen, liver, i ntestinal tract, bones and bone

r.:arrow. Mild i nfi 1 tration of the bones causes asymptomatic os teoporotic and osteo­

sclerotic changes , whereas massive infiltration can cause collapse of several vertebrae .

The marrow lesions of systemi c mastocytosis may be foun d as a direct result of

search in a patient ~1ith urticaria pigmentosa or may

for sowe reason unre l ated to s uspected mastocytosis.

~ere is no clinical suggestion of mastocytos is, the

be detected in a biopsy performed

In the latter instance, 1~hen

lesions of mast cell disease are frequently overlooked or misinterpreted because of the difficulty of identifying mast

cells in routine sections and the changes inherent in the mast cells in this disease.

~ars obtained by bone marrow aspirate may suggest the diagnosis of mastocytosis if

large numbers of mast cells are present; the number should exceed 7% s ince up to that

percentage has been reported in patients without mast cell disease. In many i nstances,

the mast cell s in the marrow in mas tocytosis are associ ated with an increase i n reticulin

fibers and are not readily aspirated . As a result, the pathologist is not al erted to

the possibility of mast cell disease from the smears.

The marrow infiltration in mastocytosis may be di ffuse or focal . The focal

lesions may take several forms: mas t cell aggregates , fibrotic foci associated with

mast cells, lymphocytic aggregates surrounded by a coll ar of mast cel l s or a focus of

em 2 Page 2

~st cells surrounded by a collar of lymphocytes. Fibroti c foci may be found in

a paratrabecular location and nodular granulomatous foci may be present . A pro­

minent perivascul ar arrangement of mast cell s i s sometimes noted; hyperplasia of

the vessel wall and perivascul ar col lagenous fibrosis may occur. Eosinophi l ia i s

usually prominent in the area of the mast cell aggregates and may be the most

coospicuous morphologi c finding. The bone trabeculae may show osteoblastic and

~teolytic changes in the same section. Blood eosinophilia and hypocholestero_lemia

a~ frequently associated laboratory findings.

A major difficulty i n the diagnos is of mast cell lesions results from the

frequent ly abnormal morphol ogy of the mast cell s in th i:s disorder. The cell s often

resemble histiocytes i n that they posses-s abundant eosinophilic cytoplasm. The

granules are difficult to identify even \~hen the true nature of the l esion is

suspected. In the fibrotic foci, the mast cells may have a spindly appearance and

~semble fibroblasts. Large fibrotic lesions may be misinterpreted as idiopathic

I!Yelofibrosis. The identification of the mast cells is best accomplished with the

Giemsa or to luidine blue 0 stains, the von Leder chloroacetate reaction or electron

microscopy. ~lith the toluidine blue 0 stain, the mast cell granules appear reddi sh

purple; the staining of the granul es can be enhanced in decalci fied tissue by treat­

ment of the section with potassium permanganate followed by oxalic acid prior to the

staining procedure .

The marrow lesions in systemic mastocytosis are similar to the changes described as "the eosinophil ic fibrohistiocytic lesion".

Case 2 Pagel"

REFERENCES

I. Brunning, R. 0.: Bone marro'rl . Chapter 22 in Rosai, J. : Ackernan's Surgical Pathology, St. louis , The C.V. Nosby Co. (in press, 1980).

2. Burgoon, C. F., Graham, J .H., and McCaffree, D.l.: Mast cell disease . Arch . Derm. , 98: 590, 1968 .

3. !·Iut ter, R.D., Tannenbaum, M., and Ultmann, J.E.: Systemic mast cell di sea.se . Ann. Int. Med ., 57:887, 1963.

4. Roberts, P.L., t·icDonald, H.B., and \~e ll s, R. F.: Systemic mast cell disease in a pat ient with unusual gastrointestinal and pulmonary abnormalities. Am. J. Jl.ed .• 45:638, 1968.

5. Sagher, F. , and Even-Paz, Z.: Jolastocytosis and the mast cell, 1967, Chicago, Yearbook loledical Publishers .

6. TeVelde, J., Vismans, F.J.F.E., Leenheers-Binnendijk, l., et al.: The eosino­philic fibrohistiocytic lesion of the bone marrow . A mastocellular lesion in bone disease . Virch. Arch . (A) Path. Anat. and Histol., 377:277, 1978.

7. Woessner, S., LaFuente, R., Pardo, P., et al.: Systemic mastocytosis: a case report. Acta . Hematol ., 58 : 321, 1977.

Ca~e ,3 - l YHPH NODE, CERVICAL "Post-transplant malignant l ymphoma"

This i s a typical exampl e of the type of lymphoreticular proliferation that has

been described v1i th increasing f requency in trans plant recipients under the term of

"pos t-transp 1 ant rna 1 i gnant lymphoma". Ther e i s tota 1 effacement of the architecture

by a pleomorphic infiltrate in 1~hich pl as ma cells, plasmacytoid cells and immuno­

bla,sts predominate. lmmunoperoxidase stains showed a polyclonal pattern of cyto­

plasmic immunoglobulin in the prol iferating lymp hoid cells. Evidence of EBV infecti on

was documented in t he patient.

In 1977, we reviewed the cl i ni cal evol ution, pathologic distribution, and morphology

of 27 cases r eport ed as "mal ignant l ymphomas " to the ACS/HIH Organ Transplant Registry.

The find i rrgs documented a disti nct i ve clinicopathologic entity. The clinical evolution

from t he onse t of symptoms to dea t h tended to be extremely rapid 1·li thout s i gni f i cant

response to any mode of therapy . The onset could occur anytime in t he post-transplant

period, t he shortest interval in thi s series being 1 month. Morphologically, the

process was composed of a monotonous proli feration of large "i mmunobl astic" and plasma­

cytoid cells infi ltrating organs in a duff use pattern quite atypical for histiocytic

lymphomas. Determinati on of in t race 11 u l ar i nmunob lobuli ns by the i nmunoperoxi dase

techniques indicated that the process represen t ed, in virtua lly every case, a poly­

clonal proli feration of B-lymphocytes. Documentation of acute Ebstei n- Barr virus

infection 1~as obtained in sever al cases , raising the possibility of a. viral stimulus

fur this syndrome.

It is possible tha t we are in the presence of an EBV-induced B-lymphocyte prolifera­

tion which, by virtue of this patient ' s induced, defective T-cell response to EBV has

progressed to a condition 1·1hich has many of the features of neoplastic process.

Th i s hypothesis fits nicely with the well-konm~n stat ement made by Oameshek and

Gunz to the effect that infectious mononucleosis is "a gen·eralized proliferation of

one of the 1~hite cell-forming tissues, [that] has many if not all of the fe atures

of acute 1 eukemi a with one no tab 1 e except ion, i.e. , its revers i bi 1 i ty" .

Recent evidence indicates that this reversibi l ity is dependent upon the presence

of suppressor T-cells 1~hich control and eventually abol ish the proliferation of EBV­

infected 8-lymphocytes. I t i s easy to conc~ive how, in the presence of an impa i red

T-cell function as the result of i mmunosuppression, the 8-cell proliferation could

proceed i n an unrestrained f ashion, acquiring in the process the morphol ogic and

behaviora l feature s of a neoplastic process. This interpretation, if correct, is a

remarkable "experi ment of nature " 1 inking in humans a well-documented infection by an

oncogenic virus with the neoplastic state. Obvious ly, this is a matter of great prac­

tical importance because, if this is indeed the case, chemotherapy may not be the best

Case 3 Page 2

therapy for these patients . Instead, di scontinuation of the il111lunosuppression could

prove a much more effective measure in that it might s till revert the process .

It should al so ment ion in this regard that many of the "lymphomas" developing

in pati ents with natural i mmunodefic i enci es have very similar morphol ogic and

clinical features to the "post-transplant lymphomas", as we have found out in a

recent review of the cases collected by the liTIIlunodeficiency Cancer Registry at the

University of Hi nnesota.

Case 3 Page 3

REFERENCES

1. Fri zzer<~, G., Rosai, J., Dehner, L.P ., et al.: lympho-reticular disorders in primary tmmunodeficienci es (PID). New findings based on an up-to-date histologic review of 35 patients . Lancet (submitted for publication, 1979) .

2. He r tel, B. F. , Rosai, J., Dehner, L.P., and Simroons , R.L.: lymphopro l i ferative disorder s i n organ transpl ant r ecipients. (Abstract) Lab . Invest. , 36:340~ 1977 . .

3. Holahan, K., Ascher, N.L., Sirm1ons, R.L., et al.: EB vi rus- induced fata l i rrmuno­prol iferative disease in a renal transpl ant recipi ent. A reevaluation of pos t­transplant l ymphoma. Transplantation (in press, 1979) .

4. Klein, G.: The Epstein-Barr virus. and neoplasia. N. Engl. J . Hed ., 293:1353, 1976.

5. Louie, S., and Schwartz , R.S.: Irrmunodeficiency and the pathogenesis of lymphoma and leukemia . Semin. Hematol. , 15 : 117, 1978 .

6. ~latas, A.J., Hertel , B. F., Rosai, J., et al.: Post-transplant ma l ignant lymphoma . Distinctive morphologic features related to its pat hogenesis. Am. J. t1ed., 61:716 , 1976.

7. Ziegl er, J .L., McGrath, !. T., Gerger, P., et al.: Epstein-Barr vi r us and human malignancy. Ann. Intern. Med., 86:323, 1977.

Case 4 - SKIN, SHOULDER - Sinus histiocytosis with massi ve lymphadenopa thy

The section shows a nodular dermal i nfi ltrate of inflammatory appearance composed

of lymphocytes, plasma cells, neut rophi les, and numerous hist i ocytes of l arge vesicu­

lar nucleus and abundant pale cytoplasm. Some of these histiocytes contai n phago­

cytosed l ymphocytes in thi er cytoplasm.

The microscopic appearance i s consistent with the cutaneous manifestat ion of sinus

histiocytosis with massive lymphadenopathy ( SHML) . Thi s is one of ten cases that 11e

have recentl y reviewed of SHML man i festing 1-1ith skin l esi ons. Increasing experience

with this disease has sh01·m tha t SHHL tends to involve extranoda 1 structures more

oft~n than indicated in the original descriptions. The microscopic appearance in these -

sites is quite s i mil ar to that seen in the lymph nodes in t erms of cellular composition

of the infiltrate. On the other hand, t he overall arch itect ure is somewhat variable ,

~inl y as a funct i on of t he type of tissues and structures involved. Foremost in

this regard is the absence in the ski n and most other extranoda 1 s ites of lymph node

sinuses , l'ihose alterati ons represent one of the mo.st i mportant hal l marks of SHNL. It

has thus become evident that t he designation "sinus histiocyt osis" is not appropriate

ohen applied to most ex:tr anodal l esions, including those in the skin . The alternative

Bes i gna t i on tha t 1-1e have chosen to describe th i s phenomenon is. that of "cutaneous

involvement by SHHL, " analogous to the use of terms such as "cutaneous invol vement by

ulcerative co 1 iti s " or "cutaneous i nvol vement by benign mucous membrane pemphigoid"

to indicate s kin invol vement by conditi ons primarily affect i ng other organ systems.

The recognition of a cutaneous lesion of SH~ll i s rarely a problem, since the

nature of the disease is usually evi dent on t he basis of the lymph nodal man ifestations .

However, i t is important to describe the diagnostic criteria and differential diagnosi s

of this di sease 1-1hen located in the skin, since this not only may be the first source

of biopsy materia l but, as the Seminar case demons trates, it may also be the only

obvious site of the disease. In this regard, i t shou ld be mentioned that 1~e have

now seen several other patients with SHML in 11hom an extranodal focu s (such as an

orbital mass) was t he predominant manifestat i on of t he di sease, 1~he reas the cervical

no.da l enl argement was minimal or absent. Thus, the designation of "massive lymphadeno­

pathy" does not accurately describe this parti cu 1 ar group of cases.

The cutaneous 1 esi on of SH~1L can be defi ned as a derma 1 i nfi 1 t rate predominantly

composed of mat ure histiocytes (some foafl\Y and/or multinucl eated), l ymphocytes, and

plasma cells , with or without associated vascular proliferation a.nd fibrosis and

usually accompanied by relati ve l y minor and nonspecific epidermal changes. Two

additional features are the segregation bet ween the histiocytes and the other

Case 4 Page 2

inflal!l1latory cells , the former sometimes arranging in tissue spaces suggestive of

lymph vessels; and t he presence of lymphocytes and other inflarrrnatory eel l s within

the cytopl asm of the histiocytes . Unfortunately, these features 1•1ere us ually not

as promi nent in the skin as t hey were in the lymph nodes, and sometimes they were

absent.

The foll owing diseases should be considered in the differential diagnos i s on

aicroscopic grounds; dermatofibroma , xanthoma , Tangier disease, histiocytosi ~ X, reticulohistiocytoma, juvenile xanthogranuloma, leprosy and Hodgkin's disease : The

skin lesions of SHML had a tendency to involute spontaneously; this appl ied to all

four cases in which we have f oll ow-up information.

The other mos t common site of extranodal involvement by SHML are the upper

respiratory tract , eye and adnexa (particularly orbit), and skeletal system. \~e

Mve also seen cases located in the testicl e, epididymis, central nervous system

(extensions from peri dura 1 masses), trachea and thyroid.

Case 4 ~

REFERENCES

I. Foucar, E., Rosa i , J., and Dorfman, R. F. : The ophthalmologic manifestations of sinus histiocytosis with mass i ve l ymphadenopathy. Am. J. Ophthal mol ., 87 : 354' 1979.

2. Foucar, E., Rosai, J., and ·Dor fma n, R. F. : Sinus his t i ocytosis with massive lymphadenopathy. Ear, nose , and t hroa t manifestat i ons . Arch. Otolaryngol:, 104 :687' 19 78.

3. Lampert , F., and Lennert , K. : Sinus hi s tiocytos i s wi th massive lymphadenopa thy. Fifteen new cases. Cancer ! 37 : 783, 1976.

4. Rosai , J., and Dorfman, R. F. : Sinus histi ocytosis wi th massive lymphadenopathy; A pseudolymphomatous benign disor der. Analys is of 34 cases . Cancer, 30 :1174, 197.2.

5. Sanchez, R., Rosa i , J., and Dorfman, R. F..: Sinus hi s t iocytosis with massive lymphadenopathy: an analysis of 113 cases with special emphasis on its extra­nodal ma ni festat ions. Lab. Inves t. , 36:21, 1977 (abstract).

6. Thawerqni, H. , Sanchez, R. L. , Rosa i , J. , et a 1. : The cutaneous mani fes ta ti ons of sinus histiocytosis . with massive lymphadenopa thy. Arch. Dermato l ., 114:191, 1978.

7. Wal ker, P. O., Rosai, J., and Dorfman , R.F.: The osseous manifes t a tions of sinus histi ocytosis ~lit h massive lymphadenopathy . J . Bone Joint Surg . , (Am.) ( In press, 1979).

Case 5 - STOMACH - 11ultipl e carcinoid tumors (in a patient with multiple endocrine

adenomatosis)

The stomach from this case shows t1~o lesions: a diffuse hyperplasia of the fundal

RJcosa consistent with ~1enetriere' s disease, and multiple pri mary endocrine gastric

turors of carcinoid type , composed of argyrophylic cells and associ ated 1~ith diffuse

hyperp las i a of mucosal argyrophyl i c cel l s .

Thi s i s one of two pat i ents 1~ith mul tiple pri mary t umors of t he stomach , gi"ant

~pertrop hic gastropathy , and e levated serum gastri n l evels f ul f i l li ng the criteri a

for Zoll inger-Ellison syndrome and suggestive of MEA I tha t \ve have recent ly studied .

oross examination revealed multi pl e submucosal neoplasms in one case and only hyper­

trophic gastric folds in the other. Mjcroscopically, the gyriform pattern of growth ,

ronsisting of fes toons and ribbons of small dark cells, was considered characteristic

of that previously associ a ted with gastrin-secreting pancreatic islet ce 11 tumors. These

n~plasms were also uniformly argentaffin-negative and argyrophil-positive. An indepen­

&nt pancreatic tumor in one patient l acked the gyriform appearance and was both argen­

taffin and argyrophi l -negati ve. 11T111unohistochemical techni ques fa il ed to l ocal ize

intracytopl asmic gastri n withi n the gastri c tumors . Ultrastructura l studi es revea l ed

the presence of 1 arge numbers of membrane-bound cytoplasmic granul es of neurosecretory

type. The granules i n both gas t ri c tumors were si milar in tha t their outer electron-

dense membranes encompassed homogeneous cores of variable intensity.

~the basis of our data, we have reached some conclusions regarding these novel

935tric neoplasms. First, ~1e have concluded that the gastric tumors represent

lllltiple primary tumors rather than metastases from the neighboring pancreatic neo­

plasms. We feel that this concl usion ·is supported by the following evidence: (1)

Isolated metastases from pancreatic neoplasms to the gastr i c submucosa without wide­

spread n-e tastat i c dissemi nation el se1~here woul d be most unusual ; (2) The in situ

prol iferati on obser ved i n the gas tri c gl ands argues s t rongl y for an intrins i c gastric

neoplas t i c process; ( 3) In both cases, · the gastric t umo rs and the pancreatic tumors

Sh!i'~ed different histochemi cal char acteristics when subject ed to the argyrophi 1 reac­

tion; (4) There was a stri king differe·nce between the e l ect ron mi croscopic appearan­

~s of the neurosecretory granul es identified in the gastric tumors when compared

vith those identified in the pancreatic metastases.

We think that these gastric tumors may be designated carcinoids. We have chosen

this term in order to follow the nomenclature of the World Health Organization which

defines "carcinoid" as a generi c term for a tumor which has originated from any ce 11

of the diffuse endocrine sys t em, outs i de of the pancreas . \~e have a 1 so cone 1 uded

that t he availabl e evi dence sugges ts t hat these gas t r i c neopl asms do not ari se from

Case 5 Page '2

S or gas t rin- producing cells . Our reasons for this conclusion are as fo ll ows : (1)

Tfie tumors and the hyperp 1 as tic argyrophil cells are pr esent i n the fundus of bot h

stomachs , a site known to be poorly populated by G-cells; (2} The ultramicroscopi c

appearance of the granul es from the one s t omach tumor ex ami ned differ from those of

known gastrin- producing tumors; (3) The .immunoperoxidase reaction for gastrin

was negat i ve; (4) The serum gastrin level remained e l evated after total gastrectomy

in one pat i ent studied.

There are four pass i b l e endocrine cells of the huma n stomach ~1hi ch may have gi ven

rise to these neoplasms . They comprise t he G or gastrin cell, the E.C. or enterochro­

ma ffi n cell, the E.C. -L. or enterochromaffin-li ke cell, and the D cell v1hich resembl es

the D cell of the pancreatic islets . Ne have effectively excl uded the G cell as the '

~e ll of origi n of these tumor s . The enterochromaf f i n cell is not a likel y candidate ,

because ,of the fact that enterochromaffi n ce 11 s are argentaffi n-pos i t i ve whereas the cells comprising our gastric tumors are uniformly argentaffin-negative . That leaves

the enterochromaff i n-1 ike ce 11 and the D ce 11 as pass i b 1 e progenitors for these

neoplasms .

It is possible that the diffuse gastr i c endocrine cel l proliferation reported by

some authors in association wi t h the Zo ll i nger-Ell i son syndrome represen t s t he pre­

cursor stage for t he disease exemp 1 i f i ed by Case 5.

Cose 5 Page 3

REFERENCES

L Balasa , R.l~., Erlandsen , S.L., Martinson, E.J., et al.: Hultiple primary gastrin­secreting tumors of the stomach associated with Henetrier' s disease: histologic, ultrastructural, and i lll11unohistochemical findings . Lab . Invest., 34:2, 1976 (abstract).

l . Bl ack, W.C., and Haffner , H. E.: and multiple carcinoid tumors. Cancer, 21: 1080, 1968.

Diffuse hyperp l asia of gas t ric argyrophil ·cells An histochemical and ultrastructural study.

J. Bordi, C., Cecconi, G .• Togni, R., et al.: Gastric endocrine cell proliferation. Association with Zollinger- El lison ~yndrome . Arch. Pathol ., 98:274, 1974.

t. Larsson, L. -I. , Rehfe 1 d, J . F. , Stockbrugger, R. , et a 1. : tumors associated with hypergastrinemia of antral origin. 1978.

Hixed endocrine gastric Am. J . Pathol., g3:53,

5. Nabeyama, A., Murata, F. , Hatsuda, H. , et al.: Ultrastructural classification of endocri ne-1 ike ce 11 s in the mucosa of human stomach. Tohoku J . Exp. ~led. , 103: 17. 1971.

6. Pearse, A. G. E., Coulling, I. , Weavers, B., et al.: The endocrine polypepti de cel l s of the human stomach, duodenum, and jejunum. Gut, 11:649, 1970 .

7. Solcia, E., Capella, C., Vassallo, G., et al.: Endocrine cells of the gastric mucosa. Int . Rev. Cytol., 42:223, 1975 .

Case 6 - APPENDIX - Goblet cell carcinoid (adenocarcinoid)

Thi s is a good example of a speci f ic t ype of primary appendi ceal neoplasm of

dubious histogenesis, but 1·1hich i s generally regarded as a morphol ogic variant

of carcinoi d tumor . Accordi ng to th is scheme, carcinoid tumors of the appendix

can be roughly divi ded i nto three categories. The "classic" type is for med by

solid nests of smal l monotonous cells ~lith occas i onal acinar or rosette formation.

Mitoses are exceedingly rare. A peculiar retratti on of t he t umor periphery from the

stroma i s evident. Some of the cells are found within intraappendi ceal nerves. The

second type, referred to as the "t ubular type adenocarci no i d" by ~larkel et al . , is

often misdiagnosed as primary or metastati c carci noJT1a . 1 t i s characterized by gl an­

dular forma~ i on ~1ithout soli d nests. J·lucin stains are positive, 1~herea s ar-gentaffin

and diazo reactions are negative. The 1 ack of mitoses and atypia, orderly arrange­

rent, and origi n at the base of t he glands with an othen·li se norma 1 mucosa should

suggest t he diagnosis . On occasion, the cytoplasmic granules of t hese cel ls ar e

large and acidophilic, simulating those of Paneth cells, a f eature also someti mes

exhi bited by normal Kultschitsky's cells. Electron microscopic examination ~till be

diagnost ic even 1~ith formal in-fi xed material because of the presence of neurosecre­

tory granules. The third type, represented by the Seminar case, i s variously called

r.oc inous carcinoid tumor, goblet cell carcinoid , goblet cell type adenocarcinoid and

microglandular car cinoma. Grossly, i t may be fo und i n any portion of the appendix

and appears as an area of whitish, sometimes mucoi d induration wi thout dilatation

of the l umen. 1-li croscopica lly, and like the other tl-10 carcino id types, i t is charac­

terized by a predominantly submucosal gro~1th. Extensi on i nt o the muscle and serosa

are conmon, but the mucosa is characteristically spared, except for areas of apparen t

connection between tumor nests and the base of t he crypts . The tumor itse If i s formed

by small uniform nests of signet ring cells, often arranged in a mi croglandular fashion,

and someti mes accompanied by extracellular mucus. Focal resemblance to Br unner glands

and Paneth cells has been noted. Acute appendi citi s is a common complication. ~1uci­

cacrmine stains are consistently positive, and argentaffin cells show cytoplasmic

granules i n about 88% of the cases. Electron mi croscopi c. studies have sh01~n mucin

droplets and neurosecretory type granules, although t here is controversy ~1hether they

are located in the same ce 11. The behavior of t hi s tumor i s more aggress. i ve than the

other two types of ca re i noi d: metastases have been documented in B to 20% of the cases.

Because of th i s, we favo·r the perf ormance of a r i ght hemicolectomy f or this t umor t ype,

especially if the neop 1 asm has spread beyond the appendix and/or shO\·IS a high mitotic

count.

REFERENCES

1. Abt, A. B. , and Carter, S. L. : Gob 1 e t ce 11 carci noid of t he appendix. An ultra­structural and hi s t ochemical study. Arch . Pathol. Lab. t-Ied., 100 :301 , 1976.

2. Cooper, P.H. , and Harkel, R.L.: Ultrastructure of the goblet cell type of adena­carcinoid of the appendix. Cancer, 42:2687, 1978.

3. Subbuswall\Y, S . G. , Gibbs, N. M., Ross , C. F., et al . : Goblet cell carci noid of the appendi x. Cancer , 34:338 , 1974 .

4. Warkel, R. L., Cooper, P.H., and Hehlig, E. B. : Adenocarcinoi d, a mucin-producing carci noi d t umor o f t he appendix . A s t udy of 39 cases. Cancer, 42:2781, 1978.

5. Wolff, M. , and Ahmed, N. : Epithelial neopl asms of the ve rmiform appendi x {excl u­sive of carcinoi d ) . L Adenocarcinoma of the appendix. Cancer, 37:2493, 1976 .

Case 7 - TESTIS - Seminoma with trophoblastic giant cell s

This testicular tumor has ma ny of the features associated with classical seminoma,

oot i n addition, it contains a good number of multinucleated giant cells with an appear ­

ahce consistent 1~ith syncyti otrophobl ast. Many of t hese cell s are closely re l ated to

the wall of blood vessels. Immunoperoxidase stains shows presence of human chori onic

gonoootropin in the cytoplasm of these cells , confirming their trophoblastic differen­

tiation. . The presence of these ce 11 s does not indicate that this tumo1· has a component of

choriocarcinoma . Tt should sti ll be diagnosed as seminoma , but the presence of these

cells and of e l evated level of serum HC G should be tak·en as an indi cation that the tumor

~ill probabl~ run a more aggressive cl-inical course than i n t he usual case , and more

akin to that of anaplastic seminoma . Anaplastic seminomas, as currently defined, comprise

about 5% of all seminomas; they have the avera 11 1 i ght and electron microscopic appear­

ance of classical seminomas, but mitoses are more frequent (three or more per high

~er field) , the nuclei l arger and more hyperchromatic, the cytoplasm scantier and

necros is more pronounced. As indicated, scattered mul t inucleated gi ant cells with

the appea~ance of syncytiot rophobl as t ar e often found. These have been sho~m t o

contain chorionic gonadotropin, and patients with t hese tumors may have serum eleva-

tion of this hormone. The presence of these cells {seen in 11% to 14% of all seminomas)

Is not justification to label the tumor as a choriocarc inoma , but it has been our

e~erience that many of the seminomas containing these elements 1~ere of the anaplastic

variety. We have recently revie1~ed a s eries of seminomas of the testis associated

with serum elevation of chori onic gonadot ropin; most of the tumors \~ere of the ana­

plastic variety and/or contained scattered syncytiotrophobl as tic ce ll s. The natura l

history of anaplastic seminoma i s not well known because the mo rphologic criteria

for its i denti fi cation have been defined only recently; however, it seems that

patients with this tumor do worse, stage for stage, than those with classical seminoma.

The rost i~ortant differential diagnos i s of anaplastic seminoma is with embryonal

carcinoma; the latter shows more nuclear variability in size and shape, prominent

overlapping of nucle i and foca 1 clumping of ce 11 s i n a carcinomatoid fashion .

This case a 1 so i 11 us tra tes ~~e 11 the importance that i mmunocytochemi ca 1 techniques

(particularly i mmunoperoxi dase) have acquired in the diagnosis and cl ass i f i cation of

human tumors.

Case 7 Page 2

REFERENCES

J, Janssen , 1-1., and Johnston, H. H. : Anaplastic seminoma of t he testis. Ultra ­structura l analysis of t hree cases. Cancer, 41 :538, 1978.

2. Kademian-, ~1., Bosch, A. , Cal dwell, W. L., et a l. : Anaplas tic semi noma . Cancer, 40:3082, 1977.

l. Lange, P.H . , l~cfn tire , K.R., human chor i onic gonadot rop i n germ--cell t esticul ar cancer .

Ha ldmann, T. A. , et a 1 . : Serum a 1 ph a fetoprotei n and in the di agnosis and ma nagement of nonserninomatous

N. Engl. J . Med . ,_ 295:1237, 1976.

4. Lange, _P.H., Nochomovitz, L.E. , Rosai, J. , et al.: Serum a l pha-fetoprotein and huma.n cho h onic gonadotropin in patients with semi' noma: analysis of 31 cases. ( In preparat i on, t o be submitted to J. Uro 1. , 1979) .

5. Nochomovi tz , L.E., and Rosai, J . : Current concepts on the hi stogenesis, pathology, and i mmunochemi stry of germ cell t umors of t he test i s. Pa thol. Ann., 13: 327, 1978.

6. Nochomovi tz , L. E. , Rosai, J ., Fral ey, E. E., and Lange, P. H. : AnaPJ·astic semi noma of t he testis. A morphol ogic and i mmunochemi cal s t udy of 16 HCG-secreting semi nomas. (in pr eparation, to be submitted t o Am. J . Clin . Pathol., 1979).

]. Tayl or, C.R., Kurman, R. J ., •and ~/arner, N. E. : The potenti al value of i rl'l11un ohisto­losic techniq ues in the c lassifi cation of ovari an and tes ticul ar tumors. Hum. Pathol ., 9:417, 1978.

Case 8 - SKIN Masson's hemangioma

The section shows a marked pro l iferation of large blood vessels, many of vlhich

exhi bit partial or total obliteration of t he l umen by a complex - - sometimes

papi ll ary-- proliferation of endothelial cel l s supported by t hi n f ibrous septa.

~nas tomosing channels are thus formed. In some of the sections, t hrombi in vari ous

stages of evolut i on are present . \~e interpret this les i on as a beni gn large vessel

hemangioma in which thrombos i s and exuberant recanalization has occurred . Thi.s

change \~as or i ginal ly described by Masson i n hemorrhoi ds and is someti mes confused

with angiosarcoma.

In 1976, we co 11 ected 17 cases occurring in the skin and soft ti ssues. They pre­\

sented either in a pure form with a c l i ili cal appearance r eminiscent of an ordinary

hemangioma, or more commonly, as a foca 1 change in pyogenic granulomas or hemangiomas.

Of the 14 cases with available f ollow-up information, there 1~as no instance of

local recu'rrence, with the possibl e exception of .an unusual case of pyogenic granuloma

recurring with multiple satell ites around t he excision site, a phenomenon previ ous ly

described.

The microscopic differenti a l di agnos is of Masson's hemangioma incl udes several

types of benign and malignant vascul ar proliferation.

Ang i olymphoid hyperpl asia with eosinophi l ia, also known as pseudo- or atypical

pyogenic graliul oma, shares vii th Masson's he mang ioma a predi 1 eeti on fo r the head and

neck regi'on, the reddish or blue color , the nodular appear ance, and, at a microscopi c

le.vel, the marked pmli f eration of endothelial cel l s. However, it usually shows a

prorninent inflammatory component, in the form of lymphoi d fa 11 i cl es and/or mass i ye

eosinephilic i nfi ltrate, tha t is lacking i n Masson's hemangioma . The endothel i al

proliferation is haphazar d and rather solid , and it does not result i n the t ypical

~nas tomosing channel s of the l atter les i on. Finally, the process has ill-defi ned

margins, whether located in the dermis or subcutaneous tissue, and is never fu lly .

contained withi n a vascular 1~a l l, as it is ah1ays the case l·lith Masson's hemangioma .

Cutaneous angi osarcomas also commonl y affect the head and neck regions and t hey

~an exhibit papi 11 ary growth patterns on microscopic examination . However, they often

f9nn anastomos ing vascular channels lined by anaplastic endothelial cells with

invasive growth and frequent mitoses. These papillary fronds usually consist of­

pi l ed-~p cells i n c l umps, in contrast to t he single layer of endothelial cel ls

without nucl ear anaplasi a seen in f1as.son' s hemangioma. Occasionally , the

villi i n Masson's 1 es ion appear to be covered by mult i ple 1 aye r s of endothe 1 i a 1 cells,

but they never exhi bi t frank anaplasia or necrosis. In addition, cutaneous angio­

sarcomas present as dermal in filtr at i ve neoplasms r ather ·than intravascular growths.

[as~ 8 Page 2

The differentiation from Kaposi's sarcoma should pose no diff iculty. The latter

les ion has a quite different clinical presentation and is characteriz-ed mi croscopi ca lly

bf vascu 1 ar s 1 its, spindle ce 11 s, and extravasated red b 1 ood ce 11 s, with no papillary

tronds or anastomosing channels. Intravascular grovtth is not prominent.

In some cases located in the fingers, the possibility of confusion 1~ith pigmented

vi llonodular synovitis also arises.

The his to genesis of Hasson's hemangioma is still debated. I ts f orm of presen te~­

tion, association 14ith other lesions, and pattern of gr01~th suggest that it is' not

a true neoplasm but rather a lesi on of reactive nature. The question remains as to

whether the endothelia.] prol iferat ion is a primary event and the thrombosis secondary,

as postulated by M~sson or whether it simply reflects the exuberant grm~th phase of

an organi zing thrombtlS , as p-refeHed by rros t authors a.t the present time .

Salyer et a 1. compared the changes seen in this entity, l·lh i ch they refer to as

in travascular angiomatosis, vtith those of angiosarcoma and with a large number of

arterial thrombo-embol i and venous thrombi obtained at autopsy. Their conclusion

was t hat all the features of Masson's hemang.ioma could be seen in organizing

thrombo-embol i and, therefore, regarded the former as a peculiar morphologic feature

of thrombus undergoing o.r gan i za t i on.

The importance of Masson's hemangioma resides in its capacity to s i mulate the

gro\ith pattern of <1 mali gnant vascular tumor. It should be recognized by t he patho­

logi·st on the basis of its characteristic appearance and l ocation. It should also

be identified as a perfectly benign condition, as clearly evi denced by the follo1~-up

of our cases and those of similar nature reported by other investigators under the

designation of intravascular papillary endothelial hyperplasia.

Case 8 Page 3

REFERENCES

1. Burnett , R.A.: A cause of erroneous diagnosis of pigmented villonodular synovitis . J . Clin. Pathol., 29:17, 1976.

2. Clearkin, K. P., and Enzi riger , F.M. : Intravascular papi llary endothelial hyperp l asia. Arch. Pathol . , 100:441, 1976.

J, Kuo, T. T., Sayers, C. P., and Rosai, J.: Masson's "vegetan t intravascular· hemangioendot heli oma: " a lesion often mistaken for angiosarcoma. Study ' of seventeen cases 1 ocated in the skin and soft t i ssues . Ca.ncer, 38 : 1227, 1976.

~. Nasson , P.: He)nangioendotheliome (Paris) , 93:517, 1923.

, / yegetant i ntr a vasc ul ai re .

S. ~Iasson, P.: Vegeta nt intravascular hemangioendothelioma. His tology, Diagnosis and Technique , 2nd ed. Detroit , Wayne Press, 1970 ; pp. 306.

Bull. Soc . Ana t.

In Human Tumors , State University

6. Rosai, J., Sumner, H.W., Kost i anovsky, H. , and Perez-~lesa, C.: Angiosarcoma of skin-- A clinicopathol ogic and fine .s tructural study. Hum. Pathol . , 7:83 , 1976.

7. Salyer, W. R., and Salyer, D.C.: distinction from angiosarcoma.

Intravascular angiomat osis : Cancer, 36: 995 , 1975.

deve l opmen t and

Case 9 - SOFT T1 SSUE t•tyospherul osi s

The· sections sho1~ a cystic formation in the subcutaneous fat lined by a fibrous

wall containi ng infla11111atory cells, including multinuc]eated giant cells. The

distinctive feature is the presence 1~ithin the cavity of l arge "bags ", each containing

a variable but usually large number of pale eosinophilic spheru les suggestive of

fungal spores or some other organism. This is a good example of the condition recently

described as rljyospherul os is. Th is 1~as first reported in Kenya and Uganda as s.ubcutan­

rous nodules, and later in St. louis, USA, presenting in the paranasal sinuses; nose

or middl e ear in indivi duals who had had previous operations i n the region. It v1as

concluded that the disorder was related to the use of hemostati c packing containing

petrolatum- based ointments and gauze. ·

In a recent case seen at our Institution, 1~e performed a series of studies in

order to ascertain the nature of these mysterious "organisms " .

The morphologic features of these formations and thei r positivity vlith stains for

hernoglobi n, peroxi dase , and 1 i pofusci n strongly suggested that they represent nothing

roore than collections of erythrocytes altered by a foreign substance. This interpre­

tation was confirmed by experimental production of these structures by the action of

tetracycline ointment on a pure preparation of human erythrocytes. 'tlheeler and

~Gavran fu rther confirmed this by producing myospherules in vitro using either lanolin

or petrolatum, the t wo components of the vehicle of Achromycin. l~ost interestingly,

!trey also .showed that human fat 1~as capable of producing myospherules in vitro.

Beurlet. et al reached independently similar conclusions on t he nature of the

spherules on the basis of histometric comparison with normal red blood cells.

r.se 9 f:ge 2

REFERENCES

1. Beur l et, J., Groussard, 0., Ravi s se , P., et al.: enigme posee par de curie ux <<sacs de bi lles» . Arch. Anat. Cytol . Path., 27 :5, 1979.

La myosphe'rulose: une A propos de quat re observat ions .

1. Editori a 1 : Hyospherulos is unmasked? Lancet, 2:358, 1978.

?. ~riakos, M.: ~~ospherulosis of the paranasal sinuses , nose and middle ear. A possible iatrogenic di sease . Am. J . Cl in. Pathol. , 67:118 , 1977 .

!. HcCl atchi e , S., Harambo, ~1.14., and Bremner, A. D.: 11yospherulosis. A previous ly unreported disease? Am. J. Clin. Pathol., 51:699, 1969 .

5. Rosai, J.: The nature of lllYOSpherul osis of the upper respirat ory tract . Am. J. Clin. Pathol. , 69:475 , 1978.

6. Wheeler, T. M., and ~kGavran, ~I. H.: "l·~ospherulosis - further observations" . Am. J. Clin . Pathol. , (in press, 1979) .

tase 10 - SPLEEN - Histiocytoid lymphangioma

The section shows replacement of the spl enic parenchyma by a cellul ar tumor

coffiposed of dilated lymphatic vessel s . The lumina are large and occupied by

l~ph. The most distinctive feature of the neoplasm is the appearance of the

~plastic endothelial cells . They are plump and resemble either epithelial cells

orhistiocytes. Their nucleus is prominent and vesicular, occasionally deeply

indented. The cytopl asm is abundant, eosinophilic, sometimes vacuolated.

This tumor probably represents the lymph vessel counterpart of the blood ·

'lessel lesion that ~1e have proposed to designate as hist i ocytoid hemangioma . The

premise of this proposal is that a number of previously described entities of skin,

wft tissue, large1vessels, bone and heart actually constitute different manifesta­

tions of the same basic process, characterized by the pro 1 iferati on of a highly

dis tinctive cell type descriptively identified as a "histiocytoid endothelial cell".

The entities in question are angiolymphoid hyperplasia with eosinophilia and related

cutaneous, subcutaneous and mucosal disorders; atypica 1 vascular pro 1 iferation of

large vesse 1 s ( i ncl udi ng aorta); hemangioendothelioma of bone; hemangioendothel ioma of

spleen; and endocardial benign angioreticuloma of the heart . The main cell that pro­

liferates in all of these condi ti ons has the basic features of an endothelial cell

hut also exhibits histochemical and ultrastructural characteristics that are more

a.~in to those of a histiocyte.

The studies of Eady et al. on a series of 4 cutaneous cases of this condition

showed that these cells exhibit marked histochemical and ultrastructural differences

with normal endothel ial cells. Instead of the high alkaline phosphatase activi ty and

low level of non-specific esterase, acid phosphatase and respiratory enzymes character­

istic of the endothelium of normal capillaries, these "extraordinary" cells sho~~ed a

negative ·alkaline phosphatase reaction (both by the Gomori lead phosphate and the

ozo-dye method) and a very in tense positivity for nonspecific esterase, acid phos­

phatase, dehydrogenase, gl ucose-6- phosphate dehydrogenase, cytochrome oxidase and

IIAOH diaphorase. Ult rastructurally, the cells were separated by extensive gaps,

alternating with areas of interdigitation and intercellular tight junctions. Their

,cytoplasm contained prominent 100 to 150 X cytofilaments and bundles of finer fila­

~nts associated with dense bodies; occasional microbodies were also observed. A notable feature of the cytoplasm was the presence of l arge membrane-bound vacuoles,

either single or multiple. Weibel-Palade bodies (a characteristic albeit not patho­

gnomonic cytoplasmic marker of endothelial cells) were sparse, particularly in the

larger cells . A basal 1 umi na ~1as present on the side opposite to the 1 umen; it was

thin, fragmented and sometimes multilayered.

Case. 10 Page 2

These unusual features could be the expression of a morphologic abnormal ity or

~present an overgrowth of a specific and as yet undef ined s ub- population of endo­

thel i al cel ls, s uch as t~ajno's "contractile endothelial cell". ~lhether this group

of proliferative diseases is of a reactive or neoplast ic nat ure is not i mmediately

apparent , although the lattE!r is favored. Ho~1ever, it is clear that the behavior

of these l esions, as a group, i s quite i ndol ent and even self-limited, i n contrast

to t he aggress ive behavior and of ten fatal outcome of the true angiosarcomas .tha t

they so closely r esembl e on microscopic grounds.

Case 10 Page 3

TABLE I

OJSEASES INCLUDED IN THE SPECTRUM OF Hl STJ OCYTOID HEMANGIOMAS

Skin, oral cavi ty , anditory canal and peni s

Angiolymphoi d hyperplasi a wi th eosinophi l ia Subcutaneous angioblasti c lymphoid hyperplasi a

wi th eosinophi l ia Pseudo or atypi cal pyogenic granuloma Papul ar, angi op 1 asia I nfl anrnatory a r teri overious hemangioma Inf l ammatory angiomatoses Atypical vascular prol i ferati on with infl ammat ion Some reported cases of cutaneous angiosarcoma and

Kaposi's sarcoma

Large vessels

Int ravenous atypi cal vascul ar prol i ferat i on ? Some reported cases of angiosarcomas of vessels

Soft t issue

"Epithel ioid" hemangioma Some reported cases of hemangioendotheli oma and angiosarcoma

Spleen

Some reported cases of hemangioendothel i oma

Bone and periosteum

fola ny ( ? 100st) re110rted cases of angioendothelioma , hemangioendothelioma and low grade angiosarcoma

Heart

Endocardia l beni9n angioreticuloma

,Case 10 Page 4

TABLE II

DISEASES NOT INCLUDED IN THE SPECTRUM

Of HISTIOCYTO ID HEt1ANGI OHAS

Kimura's disease of the Orient

l·lasson ' s "vege t ant intravascular hemangioendothelioma"

Intr~vascu l ar papi l Tary endothelial hyperp l asia

Pyogenic granul oma with recurrent satel lites

Intravenous pyogen i c granul oma

Prol iferating angi oendot he 1 i omat os i s

True angi osarcoma of ski n , soft tissue , large vess-els, bone and ot her organs

Nal ignant endovascular papi l l ary angioendothel ioma

Case 10 Page 5

REFERENCES

I. Castro, C., and Winkelmann, R. K. : Angiolymphoid hyperplasia with eosinophi lia in the skin . Cancer, 34 :1696, 1974.

2. Eady, R.A.J., and l~ i lson Jones, E.: chemical and ultrastructural study.

3. Hartmann, W. H., and Stewart, F. W.: characterized by indolent course.

Pseudopyogenic granuloma : enzyme hi~to-Hum. Pathol . , 8:653, 1977. '

Hemangioendothelioma of bone; unusual tumor Cancer, 15:846, 1962.

4. Reed, R.J ., and Terazaki s, N.: Subcutaneous angioblastic lymphoid hyperplasia with eosinophilia (Kimura's disease). Cancer, 29:489 , 1972.

5. Rosai, J., and Akerman , L.R.: Intravenous atypical vascular proliferation; a cutaneous lesion simulating a malignant blood vessel tumor. Arch. Dermatol., 109:714, 1974 .

6. Rosai, J., Gold, J., and Landy, R.: The histiocytoid hemangiomas. A unifying concept embraci ng several previously described entities of skin, soft tissue, l arge vessel s, bone and heart . Hum. Pathol., (in press , Nov. 1979).