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Dermatopathology
The Dermatopathologic Manifestations of Systemic Disease:
Novel Considerations Regarding Cutaneous Lymphoid Proliferations
Sunday, February 27, 2005 - 7:30 PM
Rivercenter Salon E
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Moderator:
A. Neil Crowson
Regional Medical Lab
Tulsa, OK
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Clinical histories are printed below.
Click on the case numbers for text and references of each case.
Click on each slide thumbnail image for an enlarged view
Submitted by:
A. Neil Crowson
Regional Medical Lab
Tulsa, OK
A 74 year old woman developed a psoriasiform, papular and plaque-like eruption of the back, arms,
legs, palms and soles whilst on Cozaar (losarten – a potent angiotensin-type I receptor blocker),
atenolol (a beta-blocker), the diuretic hydrochlorothiazide and verapamil (a calcium channel blocker).
There was no involvement of facial skin and no lymphadenopathy was detectable. Apart from severe
arterial hypertension, an examination and review by an internist showed no systemic disease. An initial
skin biopsy in December 2000 showed a superficially disposed atypical small lymphoid infiltrate with
coarse sclerosis of the collagen table, in concert with an epidermotropic atypical lymphoid infiltrate
suggesting large plaque parapsoriasis in evolution to mycosis fungoides (Figs 1A, 1B and 1C). Flow
cytometry of peripheral blood showed changes consistent with a reactive process by virtue of a Th/s
ration of 2.6:1 with normal expression of CD2,3,5 and 7 with no aberrant loss of surface antigen
expression; no Sezary cells were detectable. After subsequent enquiries concerning the drug history, the
patient was referred to a dermatologist with a specific interest and training in pharmacotherapeutics,
and a second biopsy was performed in January 2001 followed by modulation of the drug regime in concert
with topical steroid therapy (0.1% triamcinolone). As the last agent added to the patient's drug regime was the
cozaar, that agent was discontinued first, in concert with the thiazide. The second biopsy pair showed
similar features to the first, but with important distinctions. First, the intensity of the infiltrate
was much reduced, as was the degree of epidermotropism. Secondly, the involvement of the epidermis
was patchy as opposed to continuous (Figs 2A and 2B). At follow up 2 months later the rash was slightly
improved and she commenced tanning bed therapy for 3 minutes 3-4 times week. At follow up 1 month later
new lesions were still developing and the atenolol was then discontinued. Three weeks later the eruption
was markedly improved with a reduction of the involved surface area by 80%. She then restarted cozaar
under the guidance of her internist, with an immediate and dramatic flare of the eruption on examination
in June 2001. The cozaar was again discontinued and by July the rash was largely resolved. In September
the verapamil was also discontinued. By October 2001 all that remained of the rash were two small
eczematous patches on the back. Clonidine was substituted for anti-hypertensive therapy and atenolol was
re-introduced. The tanning bed was tapered. The conclusion was that cozaar and verapamil were
synergistic in provocation of the eruption.
Her hypertension was unstable and 18 months later an alternate calcium channel blocker and beta
blocker (Toprol and Norvasc respectively) were substituted with flaring of the eruption. A rebiopsy at
that time (January 2003) showed changes held to be compatible with a lymphomatoid drug eruption (Figs 3A
and 3B). In particular, there was directed migration of small lymphoid forms into areas of maximum
antigenic processing, namely, acrosyringia and hair follicles, with a significant reduction in the
intensity of the infiltrate. The calcium channel blocker was discontinued, methyldopa was substituted,
and the rash resolved. She remains in dermatologic remission, with no evidence of a rash on the
previously involved trunk at the last examination in October of 2004 (Fig 4).
Case 1 - Figure 1A - The punch biopsy of skin shows a heavy band like infiltrate of small, irregularly contoured lymphocytes embedded in coarse, horizontally-disposed collagen fibers. There is continuous haphazard epidermotropism suggesting patch/plaque mycosis fungoides.
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Case 1 - Figure 1B - The punch biopsy of skin shows a heavy band like infiltrate of small, irregularly contoured lymphocytes embedded in coarse, horizontally-disposed collagen fibers. There is continuous haphazard epidermotropism suggesting patch/plaque mycosis fungoides.
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Case 1 - Figure 1C - The punch biopsy of skin shows a heavy band like infiltrate of small, irregularly contoured lymphocytes embedded in coarse, horizontally-disposed collagen fibers. There is continuous haphazard epidermotropism suggesting patch/plaque mycosis fungoides.
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Case 1 - Figure 2A
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Case 1 - Figure 2B
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Case 1 - Figure 3A - The punch biopsy specimens show a band like infiltrate of small lymphocytes with a directed pattern epidermal migration into an epidermis surmounted by parakeratotic mounds of plasma-containing scale crust. There is prominent involvement of the adnexal structures, which are sites of maximal antigenic processing. This is the classical pattern of lymphomatoid hypersensitivity.
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Both punch biopsy specimens show a band like infiltrate of small lymphocytes with a reduction on cell density over the orginal biopsy, in concert with discontinuous haphazard epidermal migration.
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Case 1 - Figure 3B - The punch biopsy specimens show a band like infiltrate of small lymphocytes with a directed pattern epidermal migration into an epidermis surmounted by parakeratotic mounds of plasma-containing scale crust. There is prominent involvement of the adnexal structures, which are sites of maximal antigenic processing. This is the classical pattern of lymphomatoid hypersensitivity.
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Case 1 - Figure 4 - Clinical examination shows no evidence of the rash at the truncal site of former maximal involvement.
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Submitted by:
A. Neil Crowson
Regional Medical Lab
Tulsa, OK
A 68-year-old male presented with a solitary fleshy 1.4 x 0.9 cm diameter lesion on his back. A shave
biopsy was interpreted as a lichenoid tissue reaction with epidermal hyperplasia; no atypical lymphoid
cells were seen in the infiltrate. Over the next eight weeks, the lesion grew to a 2.8 x 2.5 cm
tumefactive nodule and a second biopsy was obtained.
Case 2 - Figure 1 - There is a lichenoid infiltrate which is devoid of atypical lymphocytes. The epidermis shows mild hyperplasia.
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Case 2 - Figure 2 - The second biopsy shows marked epidermal hyperplasia and a sheet like dermal lymphoid intiltrate.
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Case 2 - Figure 3 - The keratinocytes are markedly atypical, as are large , non-cohesive cells in the dermis.
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Case 2 - Figure 4 - A cytokeratin immunostain (AE1/3) decorates the epidermis but spares the dermal infiltrate.
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Case 2 - Figure 5 - A CD30 immunostain strongly decorates the atypical dermal mononuclear cell infiltrate.
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Case 2 - Figure 6 - There is dot-like accentuation of CD30 expression in the Golgi region.
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Case 2 - Figure 7 - A CD20 preparation decorates background small lymphoid forms.
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Case 2 - Figure 8 - An anaplastic lymphoma kinase (ALK) preparation is negative.
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Case 2 - Figure 9 - A CD3 preparation strongly decorates small mature background T-cells; the larger cells show progressive loss of staining.
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Submitted by:
Lorenzo Cerroni
Medical University of Graz
Graz, Austria
A 86-year-old woman with a large erythematous tumor on her left lower leg (Fig 1). The tumor was
slowly growing for the last few months. The surrounding skin was normal. Complete staging
investigations, including bone marrow biopsy, were negative. The patient had neither paraproteinemia nor
Bence-Jones proteins in the urine. A biopsy was performed under local anesthesia.
Case 3 - Figure 1 - Violaceous skin nodule.
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Case 3 - Figure 2 - A dense lymphoid infiltrate is present throughout the entire dermis. The epidermis is spared.
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Case 3 - Figure 3 - Cytomorphology shows a monomorphous population of lymphoplasmacytoid cells admixed with marginal zone cells and some plasma cells. Intranuclear PAS+ inclusions (Dutcher bodies) could be detected in some of the cells.
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Submitted by:
Lorenzo Cerroni
Medical University of Graz
Graz, Austria
A 15-year-old boy presented with sudden onset of eroded papules and small vesicles on the glans penis
and prepuce. A biopsy was taken under local anesthesia. Subsequent staging investigations at
presentation were negative.
Case 4 - Figure 1 - Eroded papules and small vesicles on the glans penis and prepuce.
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Case 4 - Figure 2 - There is an ulcerated, nodular infiltrate of mononuclear mid-sized cells, some with reniform nuclei located in the dermis with involvement of the epidermis by epidermotropic cells. Several mitoses could be seen. Immunohistochemical analyses showed positivity for S-100 and CD1a. A diagnosis of Langerhans cell histiocytosis was made, and a circumcision was performed.
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Case 4 - Figure 3 - There is an ulcerated, nodular infiltrate of mononuclear mid-sized cells, some with reniform nuclei located in the dermis with involvement of the epidermis by epidermotropic cells. Several mitoses could be seen. Immunohistochemical analyses showed positivity for S-100 and CD1a. A diagnosis of Langerhans cell histiocytosis was made, and a circumcision was performed.
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Submitted by:
Cynthia M. Magro
Ohio State University
Columbus, OH
A 36-year-old female status post living related donor renal transplant in 1991 developed redness,
swelling and warmth in her right lower extremity from the mid-calf down in September 2001. Her primary
care physician treated her with antibiotics for a presumptive diagnosis of cellulitis without
improvement. In March 2002, an incisional biopsy was performed.
The EBER RT-IS-PCR assay showed numerous cells demonstrating dominant nuclear expression; the vTK
assay was negative. HHV8 RT-IS-PCR revealed positive co-expression of the virus in the tumor cells. The
oligoprobe assay showed λ light chain restriction. Subsequent studies showed monoclonal IgG λ
paraproteinemia. Imaging studies demonstrated a soft tissue mass associated with her transplanted
kidney, but a biopsy was never obtained.
At the time of the diagnosis of plasmablastic lymphoma, she had been on immunosuppressive therapy for
11 years with cyclosporin, imuran and prednisone. She was treated with a decrease in her
immunosuppressive regimen and was started on intravenous acyclovir. This resulted in normalization of
the PET scan; however, her cutaneous disease continued to progress. Surgical resection of the mass
revealed a diffuse large B cell lymphoma with λ light chain restriction; many of the cells showed
EBER-1 and EBER-2 expression. Following resection of the tumor mass, she was treated with local external
beam radiation with resolution of the skin lesions. She has had no cutaneous recurrences to date, but
she has a persistent, albeit quantitatively decreased, IgG lambda monoclonal gammopathy and persistence
of the mass within the transplanted kidney.
Case 5 - Figure 1 - There is a confluent proliferation of severely atypical plasmacytic cells associated with effacement of the dermal architecture.
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Case 5 - Figure 2 - There is a confluent proliferation of severely atypical plasmacytic cells associated with effacement of the dermal architecture.
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Case 5 - Figure 3 - Detection of EBV RNA by in situ hybridization. EBV RNA was detected in some of the tumor cells after in situ hybridization for EBER-1 and -2; note the strong nuclear signal.
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Case 5 - Figure 4 - Detection of HHV8 RNA by RT in situ PCR. HHV8 RNA was detected after in situ amplification of the corresponding cDNA using primers specific for the T0.7 viral message, which is expressed in latent and active infection. Note the strong nuclear signal in many of the tumor cells.
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Submitted by:
Cynthia M. Magro
Ohio State University
Columbus, OH
The patient was a 65 year old woman who first presented in 2001 with a left posterior thigh mass. She
was asymptomatic at this time. A biopsy was performed and she underwent a complete hematologic
assessment which did not reveal disseminated extracutaneous disease. She then she was treated with
systemic chemotherapy
The patient then developed a recurrence at the same site in 2003. The tumor was morphologically and
phenotypically identical to the earlier tumor although the cells were smaller and exhibited less atypism.
Approximately 6 months later another recurrence developed which was now compatible with a large cell T
cell lymphoma still manifesting CD20 positivity, weak CD10 expression and prominent CD8 staining. Most
recently in November of 2004 she developed another recurrence compatible with a diffuse large cell T cell
lymphoma exhibiting a CD8 phenotype with co-expression of CD20. As well molecular studies revealed a
pure population of T cells; in addition there was evidence of B cell clonality with two defined molecular
peaks constituting essentially 100% of the infiltrate. She is currently alive and well with persistent
cutaneous disease although in the absence of any known extracutaneous dissemination.
Case 6 - Figure 1 - There is a diffuse and nodular pan dermal lymphocytic infiltrate associated with effacement of the dermal architecture.
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Case 6 - Figure 2 - Higher power magnification reveals that the cells have a large pleomorphic appearance. The cells are in the 20 micron size range manifesting prominent nucleoli. There was also perineural accentuation with focal endoneurial extension.
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Case 6 - Figure 3 - Phenotypic studies revealed that the infiltrate was a T cell showing CD8 positivity and weak CD20a nd CD10 expression.
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Case 6 - Figure 4 - A) GeneScanning image for TCR beta gene rearrangement shows a single distinct peak of 249 base pairs in size indicative of monoclonality with no evidence of a polyclonal background. B) GeneScanning image for IgH gene rearrangement shows two distinct peaks of 91 and 102 base pairs in size indicative of a dual clonal population (oligoclonal). C) Positive control.
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Submitted by:
Sabine Kohler
Stanford University
Palo Alto, CA
A 79 year old man with progressive erythematous tumors on left lower leg. Also has several papules on
right lower leg.
Case 7 - Figure 4 - Large lymphocytes, some with features of immunoblasts, others with features of centroblasts.
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Case 7 - Figure 5 - CD20. Staining with the CD20 antibody reveals a B-cell phenotype.
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Case 7 - Figure 6 - Large lymphocytes, some with features of immunoblasts, others with features of centroblasts. bcl-2: The tumor cells are strongly and uniformly bcl-2 positive.
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Case 7 - Figure 7 - Ki-67: The proliferative rate as measured by staining with Ki-67 is in excess of 80%.
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Submitted by:
Sabine Kohler
Stanford University
Palo Alto, CA
A 62 y.o. man with diagnosis of lupus profundus and 7 year history of recurrent subcutaneous nodules.
Now presents with fevers, chills and fatigue.
Submitted by:
Elaine S. Jaffe
National Cancer Institute
NIH, Bethesda, MD
A 7 year old girl presented with an enlarging lesion of the right forehead, over a period of 8
months. A bone marrow biopsy was reported as negative. The skin lesion was biopsied.
Case 9 - Figure 1 - There is a diffuse infiltrate in the dermis, with sparing of the epidermis.
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Case 9 - Figure 2 - The cells have an infiltrative growth pattern, and there is a Grenz zone.
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Case 9 - Figure 3 - The cells have finely distributed chromatin, and inconspicuous nucleoli.
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Case 9 - Figure 4 - The cells are positive for CD4. Staining is weaker than that of normal T-cells, which are focally seen.
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Case 9 - Figure 5 - CD56 is strongly positive in neoplastic cells, but negative in normal lymphocytes.
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Case 9 - Figure 6 - Neoplastic cells show nuclear staining for terminal deoxynucleotidyl transferase (TdT).
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Submitted by:
Elaine S. Jaffe
National Cancer Institute
NIH, Bethesda, MD
A 51 year old female had a history of systemic mastocytosis associated with a myelodysplastic
syndrome. She underwent an HLA-matched peripheral blood stem cell transplant. Approximately 3 years
later she developed a scalp mass. A biopsy was obtained.
Case 10 - Figure 1 - A skin biopsy from 2001 shows infiltration of the dermis by atypical mast cells with a polygonal appearance.
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Case 10 - Figure 2 - The mast cells are strongly positive for tryptase by immunohistochemistry
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Case 10 - Figure 3 - In 2004, following bone marrow transplantation, the patient developed a scalp mass. Deep dermis and subcutaneous tissues are infiltrated by large blastic cells. Rare eosinophilic myelocytes are identified.
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Case 10 - Figure 4 - The scalp mass also contains giant cells suggestive of megakaryocytes.
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Case 10 - Figure 5 - Many of the blastic cells are positive for chloroacetate esterase, but negative for myeloperoxidase (not shown).
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Case 10 - Figure 6 - The megakaryocytes show staining for p-selectin.
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