Follicular Graft-versus-host Disease: A Rare Manifestation in a Patient with the Overlap Subtype of Chronic Graft-versus-host Disease.

Graft-versus-host disease (GVHD) is a frequent and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Although skin involvement is common, generalized follicular eruption as the major clinical manifestation is rare. However, it is important for clinicians to recognize it at the earliest to initiate an appropriate therapy. We report a case of a patient with multiple myeloma who developed extensive hyperkeratotic, lichenoid folliculocentric papules with perifollicular erythema on day 53 following an allogeneic HSCT. The overall clinical and histological findings were consistent with the overlap subtype of chronic follicular GVHD.

Introduction

Graft-versus-host disease (GVHD) is the major complication of hematopoietic stem cell transplantation (HSCT), and a high mortality rate is observed in patients with severe GVHD.[1] The skin is one of the most frequently affected organs in both acute and chronic GVHD.[1] However, lichenoid follicular eruption as a major clinical manifestation of chronic cutaneous GVHD is rare; to our best knowledge, only seven cases have been reported to date [Table 1].[23456] Here, we describe a patient with multiple myeloma who had a generalized follicular eruption that appeared on day 53 following HSCT.

Table 1

Reported cases of chronic follicular graft-versus-host disease

Case	Age/sex	Days following HSCT	Clinical features	History of acute GVHD	Classification of chronic GVHD	Outcome	Reference
1	47/male	82 days	Multiple acne-like follicular papules in the malar, chin and preauricular areas* Dark pigmentation on the face, neck and extensor surfaces of both arms* Reticulate white pattern on the jugal mucosae*	Yes	Classic	Improvement	Llamas-Velasco et al.[2]
2	53/female	420 days	Generalized dark, grayish, confluent, poorly defined plaques with unevenly distributed comedo-like papules*	No	Classic	NR	Llamas-Velasco et al.[2]
3	25/male	120 days	Extensive lichenoid papular eruption on the anterior thorax, back, and shoulder* Reticulate white pattern on the buccal mucosae*	Yes	Classic	Improvement after 4 years of follow-up	Martí et al.[3]
4	25/male	240 days	Itchy follicular red papules	No	Classic	Improvement	Miyazaki et al.[4]
5	33/female	87 days	Follicular lichenoid papular eruption on the thorax, back, arms, thighs, and palmar surfaces	NR	Classic	NR	Valks et al.[5]
6	60/male	33 months	Shiny, sclerotic skin on the back of hands and feet; and pink follicular spicules on the flanks and buttocks	NR	Classic	No improvement after 1 year of follow-up	Cornejo et al.[6]
7	20/female	16 months	Dark keratotic follicular papules	NR	Classic	NR	Cornejo et al.[6]
8	51/male	53 days	Generalized follicular papules* Dark pigmentation on the face* Reticulate white pattern on the buccal mucosae and lips*	No	Overlap	Death	Our case

*HSCT. GVHD: Graft-versus-host disease, NR: Not reported, HSCT: Hematopoietic stem cell transplantation

Case Report

A 51-year-old male Taiwanese patient was diagnosed as having kappa-light chain multiple myeloma, Durie-Salmon stage IIIB in February 2012. He had undergone several cycles of chemotherapy from 2012 to 2016 and had undergone autologous HSCT in 2012 and 2014 with partial response.

Owing to disease progression, he received an allogeneic HSCT in December 2016. Unfortunately, on day 53 following allogeneic HSCT, the patient developed extensive hyperkeratotic lichenoid folliculocentric papules with perifollicular erythema on the scalp, neck, trunk, and four limbs [Figure 1a-c], and a dermoscopic examination showed a diffuse folliculocentric pattern with marked keratin plug formation [Figure 1d]. In addition, mottled hyperpigmentation on the face [Figure 1e] and a white lace-like pattern on the buccal mucosae and lips [Figure 1f] were also noted.

Figure 1

Hyperkeratotic, lichenoid folliculocentric papules with perifollicular erythema on the anterior chest wall, abdominal wall, and thighs (a and b); a higher magnification of the hyperkeratotic follicular papules with keratin plugging (arrows) on the anterior chest wall, (c) dermoscopic examination highlighted some marked keratin plugging (arrows), (d) mottled hyperpigmentation on the face, (e) a white lace-like pattern was noted on the surface of the lips (f)

Histological examination of the follicular papules on the left anterior chest wall showed follicular infundibular dilatation with keratotic plugs, basal layer vacuolization, and few apoptotic keratinocytes in the follicular epidermis. Perivascular and perifollicular mononuclear cell infiltration and pigment incontinence in the upper dermis were also seen [Figure 2a and b]. The histological picture was consistent with Grade 2 GVHD.

Figure 2

Histopathological findings showed follicular infundibular dilatation with keratotic plugs, basal layer vacuolization, and a few apoptotic keratinocytes in the follicular epidermis. Perivascular and perifollicular mononuclear cell infiltration and pigment incontinence in the upper dermis were also seen (a and b) (a: H and E, ×100, b: H and E, ×200)

The patient also developed persistent upper abdominal pain with nausea and vomiting. Upper gastrointestinal (GI) endoscopy was performed which showed reflux esophagitis, LA Grade A, and duodenal ulcers. Computerized tomography of the abdomen revealed segmental wall thickening at the terminal ileum and proximal ascending colon that was suggestive of ileocolitis. Routine laboratory studies on day 60 following allogeneic HSCT revealed anemia (hemoglobin: 9.1 g/dl), thrombocytopenia (87 × 103/μl), elevated liver transaminases (aspartate aminotransferase, 194 U/l; alanine aminotransferase, 114 U/l), and serum alkaline phosphatase (106 IU/l). However, the total bilirubin level was in the normal range. In addition, blood cultures for microorganisms and polymerase chain reaction assay for the detection of serum cytomegalovirus or Epstein-Barr virus both showed negative findings.

A diagnosis of chronic follicular GVHD with the overlap syndrome was made according to the criteria of the National Institutes of Health (NIH) consensus project. The patient was then treated with oral cyclosporine 120 mg 12 hourly for 2 weeks and intravenous methylprednisolone 2 mg/kg/day for 2 weeks with a tapering regimen. Unfortunately, the patient died on day 130 after the allogeneic HSCT due to pneumonia with septic shock and acute respiratory and renal failure, when he was on oral sirolimus 2 mg/day and oral prednisolone 15 mg/day.

Discussion

GVHD was previously classified into acute and chronic forms according to the symptoms that occur within or after 100 days following HSCT, respectively.[12] However, this conventional classification has been challenged because of the recognition that signs of acute and chronic GVHD may occur outside these designated periods.[127] In an effort to more appropriately categorize the disease, the NIH consensus project has emphasized the clinical manifestations, rather than a set period, for classification.[127]

Therefore, acute GVHD is defined by the characteristic skin findings, GI tract or liver abnormalities, and the absence of any diagnostic or distinctive features of chronic GVHD.[17] However, chronic GVHD is now classified into (i) classic chronic GVHD, with the presence of at least one diagnostic or distinctive manifestation of chronic GVHD and (ii) the overlap syndrome with features of both chronic and acute GVHD.[17]

Cases of lichenoid follicular eruptions as a major clinical manifestation of GVHD are rare.[26] The cause and pathogenesis of follicular GVHD are presently unclear. Sale et al. (1994) found that the parafollicular bulge was related to the presence of stem cell populations in that area, and it has been suggested that this region is an early target of GVHD.[38]

Follicular GVHD could occur in both acute and chronic cutaneous GVHD.[2] Our case falls into the category of the overlap subtype of chronic follicular GVHD because the patient had clinical manifestations of chronic GVHD such as mottled hyperpigmentation on the face, lichen planus-like lesions on the lips and buccal mucosae, and thrombocytopenia. Moreover, the patient had some clinical features of acute GVHD such as abdominal pain, nausea, vomiting, and liver abnormalities.

The overlap subtype of chronic GVHD is thought to be associated with an adverse prognosis compared with classic chronic GVHD.[910] A nine-center prospective analysis also found that patients with the overlap syndrome had a lower platelet count at the onset of GVHD.[10] Our patient had a low platelet count at the onset of GVHD and died shortly after the diagnosis was made.

Conclusion

The follicular epithelium is rarely involved in cutaneous GVHD. It is important for clinicians to recognize a follicular involvement as early as possible to initiate an appropriate therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Industry-University Cooperative Research Project, Taiwan (MOST 105-2628-B-010-016-MY3).

Conflicts of interest

There are no conflicts of interest.